WO2011094219A1 - Vesicular formulations - Google Patents
Vesicular formulations Download PDFInfo
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- WO2011094219A1 WO2011094219A1 PCT/US2011/022439 US2011022439W WO2011094219A1 WO 2011094219 A1 WO2011094219 A1 WO 2011094219A1 US 2011022439 W US2011022439 W US 2011022439W WO 2011094219 A1 WO2011094219 A1 WO 2011094219A1
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
- A01N25/28—Microcapsules or nanocapsules
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/30—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests characterised by the surfactants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
Definitions
- compositions and methods relating to formulations of phospholipids and surfactants relate to methods of using such formulations, including agricultural methods.
- the three amphiphats include at least one membrane forming compound (MFC), which can form the membrane of [the aggregates], and at least two membrane destabilising compounds (MDCi and MDC 2 ) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in combination with each other and/or characterized by their relatively high solubility in [the] suitable liquid medium.
- MFC membrane forming compound
- MDCi and MDC 2 membrane destabilising compounds
- the three amphiphats include at least one membrane forming compound (MFC), which can form the membrane of [the aggregates], and at least two membrane destabilising compounds (MDCi and MDC 2 ) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in combination with each other and/or characterized by their relatively high solubility in [the] suitable liquid medium.
- compositions and methods related to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants.
- the formulations are effective for the delivery of fatty acids and/or
- the vesicular formulations include about 25% to about 30% surfactant by weight based on the total weight of the vesicular formulation.
- These vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously.
- formulation refers to any composition as described herein, for example, a formulation that includes one or more phospholipids and one or more nonionic surfactants.
- a formulation may include one or more active agents as described herein; in other embodiments a formulation may specifically not include any active agents, for example active agents as disclosed herein.
- the formulation may include an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist, and/or the like.
- an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist,
- the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In some embodiments, a formulation includes ingredients or components as described herein, for example such as described in Table 8 A and Table 8B. In various embodiments, a formulation similar to or the same as the Example Formulations 1- 129; in some embodiments, the formulations are similar or the same as the Example
- Formulations 1-129 except they further include at least one active agent such as described herein (for example the active agent may be present in the formulation in an amount as described herein).
- the formulation is suitable for use in agriculture, for example it is suitable to apply to plants and crops intended for human consumption.
- the formulation is suitable for administration to a human as a pharmaceutical compositon, for example it does meet criteria for administration to humans by one or more government agencies such as the United States FDA.
- an active agent includes any agent that can exert one or more actions, for example an action which affects some sort of biological process.
- an active agent may be a pharmaceutical agent or pharmaceutically active agent.
- an active ingredient may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist or the like.
- an active agent may be an agent listed on Table 9.
- the vesicular formulations may be formulated to deliver fatty acids and phosphatidyl derivatives of fatty acids, such as arachidonic acid or omega-3 or omega-6 fatty acids.
- the vesicular formulations may optionally be formulated to include other lipids described herein, such as phophatidyl choline, and surfactants.
- the vesicular formulations may deliver essential fatty acids, such as omega-3 fatty acids, to decrease the levels of triglycerides.
- Vesicular formulations disclosed herein which deliver essential fatty acids, such as omega-3 fatty acids, may be useful in the treatment of fatty acid metabolic disorders, such as essential fatty acid deficiency and hypertriglyceridemia.
- the vesicular formulations which deliver essential fatty acids include a phosphatidyl chlo line derivative of a fatty acid, e.g., a phosphatidylcholine derivative of an omega-3 fatty acid.
- the vesicular formulation is one of the formulations set forth in Examples 1-129.
- Fatty acid metabolic disorder means a defect in one of the enzymes involved in fatty acid metabolism, and include fatty oxidation disorders, whereby the body is unable to oxidize and metabolize fatty acids due to a failure in the enzymatic pathway.
- Essential fatty acid deficiency means a deficiency in the essential fatty acids, e.g., omega-3 and omega-6 fatty acids, which can lead to physical symptoms such as hemorrhagic dermatitis skin atrophy, scaly dermatitis, dry skin, weakness, impaired vision, tingling sensations, mood swings, edema, high blood pressure, high triglycerides, hemorrhagic folliculitis, hemotologic disturbances, immune and mental deficiencies, and impaired growth.
- essential fatty acids e.g., omega-3 and omega-6 fatty acids
- the vesicular formulations maty deliver fats and fat soluble vitamins, such as vitamin E, for the treatment of disorders related to hypolididemia, including, abetalipoproteinemia,
- the vesicular formulations which deliver fats and fat soluble vitamins include a phosphatidylchloline derivative of a fatty acid, e.g., a phosphatidylcholine derivative of vitamin E.
- the vesicular formulation is one of the formulations set forth in Examples 1- 129.
- compositions and methods encompassing vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering organic matter once delivered to the subject.
- These vesicular formulations are suitable for any method of administration, e.g. , subcutaneously, topically, or intravenously. Without in any way being limited by theory, it is believed that the surprisingly effective and capacious sequestration of native organic compounds by the vesicular formulations disclosed herein occurs because of liquid crystallinity of the vesicular formulations mediated by the presence of membrane adapters such as surfactants.
- the vesicular formulation is one of the formulations set forth in Examples 1- 129. In a preferred embodiment, the vesicular formulations include about 25% to about 30% surfactant by weight.
- the vesicular formulations of lipids and surfactants are capable of sequestering native organic compounds, including arachidonic acid, upon delivery to human skin for the treatment of pain or inflammation.
- these formulations are designed such that the vesicles are able to penetrate deep tissue without diversion into the blood vessels. That is, the formulations are able to travel to the site of the pain in sufficient amount to alleviate that pain to some extent.
- delivery to the deep tissue includes delivery of the formulation beneath the skin to the muscle tissue and to the joint itself, while limiting systemic delivery and exposure to the formulation.
- the vesicular formulation is capable of sequestering arachidonic acid upon administration to human skin, and therefore is capable of altering the pathology of, e.g., pain or inflammation.
- vesicular formulations designed to sequester arachidonic acid may also be used to prevent the formation of metabolites, including eicosanoids, for the prevention and/or treatment of asthma, seborrheic eczema, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, and dysmenorrhea.
- sequestering arachidonic acid is one of the formulations set forth in Examples 1-129.
- vesicular formulations include one or more phospholipids and one or more nonionic surfactants can sequester cholesterol upon administration to human skin, thus decreasing the accumulation of or uptake of cholesterol for the treatment of hypercholesterolemia.
- vesicular formulations include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering triglycerides, thus decreasing the accumulation or uptake of triglycerides for the treatment of hypertriglyceridemia.
- the vesicular formulation capable of sequestering cholesterol or triglycerides is one of the formulations set forth in Examples 1- 129.
- the vesicular formulations disclosed herein may also be used to sequester factors involved in fatty acid metabolism, such as hormone sensitive lipase (HSL). Inhibition of HSL inhibits the conversion of triglycerides to glycerol and fatty acids, resulting in a decrease in plasma free fatty acids.
- HSL hormone sensitive lipase
- the vesicular formualtions disclosed herein may have utility where the decrease in plasma fatty acids is desired, including insulin resistance, metabolic syndrome X, dyslipidemias and abnormal lipoprotein metabolism.
- the vesicular formulation capable of sequestering factors involved in fatty acid metabolism is one of the formulations set forth in Examples 1-129.
- the vesicular formulation capable of sequestering metals is one of the formulations set forth in Examples 1-129.
- the vesicular formulation capable of sequestering toxins such as DDT is one of the formulations set forth in Examples 1-129.
- formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering inflammatory mediators (e.g., cytokines, such as interleukins, or presenting antigens) upon administration to human skin for the treatment of inflammation and inflammatory related disorders, such as asthma.
- sequestering inflammatory mediators e.g., cytokines, such as interleukins, or presenting antigens
- the vesicular formulation capable of sequestering inflammatory mediators is one of the formulations set forth in Examples 1-129.
- the vesicular formulation capable of sequestering amyloid is one of the formulations set forth in Examples 1-129.
- the vesicular formulation capable of sequestering uric acid is one of the formulations set forth in Examples 1-129.
- Provided herein are methods and compositions that relate to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering squalene, thus leading to fungistatic activity against, e.g. , hyphal fungi.
- vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously.
- the vesicular formulation capable of sequestering squalene is one of the formulations set forth in Examples 1-129.
- formulation is not necessarily meant to imply that the ingredients or components are in combination with a pharmaceutically active agent, i.e., any non-lipid non-surfactant active agent that has received regulatory approval for the treatment of fatty acid related disorders, hypocholesterolemia, hypertriclyceridemia, pain, including osteoarthritic pain, inflammation, infection, or toxicity, including metal toxicity or any of the disorders listed above.
- a pharmaceutically active agent i.e., any non-lipid non-surfactant active agent that has received regulatory approval for the treatment of fatty acid related disorders, hypocholesterolemia, hypertriclyceridemia, pain, including osteoarthritic pain, inflammation, infection, or toxicity, including metal toxicity or any of the disorders listed above.
- the vesicles elicit a therapeutic effect, namely the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
- a therapeutic effect namely the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
- Applicant believes that the vesicle components themselves are responsible for this effect.
- a pharmaceutical package or kit includes one or more containers filled with a formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for the treatment of any disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
- the formulation includes one or more phospholipids and one or more surfactants.
- the formulation does not include a pharmaceutically active agent, i.e., any nonlipid, non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the other disorders listed above.
- the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer.
- packages or kits that can be used in any of the above-described methods.
- methods for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above wherein the vesicular formulations are administered over a period of one or more weeks, for example for at least five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, sixteen weeks, twenty four weeks, four months, six months, eight months, ten months, one year, two or more years, or indefinitely.
- the formulations include one or more phospholipids, one or more nonionic surfactants, in the absence of any pharmaceutically active agent, i.e., any nonlipid non-surfactant pharmaceutically active agent that has received regulatory approval for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism,
- hypertriglyceridemia hypercholesterolemia pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above.
- a 0.1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above;
- a 1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above;
- a 1 to 5 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above; or a 1 gram, 2 gram, 3 gram, 4 gram, 5 gram, 6 gram, 7 gram, 8 gram, 9 gram or 10 gram dose of the formulation is administered to the patient
- the dose is measured as the total weight of the deformasome. In some embodiments, the dose is measured as the total weight of the lipid(s) and surfactant(s) in the deformasome.
- the dose may be administered once or twice daily for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above.
- the dose may be administered once, twice, three, four, five, six, or seven times per week in accordance with the compositions and methods disclosed herein.
- the dose may be administered every day, every other day, or two to three times a week in accordance with the compositions and methods disclosed herein.
- the lipid in the pharmaceutical composition is a phospholipid.
- the second lipid is a lysophospholipid.
- the surfactant is a non-ionic surfactant.
- the compositions form vesicles or other extended surface aggregates (ESAs), wherein the vesicular preparations have improved permeation capability through the semi-permeable barriers, such as skin.
- ESAs extended surface aggregates
- the adapatability and deformability of the vesicles allow the vesicles to penetrate beneath the skin to the muscle and the joint itself, however, the size of the vesicle prevents penetration into the vasculature and as a result prevents systemic delivery.
- the formulations are able to form vesicles characterized by their deformability and/or
- the adaptability or deformability of the vesicles may be determined by the ability of the vesicles to penetrate a barrier with pores having an average pore diameter at least 50% smaller than the average vesicle diameter before the penetration.
- the vesicular compositions provide for targeted delivery of e.g., fatty acids to phospholipase-rich sites, e.g., tissues that are part of an inflammatory process or sites containing microorganisms such as bacteria (including narcadia) or fungi. While not to be limited to any mechanism of action or by any theory, the vesicular compositions disclosed herein are broken down by phospholipases.
- phospholipases that are released as part of the inflammatory process ⁇ e.g., cancer or asthma) or that are released upon contact with a microorganism such as bacteria or fungi can lead to a number of effects including but not limited to rapid entry of the vesicular compositions into the target tissue, changes in the intracellular or intramembraneous lipid homeostasis, which may lead to increased apoptosis or altered membrance function, including increased permeability, and rapid metabolism of the vesicular composition with release of its consituents.
- a method that includes administering a formulation as described herein to a plant, seed or soil.
- the formulation is effective as one or more selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
- the formulation includes an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and synergist.
- the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
- a method for controlling weeds, pests, insects, diseases in or on a plant, a field of plants or a crop that includes administering a formulation as described herein to the plant, field of plants or crop.
- a method of administering a vesicular formulation directly to the surface of a leaf includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the surface of a leaf results in an antifungal effect.
- provided herein is a method of administering a vesicular formulation directly to the ground surrounding certain plants or weeds.
- the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the ground surrounding certain plants or weeds results in an antifungal effect at the plants or weeds.
- a method of exposing an insect to a vesicular formulation by applying the vesicular formulation to a plant or plant leaf.
- the vesicular formulation is absorbed by the leaf and introduced into the insect upon ingestion of the leaf by the insect.
- the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes one or more insecticides.
- the term "plant” refers to a plant as well as any part of a plant or plant product, including but not limited to, plant tissue, a leaf, a leaf primordial, a stem, a flower, a fruit, a root, a root hair, a protoplast, a germ plasm, a stamen, an anther, a filament, a petal, a pistel, a bud, a node, an internode, a shoot, a shoot apex, an apical meristem, a seed, a trunk, and the like.
- the term "plant” also includes multiple plants, for example a field of plants or a crop.
- plants as disclosed herein can be of any species of dicotyledonous, monocotyledonous or gymnospermous plant, including any woody plant species that grows as a tree or shrub, any herbaceous species, or any species that produces edible fruits, seeds or vegetables, or any species that produces colorful or aromatic flowers.
- the plant may be selected from a species of plant from the group consisting of Alfalfa; Almond; Anise (fennel); Anona; Apple; Apricot; Aquatic Weeds; Artichoke;
- subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse.
- primate e.g., human
- cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse e.g., cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse.
- subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
- the term subject can refer to a plant, seed or soil.
- a "sufficient amount,” “amount effective to” or an “amount sufficient to” achieve a particular result refers to an amount of the formulation disclosed herein is effective to produce a desired effect, which is optionally a therapeutic effect (i.e., by administration of a therapeutically effective amount).
- a “therapeutically effective” amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom.
- Clinical symptoms associated with the disorder that can be treated by the methods disclosed herein are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
- a "sufficient amount” or “an amount sufficient to” can be an amount that is effective to treat the symptoms of fatty acid deficiencies, hypertriglyceridemia or hypercholesterolemia or other joint or muscle pain.
- the terms “treat”, “treating” or “treatment of mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness.
- the terms “treat”, “treating” or “treatment of” mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness.
- treatment of also means managing the disease state.
- such level will be sufficiently low to provide a formulation suitable for approval by regulatory authorities.
- the term “about” means a range surrounding a particular numeral value which includes that which would be expected to result from normal experimental error in making a measurement.
- the term “about” when used in connection with a particular numerical value means ⁇ 20%, unless specifically stated to be ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 10%, ⁇ 15%, or ⁇ 20% of the numerical value.
- the term “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus percentage, the exact value of the quantitative term is also contemplated and described.
- the term “about 3%” expressly contemplates, describes and includes exactly 3%.
- alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents Q as described herein.
- alkyl also encompasses both linear and branched alkyl, unless otherwise specified.
- the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 12 (C 1-12 ), 1 to 10 (C 1-10 ), or 1 to 6 (C 1-6 ) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms.
- linear Ci_ 6 and branched C 3 _6 alkyl groups are also referred as "lower alkyl.”
- alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).
- Ci_ 6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
- aryl refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C 6 - 2 o), from 6 to 15 (C 6-15 ), or from 6 to 10 (C 6 -io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
- Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
- aryl may also be optionally substituted with one or more substituents Q as described herein.
- heteroaryl refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N.
- Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
- the heteroaryl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
- Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl.
- Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl,
- benzimidazolyl benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl.
- tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl.
- heteroaryl may also be optionally substituted with one or more substituents Z as described herein.
- alkenoyl refers to -C(0)-alkenyl.
- alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents Z as described herein.
- alkenyl also embraces radicals having "cis” and “trans” configurations, or alternatively, “Z” and “E” configurations, as appreciated by those of ordinary skill in the art.
- alkenyl encompasses both linear and branched alkenyl, unless otherwise specified.
- C 2 _6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
- the alkenyl is a linear monovalent hydrocarbon radical of 2 to 30 (C 2 _3o), 2 to 24 (C 2 _ 24 ), 2 to 20 (C 2 _ 20 ), 2 to 15 (C 2 _i 5 ), 2 to 12 (C2-12), to 10 (C2-10), or 2 to 6 (C 2 -6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 30 (C3_3o), 3 to 24 (C 3 _ 24 ), 3 to 20 (C 3 _2o), 3 to 15 (C 3 _ 15 ), 3 to 12 (C 3 _ 12 ), 3 to 10 (C 3 _ 10 ), or 3 to 6 (C 3 _ 6 ) carbon atoms.
- alkenyl groups include, but are not limited to, ethenyl, propen-1- yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.
- the alkenoyl is mono-alkenoyl, which contains one carbon-carbon double bond.
- the alkenoyl is di-alkenoyl, which contains two carbon-carbon double bonds.
- the alkenoyl is poly-alkenoyl, which contains more than two carbon-carbon double bonds.
- heterocyclyl refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms.
- the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
- the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
- the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
- heterocyclic radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzoisoxazolyl, benzisoxazinyl, benzodioxanyl, benzodioxolyl,
- benzofuranonyl benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl,
- phenanthridinyl phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazol
- halogen refers to fluorine, chlorine, bromine, and/or iodine.
- the term "optionally substituted” is intended to mean that a group, including alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl, may be substituted with one or more substituents Z, in one embodiment, one, two, three or four substituents Z, where each Z is independently selected from the group consisting of cyano, halo, oxo, nitro, Ci_ 6 alkyl, halo-Ci_6 alkyl, C 2 -6 alkenyl, C 2 _ 6 alkynyl, C3-7 cycloalkyl, C 6-14 aryl, C7-14 aralkyl, heteroaryl, heterocyclyl, -C(0)R e , -C(0)OR e , -C(0)NR f R g , - C(NR e )NR f R g , -OR e , -OC(0)R
- solvate refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. [0052] In accordance with this disclosure, the term “comprising” is inclusive or open- ended and does not exclude additional, unrecited elements or method steps; the term
- the formulation provided herein includes at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, optionally suspended in a pharmaceutically acceptable medium, preferably an aqueous solution, preferably having a pH ranging from 3.5 to 9.0, preferably from 4 to 7.5.
- the formulations disclosed herein may optionally contain buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners.
- the formulations disclosed herein include a mixture of more than one lipid, preferably more than one phospholipids.
- the formulations disclosed herein consists essentially of at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers,
- the formulations disclosed herein include least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
- lipid is any substance, which has properties like or similar to those of a fat. As a rule, it has an extended apolar group (the “chain”, X) and generally also a water-soluble, polar hydrophilic part, the “head” group (Y) and has the basic Formula II:
- n is equal to or larger than zero.
- all amphiphilic substances including, but not limited to glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, isoprenoid lipids, steroids or sterols and carbohydrate-containing lipids can generally be referred to as lipids, and are included as such in this disclosure.
- a list of relevant lipids and lipid related definitions is provided in EP 0 475 160 Al (see, e.g. p. 4, 1. 8 to p. 6, 1. 3) and U.S. Patent No. 6,165,500 (see, e.g., col. 6, 1. 10 to col. 7, 1. 58), each incorporated herein by reference in their entirety.
- a phospholipid is, for example, a compound of Formula II:
- R 1 CH 2 — CHR 2 — CR 3 H— O— PH0 2 — O— R 4 (II) wherein R 1 and R 2 cannot both be hydrogen, OH or a C1-C3 alkyl group, and typically are independently, an aliphatic chain, most often derived from a fatty acid or a fatty alcohol; R generally is a hydrogen.
- the OH-group of the phosphate is a hydroxyl radical or hydroxyl anion (i.e., hydroxide) form, dependent on degree of the group ionization.
- R 4 may be a proton or a short-chain alkyl group, substituted by a tri-short-chain alkylammonium group, such as a trimethylammonium group, or an amino-substituted short-chain alkyl group, such as 2-trimethylammonium ethyl group (cholinyl) or 2-dimethylammonium short alkyl group.
- a sphingophospho lipid is, for example, a compound of Formula IIB:
- R 1 is a fatty-acid attached via an amide bond to the nitrogen of the sphingosine and R 4 has the meanings given under Formula II.
- a lipid preferably is a substance of formulae II or IIB, wherein R and/or R are acyl or alkyl, n-hydroxyacyl or n-hydroxyalkyl, but may also be branched, with one or more methyl groups attached at almost any point of the chain; usually, the methyl group is near the
- R and R may moreover either be saturated or unsaturated (mono-, di- or poly-unsaturated).
- R 3 is hydrogen and R 4 is 2-trimethylammonium ethyl (the latter corresponds to the phosphatidyl choline head group), 2-dimethylammonium ethyl, 2-methylammonium ethyl or 2-aminoethyl (corresponding to the phosphatidyl ethanolamine head group).
- R 4 may also be a proton (giving phosphatidic acid), a serine (giving phosphatidylserine), a glycerol (giving phosphatidylglycerol), an inositol (giving phosphatidylinositol), or an alkylamine group (giving phosphatidylethanolamine in case of an ethylamine), if one chooses to use a naturally occurring glycerophospholipid. Otherwise, any other sufficiently polar phosphate ester, such that will form a lipid bilayer, may be considered as well for making the formulations of the disclosure.
- Table 1 lists preferred phospholipids in accordance with the disclosure. Table 1
- Total Lipid * concentration range (w-%) 0.5-45 0.5-45 0.5-40 0.5-40 0.5-40 0.5-40
- Total Lipid includes phospholipid (s), surfactant (s)t and all lipophilic excipients
- the preferred lipids in context of this disclosure are uncharged and form stable, well hydrated bilayers; phosphatidylcholines, phosphatidylethanolamine, and sphingomyelins are the most prominent representatives of such lipids. Any of those can have chains as listed in the Table 1, the ones forming fluid phase bilayers, in which lipid chains are in disordered state, being preferred.
- Different negatively charged, i.e., anionic, lipids can also be incorporated into vesicular lipid bilayers.
- Attractive examples of such charged lipids are phosphatidylglycerols, phosphatidylinositols and, somewhat less preferred, phosphatidic acid (and its alkyl ester) or phosphatidylserine. It will be realized by anyone skilled in the art that it is less commendable to make vesicles just from the charged lipids than to use them in a combination with electro- neutral bilayer component(s).
- the charged bilayer lipid components can in principle have any of the chains listed in the Table 1.
- the chains forming fluid phase lipid bilayers are clearly preferred, however, both due to vesicle adaptability increasing role of increasing fatty chain fluidity and due to better ability of lipids in fluid phase to mix with each other.
- the fatty acid- or fatty alcohol-derived chain of a lipid is typically selected amongst the basic aliphatic chain types given in the following tables:
- Suitable fatty residues can furthermore be branched, for example, can contain a methyl group in an iso or anteiso position of the fatty acid chain, or else closer to the chain middle, as in 10-i?-methyloctadecanoic acid or tuberculostearic chain.
- Relatively important amongst branched fatty acids are also isoprenoids, many of which are derived from 3,7,1 l,15-tetramethylhexadec-trans-2-en-l-ol, the aliphatic alcohol moiety of chlorophyll.
- Examples include 5,9,13,17-tetramethyloctadecanoic acid and especially 3,7,11,15- tetramethylhexadecanoic (phytanic) and 2,6,10,14-tetramethylpentadecanoic (pristanic) acids.
- a good source of 4,8,12-trimethyltridecanoic acid are marine organisms. Combination of double bonds and side chains on a fatty residue are also possible.
- suitable fatty residues may carry one or a few oxy- or cyclic groups, especially in the middle or towards the end of a chain.
- alicyclic fatty acids are those that include a cyclopropane (and sometimes
- 2-(D)-Hydroxy fatty acids are more ubiquitous than alicyclic fatty acids, and are also important constituents of sphingolipids. Also interesting are 15-hydroxy-hexadecanoic and 17-hydroxy-octadecanoic acids, and maybe 9-hydroxy- octadeca-tra/?s-10,tra/?s-12-dienoic (dimorphecolic) and 13-hydroxy-octadeca-czs-9,zra/?s-l 1- dienoic (coriolic) acid.
- hydroxyl-fatty acid Arguably the most prominent hydroxyl-fatty acid in current pharmaceutical use is ricinoleic acid, (D-(-)12-hydroxy-octadec-cz ' s-9-enoic acid, which includes up to 90% of castor oil, which is also often used in hydrogenated form.
- Epoxy-, methoxy-, and furanoid-fatty acids are of only limited practical interest in the context of this disclosure.
- unsaturation, branching or any other kind of derivatization of a fatty acid is best compatible with the intention of present disclosure of the site of such modification is in the middle or terminal part of a fatty acid chain.
- the cz ' s -unsaturated fatty acids are also more preferable than trans -unsaturated fatty acids and the fatty radicals with fewer double bonds are preferred over those with multiple double bonds, due to oxidation sensitivity of the latter.
- symmetric chain lipids are generally better suited than asymmetric chain lipids.
- a preferred lipid of the Formula II is, for example, a natural phosphatidylcholine, which used to be called lecithin. It can be obtained from egg (rich in palmitic, Ci6:o, and oleic, Ci8:i, but also including stearic,Ci8 : o, palmitoleic, Ci6:i, linolenic, C 18:2 , and
- soybean rich in unsaturated Cig chains, but also containing some palmitic radical, amongst a few others
- coconut rich in saturated chains
- olives rich in monounsaturated chains
- saffron safflower
- sunflowers rich in n-6 linoleic acid
- linseed rich in n-3 linolenic acid
- whale fat rich in monounsaturated n-3 chains
- primrose or chemo
- sphingomyelins of biological origin are typically prepared from eggs or brain tissue.
- phosphatidylserines also typically originate from brain material whereas phosphatidylglycerol is preferentially extracted from bacteria, such as E. Coli, or else prepared by way of transphosphatidylation, using phospholipase D, starting with a natural phosphatidylcholine.
- bacteria such as E. Coli
- phospholipase D phospholipase D
- the preferred phosphatidic acid is either extracted from any of the mentioned sources or prepared using phospholipase D from a suitable phosphatidylcholine.
- R and R are aliphatic chains, as defined in the preceding paragraph with 12 to 30 carbon atoms, preferentially with 14 to 22 carbon atoms, and even more preferred with 16 to 20 carbon atoms, under the proviso that the chains must be chosen so as to ensure that the resulting ESAs include fluid lipid bilayers. This typically means use of relatively short saturated and of relatively longer unsaturated chains.
- R 4 in Formula IIB corresponds to 2-trimethylammonium ethyl
- R 1 is an aliphatic chain, as defined in the preceding paragraph, with 10 to 20 carbon atoms, preferentially with 10 to 14 carbon atoms per fully saturated chain and with 16-20 carbon atoms per unsaturated chain.
- Synthetic phosphatidyl ethanolamines (R 4 is 2-aminoethyl), synthetic phosphatidic acids (R 4 is a proton) or its ester (R 4 corresponds, for example, to a short-chain alkyl, such as methyl or ethyl), synthetic phosphatidyl serines (R 4 is L- or D-serine), or synthetic
- phosphatidyl (poly)alcohols such as phosphatidyl inositol, phosphatidyl glycerol (R 4 is L- or
- D-glycerol are preferred as lipids, wherein R and R are fatty residues of identical or moderately different type and length, especially such as given in the corresponding tables given before in the text.
- R 1 can represent alkenyl and R 2 identical hydroxyalkyl groups, such as tetradecylhydroxy or hexadecylhydroxy, for example, in ditetradecyl or
- R 1 2 dihexadecylphosphatidyl choline or ethanolamine, R can represent alkenyl and R
- hydroxyacyl such as a plasmalogen (R 4 trimethylammonium ethyl), or R 1 can be acyl, such as lauryl, myristoyl or palmitoyl and R can represent hydroxy as, for example, in natural or synthetic lysophosphatidyl cholines or lysophosphatidyl glycerols or lysophosphatidyl ethanolamines, such as 1 -myristoyl or 1-palmitoyllysophosphatidyl choline or -phosphatidyl ethanolamine; frequently, R represents hydrogen.
- a lipid of Formula IIB is also a suitable lipid within the sense of this disclosure.
- n l
- R 1 is an alkenyl group
- R 2 is an acylamido group
- R 3 is hydrogen
- R 4 represents 2-trimethylammonium ethyl (choline group).
- a lipid is known under the name of sphingomyelin.
- Suitable lipids furthermore are a lysophosphatidyl choline analog, such as 1- lauroyl-l,3-dihydroxypropane-3-phosphoryl choline, a monoglyceride, such as monoolein or monomyristin, a cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmalogen, a ganglioside or a glyceride, which does not contain a free or esterified phosphoryl or phosphono or phosphino group in the 3 position.
- a lysophosphatidyl choline analog such as 1- lauroyl-l,3-dihydroxypropane-3-phosphoryl choline
- a monoglyceride such as monoolein or monomyristin
- a cerebroside such as monoolein or monomyristin
- ceramide polyhexoside such as monoolein or monomyristin
- sulfatide
- a glyceride is diacylglyceride or 1 -alkenyl- l-hydroxy-2-acyl glyceride with any acyl or alkenyl groups, wherein the 3 -hydroxy group is etherified by one of the carbohydrate groups named, for example, by a galactosyl group such as a monogalactosyl glycerin.
- Lipids with desirable head or chain group properties can also be formed by biochemical means, for example, by means of phospholipases (such as phospholilpase Al, A2, B, C and, in particular, D), desaturases, elongases, acyl transferases, etc., from natural or synthetic precursors.
- phospholipases such as phospholilpase Al, A2, B, C and, in particular, D
- desaturases elongases
- acyl transferases etc.
- a suitable lipid is any lipid, which is contained in biological membranes and can be extracted with the help of apolar organic solvents, such as chloroform.
- lipids also include, for example, steroids, such as estradiol, or sterols, such as cholesterol, beta-sitosterol, desmosterol, 7-keto-cholesterol or beta-cholestanol, fat-soluble vitamins, such as retinoids, vitamins, such as vitamin Al or A2, vitamin E, vitamin K, such as vitamin Kl or K2 or vitamin Dl or D3, etc.
- the less soluble amphiphilic components include or preferably include a synthetic lipid, such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linolyl, linolenyl, linolaidyl, octadecatetraenoyl, gondoyl, eicosaenoyl, eicosadienoyl, eicosatrienoyl, arachidoyl, cis- or trans-docosaenoyl, docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stea
- the more soluble amphiphilic components(s) is/are frequently derived from the less soluble components listed above and, to increase the solubility, substituted and/or complexed and/or associated with a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several, mutually independent, selected substituents or with a different material for improving the solubility.
- a further suitable lipid is a diacyl- or dialkyl-glycerophosphoetha- nolamine azo polyethoxylene derivative, a didecanoylphosphatidyl choline or a
- the amount of lipid in the formulation is from about 1% to about 12%, about 1% to about 10%>, about 1% to about 4%, about 4% to about 7% or about 7%) to about 10%) by weight.
- the lipid is a phospholipid.
- the phospholipid is a phosphatidylcholine.
- the lipid in the formulation does not include an alkyl- lysophospholipid. In some embodiments, the lipid in the formulation does not include a polyeneylphosphatidylcholine .
- surfactant has its usual meaning.
- a list of relevant surfactants and surfactant related definitions is provided in EP 0 475 160 Al (see, e.g., p. 6, 1. 5 to p.14. 1.17)and U.S. Pat. No. 6,165,500 (see, e.g., col. 7, 1. 60 to col. 19, 1. 64), each herein incorporated by reference in their entirety, and in appropriate surfactant or pharmaceutical Handbooks, such as Handbook of Industrial Surfactants or US Pharmacopoeia, Pharm. Eu.
- the surfactants are those described in Tables 1-18 of U.S. Patent Application Publication No.
- Preferred surfactants to be used in accordance with the disclosure include those with an HLB greater than 12.
- the list includes ionized long-chain fatty acids or long chain fatty alcohols, long chain fatty ammonium salts, such as alkyl- or alkenoyl-trimethyl-, -dimethyl- and - methyl-ammonium salts, alkyl- or alkenoyl-sulphate salts, long fatty chain dimethyl- aminoxides, such as alkyl- or alkenoyl-dimethyl-aminoxides, long fatty chain, for example alkanoyl, dimethyl-aminoxides and especially dodecyl dimethyl-aminoxide, long fatty chain, for example alkyl-N-methylglucamide- s and alkanoyl-N-methylglucamides, such as MEGA- 8, MEGA-9 and MEGA- 10, N-long fatty chain-N,N-dimethylglycines, for example N-alkyl-
- polyethylen-glycol- acylphenyl ethers especially nonaethylen-glycol-octyl- phenyl ether, polyethylene-long fatty chain-ethers, especially polyethylene-acyl ethers, such as nonaethylen-decyl ether, nonaethylen-dodecyl ether or octaethylene-dodecyl ether, polyethyleneglycol-isoacyl ethers, such as octaethyleneglycol-isotridecyl ether, polyethyleneglycol-sorbitane-long fatty chain esters, for example polyethyleneglycol-sorbitane-acyl esters and especially polyoxyethylene- monolaurate (e.g.
- polysorbate 20 or Tween 20 polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween 80), polyoxyethylene-sorbitan-monolauroleylate, polyoxyethylene - sorbitan-monopetroselinate, polyoxyethylene -sorbitan— monoelaidate, polyoxyethylene - sorbitan-myristoleylate, polyoxyethylene -sorbitan-palmitoleinylate, polyoxyethylene- sorbitan-p- etroselinylate, polyhydroxyethylene-long fatty chain ethers, for example polyhydroxyethylene-acyl ethers, such as polyhydroxyethylene-lauryl ethers,
- polyhydroxyethylene-myristoyl ethers polyhydroxyethylene-cetylst- earyl, polyhyd roxyethylene-palmityl ethers, polyhyd roxyethylene-oleoyl ethers, polyhydroxyethylene- palmitoleoyl ethers, polyhydroxyethylene-lino- leyl, polyhydroxyethylen-4, or 6, or 8, or 10, or 12-lauryl, miristoyl, palmitoyl, palmitoleyl, oleoyl or linoeyl ethers (Brij series), or in the corresponding esters, polyhydroxyethylen-laurate, -myristate, -palmitate, -stearate or -oleate, especially polyhydroxyethylen-8 -stearate (Myrj 45) and polyhydroxyethylen-8-oleate, polyethoxylated castor oil 40 (Cremophor EL), sorbitane-mono
- lysophospholipids n-octadecylene-glycerophosphatidic acid, octadecylene- phosphorylglycerol, octadecylene-phosphorylserine, n-long fatty chain-glycero-phosphatidic acids, such as n-acyl-glycero-phosphatidic acids, especially lauryl glycero-phosphatidic acids, oleoyl-glycero-phosphatidic acid, n-long fatty chain-phosphorylglycerol, such as n- acyl-phosphorylglycerol, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl- phosphorylglycerol, n-long fatty chain-phosphorylserine, such as n-acyl-phosphorylserine, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl
- Surfactant chains are typically chosen to be in a fluid state or at least to be compatible with the maintenance of fluid-chain state in carrier aggregates.
- Table 5 lists preferred surfactants in accordance with the disclosure.
- Myrj-45 Stearoyl-E08; Myrj-49: Stearoyl-EO20 (not in the market); Myrj-59: Stearoyl- EO100; Myrj-52: Stearoyl-EO40;
- Simulsol-2599 Macrogol-10-oleate
- the surfactant is a nonionic surfactant.
- the surfactant may be present in the formulation in about 1% to about 10%, about 1% to about 4%, about 4% to about 7% or about 7% to about 10% by weight.
- the amount of surfactants in the formulation is from about 0.2% to about 0.5%.
- the nonionic surfactant is selected from the group consisting of: polyoxyethylene sorbitans (polysobate surfactants), polyhydroxyethylene stearates or polyhydroxyethylene laurylethers (Brij surfactants).
- the surfactant is a polyoxyethylene-sorbitan- monooleate (e.g.
- polysorbate 80 or Tween 80 can have any chain with 12 to 20 carbon atoms.
- the polysorbate is fluid in the formulation, which may contain one or more double bonds, branching, or cyclo-groups.
- the formulations include only one lipid and only one surfactant. In other embodiments, the formulations include more than one lipid and only one surfactant, e.g., two, three, four, or more lipids and one surfactant. In other embodiments, the formulations include only one lipid and more than one surfactant, e.g., two, three, four, or more surfactants and one lipid. In other embodiments, the formulations include more than one lipid and more than one surfactant, e.g., two, three, four, or more lipids and two, three, four, or more surfactants.
- the formulations disclosed herein may have a range of lipid to surfactant ratios.
- the ratios may be expressed in terms of molar terms (mol lipid /mol surfactant).
- the molar ratio of lipid to surfactant in the formulations may be from about 1 :3 to about 30: 1, from about 1 :2 to about 30: 1, from about 1 : 1 to about 30:1, from about 5: 1 to about 30: 1, from about 10:1 to about 30: 1, from about 15: 1 to about 30:1, or from about 20: 1 to about 30: 1.
- the molar ratio of lipid to surfactant in the formulations disclosed herein may be from about 1 :2 to about 10: 1.
- the ratio is from about 1 : 1 to about 2: 1, from about 2 : 1 to about 3: 1, from about 3 : 1 to about 4: 1, from about 4 : 1 to about 5:1 or from about 5: 1 to about 10: 1.
- the lipid to surfactant ratio is about 1.0: 1.0, about 1.25:1.0, about 1.5/1.0, about 1.75/1.0, about 2.0/1.0, about 2.5/1.0, about 3.0/1.0 or about 4.0/1.0.
- the formulations disclosed herein may also have varying amounts of total amount of the following components: lipid and surfactant combined (TA).
- the TA amount may be stated in terms of weight percent of the total composition.
- the TA is from about 1% to about 40%, about 5% to about 30%>, about 7.5% to about 15%, about 5% to about 10%), about 10% to about 20% or about 20% to about 30%.
- the TA is 8%, 9%, 10%, 15% or 20%.
- the TA will be substantially smaller than the TA for pharmaceutical embodiments.
- the TA may be from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 3%, or from about 0.1% to about 1%.
- the formulations disclosed herein do not include a pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any other disorder listed above.
- the formulations disclosed herein include one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
- formulations disclosed herein may optionally contain one or more of the following ingredients: co-solvents, chelators, buffers, antioxidants, preservatives,
- microbicides emollients, humectants, lubricants and thickeners. Preferred amounts of optional components are described in Table 7.
- the formulations disclosed herein may include a buffer to adjust the pH of the aqueous solution to a range from pH 3.5 to pH 9, pH 4 to pH 7.5, or pH 4 to pH 6.5.
- buffers include, but are not limited to, acetate buffers, lactate buffers, phosphate buffers, and propionate buffers.
- formulations disclosed herein are typically formulated in aqueous media.
- the formulations may be formulated with or without co-solvents, such as lower alcohols
- microbicide or "antimicrobial” agent is commonly added to reduce the bacterial count in pharmaceutical formulations.
- Some examples of microbicides are short chain alcohols, including ethyl and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds, such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophene, hexachlorophene, povidon- iodine; parabenes, especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or butyl- paraben, benzyl paraben; acids, such as sorbic acid, benzoic acid and their salts; quaternary ammonium compounds, such as alkonium salts, e.g., a bromide, benzalkonium
- antioxidants are butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389, CI-986, PD-127443, E-51 19, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), l-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ); aromatic amines
- BHA butylated hydroxyanisol
- BHT butylated hydroxytoluene
- LY178002 di-tert-butylphenol
- LY256548 LY256548, HWA-131, BF-389, CI-986, PD-127443, E-51 19, BI-L-239XX, etc.
- TBHQ tertiary butylhydroquinone
- phenols and phenolic acids include tocopherols (alpha, beta, gamma, delta) and their derivatives, such as tocopheryl-acylate (e.g., -acetate, - laurate, myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitable tocopheryl- lipoate), tocopheryl-POE-succinate; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6)-o-alkylas
- miscellaneous endogenous defence systems such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, heamopexin, albumin, glucose, ubiquinol-10); enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as beta- carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins), N-acetylcystein, mesna, glutathione, thiohistidine derivatives, triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and their esters (coumaric acids and esters, caffeic acid and their esters, ferulic acid, (iso-) chlorogenic acid,
- Thickeners are used to increase the viscosity of pharmaceutical formulations to and may be selected from selected from pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, including carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; completely synthetic hydrophilic polymers including polyacrylates, polymethacrylates, poly(hydroxyethyl)-,
- the formulations disclosed herein may also include a polar liquid medium.
- the formulations disclosed herein may be administered in an aqueous medium.
- the formulations disclosed herein may be in the form of a solution, suspension, emulsion, cream, lotion, ointment, gel, spray, film forming solution or lacquer.
- compositions and methods disclosed herein relate to the use of a vesicular formulation as described above for the preparation of a pharmaceutical composition for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia.
- a vesicular formulation or pharmaceutical composition includes at least one phospholipid and one nonionic surfactant for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia wherein the formulation or pharmaceutical composition is formulated for subcutaneous, topical or intravenous delivery.
- Table 7 lists preferred excipients for the formulation.
- EGTA Ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid
- EDTA Ethylenedioxy-diethylene-dinitrilo-tetraacetic acid
- formulations disclosed herein may form vesicles or ESAs characterized by their adaptability, deformability, or penetrability.
- vesicle or aggregate “adaptability" which governs the "tolerable surface curvature” is defined as the ability of a given vesicle or aggregate to change easily its properties, such as shape, elongation ratio, and surface to volume ratio.
- the vesicles disclosed herein may be characterized by their ability to adjust the aggregates' shape and properties to the anisotropic stress caused by pore crossing.
- Sufficient adaptability implies that a vesicle or an aggregate can sustain different unidirectional forces or stress, such as one caused by pressure, without extensive fragmentation, which defines a "stable" aggregate.
- a “barrier” is (as in, for example, EP 0 475 160 and WO 98/17255) a body with through- extending narrow pores, such narrow pores having a radius which is at least 25% smaller than the radius of the ESAs (considered as spherical) before the ESAs permeate through such pores.
- the term "narrow" used in connection with a pore implies that the pore radius is significantly, typically at least 25%, smaller than the radius of the entity tested with regard to its ability to cross the pore.
- the necessary difference typically should be greater for the narrower pores. Using 25% limit is therefore quite suitable for >150 nm diameter whereas >100% difference requirement is more appropriate for the smaller systems, e.g., with ⁇ 50 nm diameter. For diameters around 20 nm, aggregate diameter difference of at least 200% is often required.
- Non-destructing passage of ultradeformable, mixed lipid aggregates through narrow pores in a semi-permeable barrier is thus diagnostic of high aggregate adaptability. If pore radius is two times smaller than the average aggregate radius the aggregate must change its shape and surface-to-volume ratio at least 100% to pass without fragmentation through the barrier.
- An easy and reversible change in aggregate shape inevitably implies high aggregate deformability and requires large surface-to-volume ratio adaptation.
- a change in surface-to- volume ratio per se implies: a) high volume compressibility, e.g. in the case of compact droplets containing material other than, and immiscible with, the suspending fluid; b) high aggregate membrane permeability, e.g. in the case of vesicles that are free to exchange fluid between inner and outer vesicle volume.
- 2 r ves (Ap) is the vesicle diameter after semipermeable barrier passage driven by ⁇ and 2 r veS;0 is the starting vesicle diameter, and if necessary make corrections for the flow-effects; and 4) aligh both data sets ⁇ ( ⁇ ) vs.
- barrier penetratibility of a given suspension is a function of transport driving pressure by the following formula, where P max is the maximum possible penetratability of a given barrier (for the aggregates with zero transport resistance this penetrability is identical to the penetrability of the suspending medium flux), and p* is an adjustable parameter that describes the pressure sensitivity, and thus the transport resistance, of the tested system (for barriers with a fixed pore radius this sensitivity is a function of aggregate properties solely; for non-interacting particles the sensitivity is dominated by aggregate adaptability, allowing to make the assumption: a a proportional to 1/p*
- a pharmaceutical composition including at least one phospholipid and one nonionic surfactant.
- a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners.
- a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
- a pharmaceutical composition including at least one phospholipid and one nonionic surfactant, wherein the pharmaceutical composition sequesters organic matter upon administration.
- a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration.
- a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration.
- a pharmaceutical package or kit including one or more containers filled with the formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
- the formulation includes one or more phospholipids and one or more surfactants. In certain embodiments, the formulation does not include a non-lipid non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or other disorder listed above.
- the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer. Also provided are packages or kits that can be used in any of the methods disclosed herein.
- the formulations as described herein are used for agricultrural puposeses and applications.
- methods that include administering a formulation as described herein to a plant, seed or soil.
- the formulation may be effective as an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and/or a synergist.
- a formulation as described herein is applied in any desirable application such as in agricultural applications. For instance, the formulation may be applied to control weeds, insects, and/or fungi. In addition, the formulation may be applied to insects, crops, soils, and the like.
- the pesticide composition may be applied by any suitable method.
- the formulations may facilitate the transport of different agents into plant tissues, for example, the formulations may facilitate the penetration of cuticular wax layers.
- improved penetration into or through the cuticle could reduce the concentration of active agent required for a given application and thus significantly diminish pollution problems (Price, C. E. (1981) In: The plant cuticle (D. F. Cutler, K. L. Alvin, C. E. Price, Edits.), Academic, New York, pp. 237- 252).
- formulations as described herein are applied to plants, crops, fields and the like and are applied such that the active agent is applied at a rate of 1 g/hectar to 500 g/hectar; or at a rate of 1 g/hectar to 200 g/hectar; at a rate of 100 g/hectar to 350 g/hectar; or at a rate of 30 g/hectar to 100 g/hectar.
- the formulations are used to prepare a tank mix which may then be applied via spraying to the area, plant matter or crop needing treatment.
- the active agent concentration in the tank mix is adjusted to the particular application, depending on agricultural or non-agricultural application, the crop and the pest.
- spraying may be the preferred method of application.
- Various methods of application can also be employed when necessary. For example, in field crops systemic application via an irrigation system can be combined with foliar application.
- a package, bag or kit that includes a formulation such as described herein, and instructions for indicating that the formulation is suitable for application to a plant, seed or soil.
- the instructions indicate that the formulation is suitable for use as one or more selected from the group consisting of consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
- the formulation may include an active agent, for example, the active agent may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and/or a synergist.
- the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
- Fungicides Aliphatic Nitrogen Fungicides
- pyrametostrobin pyraoxystrobin
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Abstract
Disclosed herein are vesicular formulations that include one or more phospholipids and one or more surfactants. In certain embodiments the use of such formulations are for the delivery of fatty acids for the treatment of disorders such as, fatty acid metabolic disorders, including essential fatty acid deficiency; pain or inflammation or osteoarthritis. In certain embodiments the use of such formulations are for use in agriculture, for example for applying agents to plants and crops intended for human consumption.
Description
VESICULAR FORMULATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 61/298,532, entitled "Vesicular Formulations," filed January 26, 2010 and U.S. Provisional Patent Application No. 61/321,966, entitled "Vesicular Formulations," filed April 8, 2010, each of which are hereby incorporated by reference in their entirety for all purposes.
1. FIELD OF INVENTION
[0002] Provided herein are compositions and methods relating to formulations of phospholipids and surfactants. Certain aspects and embodiments relate to methods of using such formulations, including agricultural methods.
2. BACKGROUND
[0003] U.S. Patent No. 6,165,500 to Cevc describes a "preparation for the application of agents . . . provided with membrane-like structures consisting of one or several layers of amphiphilic molecules, or an amphiphilic carrier substance, in particular for transporting the agent into and through natural barriers such as skin and similar materials." Abstract. These transfersomes "consist of one or several components[, m]ost commonly a mixture of basic substances, one or several edge-active substances, and agents []." Col. 5, lines 28-30.
According to U.S. Patent No. 6,165,500, "[l]ipids and other amphiphiles are best suited basic substances; surfactants or suitable solvents are the best choice from the point of view of edge- active substances[, and a]ll of these can be mixed with agents in certain proportions depending both on the choice of the starting substances and on their absolute concentration." Col. 5, lines 30-35.
[0004] U.S. Patent Application Publication No. US 2004/0071767 to Cevc et al. describes "formulations of nonsteroidal anti-inflammatory drugs (NSAIDs) based on complex aggregates with at least three amphiphatic components suspended in a . . . pharmaceutically acceptable . . . medium." Abstract. "One of these components is capable of forming stable, large bilayer membranes on its own. The other at least two amphiphatic components, including an NSAID, tend to destabilise such membranes." Paragraph [0002].
[0005] U.S. Patent Application Publication No. US 2004/0105881 to Cevc et al. describes extended surface aggregates, "suspendable in a suitable liquid medium and comprising at least three amphiphats (amphiphatic components) and being capable to improve the transport
of actives through semi-permeable barriers, such as the skin, especially for the non-invasive drug application in vivo by means of barrier penetration by such aggregates." Paragraph [0002]. "The three amphiphats include at least one membrane forming compound (MFC), which can form the membrane of [the aggregates], and at least two membrane destabilising compounds (MDCi and MDC2) differentiated by their capability of forming smaller aggregates (with no extended surfaces) by either themselves or else in combination with each other and/or characterized by their relatively high solubility in [the] suitable liquid medium. Paragraph [0002]. US 2004/0105881 specifically discloses that "incorporation of a surfactant into a bilayer membrane that is built from another less soluble amphiphat, such as a phospholipid, can increase the flexibility of the resulting complex membrane . . . promoting] the capability of complex aggregates . . . to cross pores in a semi-permeable membrane that otherwise would prevent comparably large aggregates from crossing." Paragraph [0015]. Citation of any reference in this section of the application is not an admission that the reference is prior art to the application. The above noted publications are hereby
incorporated by reference in their entirety.
3. SUMMARY OF THE INVENTION
[0006] Provided herein are compositions and methods related to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants. In some embodiments, the formulations are effective for the delivery of fatty acids and/or
phospholipids in the treatment of disorders related to fatty acid metabolic disorders, including essential fatty acid deficiency. In a particular embodiment, the vesicular formulations include about 25% to about 30% surfactant by weight based on the total weight of the vesicular formulation. These vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously.
[0007] The term "formulation" as used herein refers to any composition as described herein, for example, a formulation that includes one or more phospholipids and one or more nonionic surfactants. In some embodiments a formulation may include one or more active agents as described herein; in other embodiments a formulation may specifically not include any active agents, for example active agents as disclosed herein. In some embodiments (for example embodiments that may be useful for agricultural purposes), the formulation may include an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant,
insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist, and/or the like. In certain
embodiments, the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In some embodiments, a formulation includes ingredients or components as described herein, for example such as described in Table 8 A and Table 8B. In various embodiments, a formulation similar to or the same as the Example Formulations 1- 129; in some embodiments, the formulations are similar or the same as the Example
Formulations 1-129 except they further include at least one active agent such as described herein (for example the active agent may be present in the formulation in an amount as described herein). In certain embodiments, a formulation, such as described herein
(especially those for use in agricultural applications and methods), is not suitable for administration to a human, for example, it does not meet criteria required by a government regulatory agency such as the United States Food and Drug Administration (FDA). In some embodiments, the formulation is suitable for use in agriculture, for example it is suitable to apply to plants and crops intended for human consumption. In certain embodiments, the formulation is suitable for administration to a human as a pharmaceutical compositon, for example it does meet criteria for administration to humans by one or more government agencies such as the United States FDA.
[0008] The term "active agents" as used herein includes any agent that can exert one or more actions, for example an action which affects some sort of biological process. In certain embodiments, an active agent may be a pharmaceutical agent or pharmaceutically active agent. In some embodiments (especially embodiments relating to agriculture) an active ingredient may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, pesticide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, synergist or the like. In some embodiments, an active agent may be an agent listed on Table 9.
[0009] In accordance with the compositions and methods disclosed herein, the vesicular formulations may be formulated to deliver fatty acids and phosphatidyl derivatives of fatty acids, such as arachidonic acid or omega-3 or omega-6 fatty acids. In accordance with this embodiment the vesicular formulations may optionally be formulated to include other lipids described herein, such as phophatidyl choline, and surfactants. In accordance with the
compositions and methods disclosed herein, the vesicular formulations may deliver essential fatty acids, such as omega-3 fatty acids, to decrease the levels of triglycerides. Vesicular formulations disclosed herein which deliver essential fatty acids, such as omega-3 fatty acids, may be useful in the treatment of fatty acid metabolic disorders, such as essential fatty acid deficiency and hypertriglyceridemia. In one embodiment, the vesicular formulations which deliver essential fatty acids include a phosphatidyl chlo line derivative of a fatty acid, e.g., a phosphatidylcholine derivative of an omega-3 fatty acid. In various embodiments, the vesicular formulation is one of the formulations set forth in Examples 1-129.
[0010] "Fatty acid metabolic disorder" means a defect in one of the enzymes involved in fatty acid metabolism, and include fatty oxidation disorders, whereby the body is unable to oxidize and metabolize fatty acids due to a failure in the enzymatic pathway. "Essential fatty acid deficiency" means a deficiency in the essential fatty acids, e.g., omega-3 and omega-6 fatty acids, which can lead to physical symptoms such as hemorrhagic dermatitis skin atrophy, scaly dermatitis, dry skin, weakness, impaired vision, tingling sensations, mood swings, edema, high blood pressure, high triglycerides, hemorrhagic folliculitis, hemotologic disturbances, immune and mental deficiencies, and impaired growth.
[0011] In accordance with the compositions and methods disclosed herein, the vesicular formulations maty deliver fats and fat soluble vitamins, such as vitamin E, for the treatment of disorders related to hypolididemia, including, abetalipoproteinemia,
hypobetalipoproteinemia, chlyomicron retention disease. In one embodiment, the vesicular formulations which deliver fats and fat soluble vitamins include a phosphatidylchloline derivative of a fatty acid, e.g., a phosphatidylcholine derivative of vitamin E. In various embodiments, the vesicular formulation is one of the formulations set forth in Examples 1- 129.
[0012] Provided herein are compositions and methods encompassing vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering organic matter once delivered to the subject. These vesicular formulations are suitable for any method of administration, e.g. , subcutaneously, topically, or intravenously. Without in any way being limited by theory, it is believed that the surprisingly effective and capacious sequestration of native organic compounds by the vesicular formulations disclosed herein occurs because of liquid crystallinity of the vesicular formulations mediated by the presence of membrane adapters such as surfactants. In various embodiments, the vesicular formulation is one of the formulations set forth in Examples 1-
129. In a preferred embodiment, the vesicular formulations include about 25% to about 30% surfactant by weight.
[0013] In one embodiment, the vesicular formulations of lipids and surfactants are capable of sequestering native organic compounds, including arachidonic acid, upon delivery to human skin for the treatment of pain or inflammation. In some embodiments, these formulations are designed such that the vesicles are able to penetrate deep tissue without diversion into the blood vessels. That is, the formulations are able to travel to the site of the pain in sufficient amount to alleviate that pain to some extent. In some embodiments, delivery to the deep tissue includes delivery of the formulation beneath the skin to the muscle tissue and to the joint itself, while limiting systemic delivery and exposure to the formulation. In a particular embodiment, the vesicular formulation is capable of sequestering arachidonic acid upon administration to human skin, and therefore is capable of altering the pathology of, e.g., pain or inflammation. In another embodiment, vesicular formulations designed to sequester arachidonic acid may also be used to prevent the formation of metabolites, including eicosanoids, for the prevention and/or treatment of asthma, seborrheic eczema, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, and dysmenorrhea. In various embodiments, the vesicular formulation capable of
sequestering arachidonic acid is one of the formulations set forth in Examples 1-129.
[0014] In some embodiments, vesicular formulations include one or more phospholipids and one or more nonionic surfactants can sequester cholesterol upon administration to human skin, thus decreasing the accumulation of or uptake of cholesterol for the treatment of hypercholesterolemia. In some embodiments, vesicular formulations include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering triglycerides, thus decreasing the accumulation or uptake of triglycerides for the treatment of hypertriglyceridemia. In various embodiments, the vesicular formulation capable of sequestering cholesterol or triglycerides is one of the formulations set forth in Examples 1- 129.
[0015] The vesicular formulations disclosed herein may also be used to sequester factors involved in fatty acid metabolism, such as hormone sensitive lipase (HSL). Inhibition of HSL inhibits the conversion of triglycerides to glycerol and fatty acids, resulting in a decrease in plasma free fatty acids. Thus, the vesicular formualtions disclosed herein may have utility where the decrease in plasma fatty acids is desired, including insulin resistance, metabolic syndrome X, dyslipidemias and abnormal lipoprotein metabolism. In various
embodiments, the vesicular formulation capable of sequestering factors involved in fatty acid metabolism is one of the formulations set forth in Examples 1-129.
[0016] Provided herein are methods and compositions that relate to vesicular
formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering metal (as a chelator) upon administration to human skin for the treatment of, e.g., metal toxicity. In various embodiments, the vesicular formulation capable of sequestering metals is one of the formulations set forth in Examples 1-129.
[0017] Provided herein are methods and compositions that relate to vesicular
formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering a toxin (e.g., DDT) upon administration to human skin. In various embodiments, the vesicular formulation capable of sequestering toxins such as DDT is one of the formulations set forth in Examples 1-129.
[0018] Provided herein are methods and compositions that relate to vesicular
formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering inflammatory mediators (e.g., cytokines, such as interleukins, or presenting antigens) upon administration to human skin for the treatment of inflammation and inflammatory related disorders, such as asthma. In various embodiments, the vesicular formulation capable of sequestering inflammatory mediators is one of the formulations set forth in Examples 1-129.
[0019] Provided herein are methods and compositions that relate to vesicular
formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering amyloid upon administration for the treatment of
Alzheimers disease. Such formulations may be administered intravenously in accordance with this embodiment. In various embodiments, the vesicular formulation capable of sequestering amyloid is one of the formulations set forth in Examples 1-129.
[0020] Provided herein are methods and compositions that relate to vesicular
formulations that inculde one or more phospholipids and one or more nonionic surfactants that are effective in sequestering uric acid upon administration for the treatment of gout or macular degeneration, such as AMD. Such formulations may be administered topically or intravitreally in accordance with this embodiment. In various embodiments, the vesicular formulation capable of sequestering uric acid is one of the formulations set forth in Examples 1-129.
[0021] Provided herein are methods and compositions that relate to vesicular formulations that include one or more phospholipids and one or more nonionic surfactants that are effective in sequestering squalene, thus leading to fungistatic activity against, e.g. , hyphal fungi. These vesicular formulations are suitable for any method of administration, e.g., subcutaneously, topically, or intravenously. In various embodiments, the vesicular formulation capable of sequestering squalene is one of the formulations set forth in Examples 1-129.
[0022] As used herein, the term "formulation" is not necessarily meant to imply that the ingredients or components are in combination with a pharmaceutically active agent, i.e., any non-lipid non-surfactant active agent that has received regulatory approval for the treatment of fatty acid related disorders, hypocholesterolemia, hypertriclyceridemia, pain, including osteoarthritic pain, inflammation, infection, or toxicity, including metal toxicity or any of the disorders listed above.
[0023] In certain embodiments, despite the lack of a recognized active agent, the vesicles elicit a therapeutic effect, namely the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above. Without being bound by any theory, Applicant believes that the vesicle components themselves are responsible for this effect.
[0024] In one embodiment, a pharmaceutical package or kit includes one or more containers filled with a formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for the treatment of any disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
hypercholesterolemia, or any of the disorders listed above. In certain embodiments, the formulation includes one or more phospholipids and one or more surfactants. In certain embodiments, the formulation does not include a pharmaceutically active agent, i.e., any nonlipid, non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the other disorders listed above. In various embodiments, the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer. Also provided are packages or kits that can be used in any of the above-described methods.
[0025] In one embodiment, provided are methods for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above, wherein the vesicular formulations are administered over a period of one or more weeks, for example for at least five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, sixteen weeks, twenty four weeks, four months, six months, eight months, ten months, one year, two or more years, or indefinitely.
[0026] In one embodiment, the formulations include one or more phospholipids, one or more nonionic surfactants, in the absence of any pharmaceutically active agent, i.e., any nonlipid non-surfactant pharmaceutically active agent that has received regulatory approval for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism,
hypertriglyceridemia, hypercholesterolemia pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above.
[0027] In one embodiment, a 0.1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of the disorders listed above; a 1 to 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, or any of the disorders listed above; a 1 to 5 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia, pain, including osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above; or a 1 gram, 2 gram, 3 gram, 4 gram, 5 gram, 6 gram, 7 gram, 8 gram, 9 gram or 10 gram dose of the formulation is administered to the patient for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia, hypercholesterolemia pain, including
osteoarthritic pain, inflammation, infection, including fungal or bacterial infection, or toxicity, including metal toxicity, or any of the disorders listed above. In some embodiments, the dose is measured as the total weight of the deformasome. In some embodiments, the dose is measured as the total weight of the lipid(s) and surfactant(s) in the deformasome. The dose may be administered once or twice daily for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any of
the disorders listed above. The dose may be administered once, twice, three, four, five, six, or seven times per week in accordance with the compositions and methods disclosed herein. The dose may be administered every day, every other day, or two to three times a week in accordance with the compositions and methods disclosed herein.
[0028] In some embodiments, the lipid in the pharmaceutical composition is a phospholipid. In some embodiments, the second lipid is a lysophospholipid. In some embodiments, the surfactant is a non-ionic surfactant.
[0029] In some embodiments, the compositions form vesicles or other extended surface aggregates (ESAs), wherein the vesicular preparations have improved permeation capability through the semi-permeable barriers, such as skin. The adapatability and deformability of the vesicles allow the vesicles to penetrate beneath the skin to the muscle and the joint itself, however, the size of the vesicle prevents penetration into the vasculature and as a result prevents systemic delivery. While not to be limited to any mechanism of action, the formulations are able to form vesicles characterized by their deformability and/or
adaptability. The adaptability or deformability of the vesicles may be determined by the ability of the vesicles to penetrate a barrier with pores having an average pore diameter at least 50% smaller than the average vesicle diameter before the penetration.
[0030] In some embodiments, the vesicular compositions provide for targeted delivery of e.g., fatty acids to phospholipase-rich sites, e.g., tissues that are part of an inflammatory process or sites containing microorganisms such as bacteria (including narcadia) or fungi. While not to be limited to any mechanism of action or by any theory, the vesicular compositions disclosed herein are broken down by phospholipases. Thus, phospholipases that are released as part of the inflammatory process {e.g., cancer or asthma) or that are released upon contact with a microorganism such as bacteria or fungi can lead to a number of effects including but not limited to rapid entry of the vesicular compositions into the target tissue, changes in the intracellular or intramembraneous lipid homeostasis, which may lead to increased apoptosis or altered membrance function, including increased permeability, and rapid metabolism of the vesicular composition with release of its consituents.
[0031] In one aspect, provided is a method that includes administering a formulation as described herein to a plant, seed or soil. In certain embodiments, the formulation is effective as one or more selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide,
rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist. In some embodiments, the formulation includes an active agent that is selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and synergist. In certain embodiments, the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
[0032] In certain related aspects, provided is a method for controlling weeds, pests, insects, diseases in or on a plant, a field of plants or a crop that includes administering a formulation as described herein to the plant, field of plants or crop.
[0033] In certain embodiments, provided herein is a method of administering a vesicular formulation directly to the surface of a leaf. In certain embodiments, the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the surface of a leaf results in an antifungal effect.
[0034] In other embodiments, provided herein is a method of administering a vesicular formulation directly to the ground surrounding certain plants or weeds. In certain
embodiments, the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes terbinafme or an agriculturally acceptable salt thereof. In a particular embodiment, administration of the formulation directly to the ground surrounding certain plants or weeds results in an antifungal effect at the plants or weeds.
[0035] In other embodiments, provided herein is a method of exposing an insect to a vesicular formulation by applying the vesicular formulation to a plant or plant leaf. In certain embodiments, the vesicular formulation is absorbed by the leaf and introduced into the insect upon ingestion of the leaf by the insect. In certain embodiments, the formulation includes
one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9. In a particular embodiment, the formulation includes one or more insecticides.
[0036] As used herein, the term "plant" refers to a plant as well as any part of a plant or plant product, including but not limited to, plant tissue, a leaf, a leaf primordial, a stem, a flower, a fruit, a root, a root hair, a protoplast, a germ plasm, a stamen, an anther, a filament, a petal, a pistel, a bud, a node, an internode, a shoot, a shoot apex, an apical meristem, a seed, a trunk, and the like. In certain embodiments, the term "plant" also includes multiple plants, for example a field of plants or a crop.
[0037] In various embodiments, plants as disclosed herein can be of any species of dicotyledonous, monocotyledonous or gymnospermous plant, including any woody plant species that grows as a tree or shrub, any herbaceous species, or any species that produces edible fruits, seeds or vegetables, or any species that produces colorful or aromatic flowers. For example, the plant may be selected from a species of plant from the group consisting of Alfalfa; Almond; Anise (fennel); Anona; Apple; Apricot; Aquatic Weeds; Artichoke;
Asparagus; Aster; Aubergin; Avocado; Azalea; Banana; Barley; Beans; Beet; Begonia; Bell Pepper; Bermuda ; Grass; Berries; Blackberry; Blackcurrent; Blueberry; Brassica; Broccoli; Brussel; Cabbage; Cacao; Caneberries; Canola; Cantaloup; Carnation; Carrot; Cassava;
Cauliflower; Celery; Cereals; Cherry; Chickpea; Chicory; Chili; Christmas trees;
Chrysanthemum; Citrus; Clover; Cocoa; Coconut; Coffee; Cole crops; Collard; Conifers; Corn (maize); Cotton; Cotton desiccant; Cranberry; Crucifers; Cucumber; Cucurbits; Currant; Dahlia; Dates; Deciduous fruits; Dewberry; Durum; Eggplant; Elderbery; Eucalyptus; Fallow crops; Feijoya; Field crops; Figs; Flex; Flower bulbs; Flowers; Fodder ; Peas; Fodderbeet; Forage ; Crops; Forestry; French ; Beans; Fruits; Garlic; Gladiolus; Gooseberry; Grain;
Grapefruits; Grapes (vine); Grass seed crops; Grasses; Guava; Herbs; Hop; Horseradish; Iris; Kidney Beans; Kiwi; Lawn; Leek; Legumes; Lemons; Lentil; Lettuce; Lilium; Lingonbery; Linseed; Linseed; Loquat; Lucerne; Lupins; Lychee; Macadamia Nuts; Mangel; Mango; Marigold; Marrow; Melon; Millet; Mint; Mushrooms; Mustard; Narcissus; Nectarine; Non Agricultural Land; Non Crop; Nursery; Nut; Oats; Oil palm; Oilseed rape; Okra; Olive;
Onion; Oranges; Orchids; Ornamental; Papaya; Paprika; Parsley; Parsnip; Passion Fruit; Pasture; Peach; Peanut; Pear; Peas; Pecan; Pepper; Persimmon; Phlox; Pine seed; Pineapple; Pistachio; Plum; Poinsettia; Pome Fruit; Pomegranate; Poplar; Poppy seeds; Post Harvest; Potato; Potato desiccant; Prune; Public Health; Pumpkin; Quince; Radish; Rape Seed;
Raspberry; Rice; Rose; Rubber; Rye; Safflower; Seed Treatment; Seed treatment maize; Seed treatment sugar beet; Sesame; Shallot; Sorghum; Soybean; Spices; Spinach; Sprouts; Squash; Stone Fruit; Strawberry; Subtropical & tropical fruits; Sugarbeet; Sugarcane; Sunflower; Sweet Potato; Tea; Timber preservation; Tobacco; Tomato; Triticale; TulipTurf; Vegetables; Vetch; Veterinary; Walnut; Watercress; Watermelon; Wheat; Zinnia; Zucchini; and nut producing plants insofar as they are not already specifically mentioned.
4. DETAILED DESCRIPTION OF THE INVENTION
[0038] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0039] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human), cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In certain embodiments, the term subject can refer to a plant, seed or soil.
[0040] As used herein, a "sufficient amount," "amount effective to" or an "amount sufficient to" achieve a particular result refers to an amount of the formulation disclosed herein is effective to produce a desired effect, which is optionally a therapeutic effect (i.e., by administration of a therapeutically effective amount). Alternatively stated, a "therapeutically effective" amount is an amount that provides some alleviation, mitigation, and/or decrease in at least one clinical symptom. Clinical symptoms associated with the disorder that can be treated by the methods disclosed herein are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject. For example, a "sufficient amount" or "an amount sufficient to" can be an amount that is effective to treat the symptoms of fatty acid deficiencies, hypertriglyceridemia or hypercholesterolemia or other joint or muscle pain.
[0041] As used herein, the terms "treat", "treating" or "treatment of mean that the severity of a subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is
achieved and/or there is an inhibition or delay in the progression of the condition and/or delay in the progression of the onset of disease or illness. The terms "treat", "treating" or
"treatment of also means managing the disease state.
[0042] As used herein, the term "pharmaceutically acceptable" when used in reference to the formulations disclosed herein denotes that a formulation does not result in an
unacceptable level of irritation in the subject to whom the formulation is administered.
Preferably such level will be sufficiently low to provide a formulation suitable for approval by regulatory authorities.
[0043] As used herein with respect to numerical values, the term "about" means a range surrounding a particular numeral value which includes that which would be expected to result from normal experimental error in making a measurement. For example, in certain embodiments, the term "about" when used in connection with a particular numerical value means ±20%, unless specifically stated to be ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, or ±20% of the numerical value. Moreover, where "about" is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus percentage, the exact value of the quantitative term is also contemplated and described. For example, the term "about 3%" expressly contemplates, describes and includes exactly 3%.
[0044] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl may optionally be substituted with one or more substituents Q as described herein. The term "alkyl" also encompasses both linear and branched alkyl, unless otherwise specified. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 12 (C1-12), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or a branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear Ci_6 and branched C3_6 alkyl groups are also referred as "lower alkyl."
Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). For example, Ci_6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. It is understood in the chemical arts, that the use of the longer chains described herein may be appropriate, or appropriate only in limited amounts, within a molecule so that the properties of the resulting molecule (such as solubility) are appropriate
for the use. Thus, while those in the art may use the above longer length alkyl substituents they will be used only when appropriate to provide the desired function.
[0045] The term "aryl" refers to a monocyclic aromatic group and/or multicyclic monovalent aromatic group that contain at least one aromatic hydrocarbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-2o), from 6 to 15 (C6-15), or from 6 to 10 (C6-io) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may also be optionally substituted with one or more substituents Q as described herein.
[0046] The term "heteroaryl" refers to a monocyclic aromatic group and/or multicyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, and N. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. The heteroaryl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
Examples of monocyclic heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzothiazolyl,
benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, isobenzofuranyl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, dihydroisoindolyl, and tetrahydroquinolinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, carbazolyl, benzindolyl, phenanthrollinyl, acridinyl, phenanthridinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted with one or more substituents Z as described herein.
[0047] The term "alkenoyl" as used herein refers to -C(0)-alkenyl. The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one to five, carbon-carbon double bonds. The alkenyl may be optionally substituted with one or more substituents Z as described herein. The term "alkenyl" also
embraces radicals having "cis" and "trans" configurations, or alternatively, "Z" and "E" configurations, as appreciated by those of ordinary skill in the art. As used herein, the term "alkenyl" encompasses both linear and branched alkenyl, unless otherwise specified. For example, C2_6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 30 (C2_3o), 2 to 24 (C2_24), 2 to 20 (C2_20), 2 to 15 (C2_i5), 2 to 12 (C2-12), to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 30 (C3_3o), 3 to 24 (C3_24), 3 to 20 (C3_2o), 3 to 15 (C3_15), 3 to 12 (C3_12), 3 to 10 (C3_10), or 3 to 6 (C3_6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1- yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl. In certain embodiments, the alkenoyl is mono-alkenoyl, which contains one carbon-carbon double bond. In certain embodiments, the alkenoyl is di-alkenoyl, which contains two carbon-carbon double bonds. In certain embodiments, the alkenoyl is poly-alkenoyl, which contains more than two carbon-carbon double bonds.
[0048] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and/or multicyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, or N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged ring system, and in which the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclic radicals include, but are not limited to, acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzoisoxazolyl, benzisoxazinyl, benzodioxanyl, benzodioxolyl,
benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzothiopyranyl, benzoxazinyl, benzoxazolyl,
benzothiazolyl, β-carbolinyl, carbazolyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl,
dihydrofuryl, dihydropyranyl, dioxolanyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrazolyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1 ,4-dithianyl, furanonyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, imidazopyridinyl, imidazothiazolyl, indazolyl, indolinyl, indolizinyl, indolyl, isobenzotetrahydrofuranyl,
isobenzotetrahydrothienyl, isobenzothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroindolyl, octahydroisoindolyl, oxadiazolyl, oxazolidinonyl, oxazolidinyl, oxazolopyridinyl, oxazolyl, oxiranyl, perimidinyl,
phenanthridinyl, phenathrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pteridinyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, tetrazolyl, thiadiazolopyrimidinyl, thiadiazolyl, thiamorpholinyl, thiazolidinyl, thiazolyl, thienyl, triazinyl, triazolyl, and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also be optionally substituted with one or more substituents Z as described herein.
[0049] The term "halogen", "halide" or "halo" refers to fluorine, chlorine, bromine, and/or iodine.
[0050] The term "optionally substituted" is intended to mean that a group, including alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl, may be substituted with one or more substituents Z, in one embodiment, one, two, three or four substituents Z, where each Z is independently selected from the group consisting of cyano, halo, oxo, nitro, Ci_6 alkyl, halo-Ci_6 alkyl, C2-6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-14 aralkyl, heteroaryl, heterocyclyl, -C(0)Re, -C(0)ORe, -C(0)NRfRg, - C(NRe)NRfRg, -ORe, -OC(0)Re, -OC(0)ORe, -OC(0)NRfRg, -OC(=NRe)NRfRg, - OS(0)Re, -OS(0)2Re, -OS(0)NRfRg, -OS(0)2NRfRg, -NRfRg, -NReC(0)Rf, -NReC(0)ORf, -NReC(0)NRfRg, -NReC(=NRh)NRfRg, -NReS(0)Rf, -NReS(0)2Rf, -NReS(0)NRfRg, - NReS(0)2NRfRg, -SRe, -S(0)Re, -S(0)2Re, and -S(0)2NRfRg, wherein each Re, Rf, Rg, and Rh is independently hydrogen, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C6-14 aryl, C7_i4 aralkyl, heteroaryl, or heterocyclyl; or Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0051] The term "solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of solvent bound by non- covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.
[0052] In accordance with this disclosure, the term "comprising" is inclusive or open- ended and does not exclude additional, unrecited elements or method steps; the term
"consiting of excludes any element, step, or ingredient not specified; and the term
"consisting essentially of excludes any element, step, or ingredient that materially changes a basic characteristic of the invention.
[0053] In some embodiments, the formulation provided herein includes at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, optionally suspended in a pharmaceutically acceptable medium, preferably an aqueous solution, preferably having a pH ranging from 3.5 to 9.0, preferably from 4 to 7.5. The formulations disclosed herein may optionally contain buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners. In some embodiments, the formulations disclosed herein include a mixture of more than one lipid, preferably more than one phospholipids. In some embodiments, the formulations disclosed herein consists essentially of at least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers,
antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners. In some embodiments, the formulations disclosed herein include least one lipid, preferably a phospholipid, at least one surfactant, preferably a nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
4.1. LIPID
[0054] In the sense of this disclosure, a "lipid" is any substance, which has properties like or similar to those of a fat. As a rule, it has an extended apolar group (the "chain", X) and generally also a water-soluble, polar hydrophilic part, the "head" group (Y) and has the basic Formula II:
wherein n is equal to or larger than zero.
[0055] Lipids with n=0 are referred to as apolar lipids and lipids with n>l are referred to as polar lipids. In this sense, all amphiphilic substances, including, but not limited to glycerides, glycerophospholipids, glycerophosphinolipids, glycerophosphonolipids, sulfolipids, sphingolipids, isoprenoid lipids, steroids or sterols and carbohydrate-containing lipids can generally be referred to as lipids, and are included as such in this disclosure. A list of relevant lipids and lipid related definitions is provided in EP 0 475 160 Al (see, e.g. p. 4, 1.
8 to p. 6, 1. 3) and U.S. Patent No. 6,165,500 (see, e.g., col. 6, 1. 10 to col. 7, 1. 58), each incorporated herein by reference in their entirety.
[0056] A phospholipid is, for example, a compound of Formula II:
R1— CH2— CHR2— CR3H— O— PH02— O— R4 (II) wherein R 1 and R 2 cannot both be hydrogen, OH or a C1-C3 alkyl group, and typically are independently, an aliphatic chain, most often derived from a fatty acid or a fatty alcohol; R generally is a hydrogen.
[0057] The OH-group of the phosphate is a hydroxyl radical or hydroxyl anion (i.e., hydroxide) form, dependent on degree of the group ionization. Furthermore, R4 may be a proton or a short-chain alkyl group, substituted by a tri-short-chain alkylammonium group, such as a trimethylammonium group, or an amino-substituted short-chain alkyl group, such as 2-trimethylammonium ethyl group (cholinyl) or 2-dimethylammonium short alkyl group.
[0058] A sphingophospho lipid is, for example, a compound of Formula IIB:
R1— Sphingosine— O— PH02— O— R4 (IIB)
wherein R1 is a fatty-acid attached via an amide bond to the nitrogen of the sphingosine and R4 has the meanings given under Formula II.
1 2
[0059] A lipid preferably is a substance of formulae II or IIB, wherein R and/or R are acyl or alkyl, n-hydroxyacyl or n-hydroxyalkyl, but may also be branched, with one or more methyl groups attached at almost any point of the chain; usually, the methyl group is near the
1 2
end of the chain (iso or anteiso). The radicals R and R may moreover either be saturated or unsaturated (mono-, di- or poly-unsaturated). R3 is hydrogen and R4 is 2-trimethylammonium ethyl (the latter corresponds to the phosphatidyl choline head group), 2-dimethylammonium ethyl, 2-methylammonium ethyl or 2-aminoethyl (corresponding to the phosphatidyl ethanolamine head group). R4 may also be a proton (giving phosphatidic acid), a serine (giving phosphatidylserine), a glycerol (giving phosphatidylglycerol), an inositol (giving phosphatidylinositol), or an alkylamine group (giving phosphatidylethanolamine in case of an ethylamine), if one chooses to use a naturally occurring glycerophospholipid. Otherwise, any other sufficiently polar phosphate ester, such that will form a lipid bilayer, may be considered as well for making the formulations of the disclosure.
Table 1 lists preferred phospholipids in accordance with the disclosure.
Table 1
Preferred (phospho)lipids
Rel. concentration range L1/L2 (M/M) 1/0 1/0 10/1-1/1 10/1-3/1 10/1-5/1
"Total Lipid"* concentration range (w-%) 0.5-45 0.5-45 0.5-40 0.5-40 0.5-40
*Total Lipid includes phospholipid (s), surfactant (s)t and all lipophilic excipients
[0060] The preferred lipids in context of this disclosure are uncharged and form stable, well hydrated bilayers; phosphatidylcholines, phosphatidylethanolamine, and sphingomyelins are the most prominent representatives of such lipids. Any of those can have chains as listed in the Table 1, the ones forming fluid phase bilayers, in which lipid chains are in disordered state, being preferred.
[0061] Different negatively charged, i.e., anionic, lipids can also be incorporated into vesicular lipid bilayers. Attractive examples of such charged lipids are phosphatidylglycerols, phosphatidylinositols and, somewhat less preferred, phosphatidic acid (and its alkyl ester) or phosphatidylserine. It will be realized by anyone skilled in the art that it is less commendable to make vesicles just from the charged lipids than to use them in a combination with electro- neutral bilayer component(s). In case of using charged lipids, buffer composition and/or pH care must selected so as to ensure the desired degree of lipid head-group ionization and/or the desired degree of electrostatic interaction between the, oppositely, charged drug and lipid molecules. Moreover, as with neutral lipids, the charged bilayer lipid components can in principle have any of the chains listed in the Table 1. The chains forming fluid phase lipid bilayers are clearly preferred, however, both due to vesicle adaptability increasing role of increasing fatty chain fluidity and due to better ability of lipids in fluid phase to mix with each other.
[0062] The fatty acid- or fatty alcohol-derived chain of a lipid is typically selected amongst the basic aliphatic chain types given in the following tables:
Table 2: The (most) preferred basic, straight, saturated fatty chain residues
Shorthand designation Systematic name Trivial name
12:0 Dodecanoic Laurie
13:0 Tridecanoic
14:0 Tetradecanoic Myristic
15:0 Pentadecanoic
16:0 Hexadecanoic Palmitic
17:0 Heptadecanoic Margaric
18:0 Octadecanoic Stearic
19:0 Nonadecanoic
20:0 Eicosanoic Arachidic
21 :0 Heneicosanoic
22:0 Docosanoic Behenic
23:0 Tricosanoic
24:0 Tetracosanoic Ligno eerie
Table 3: The (most) preferred monoenoic fatty chain residues
Shorthand designation Systematic name Trivial name
9-14:1 / 14:l(n-5) cis-9-Tetradecenoic Myristoleic
7-16:1 / 16:l(n-9) cis-7-Hexadecenoic
9-16:1 / 16:l(n-7) cis-9-Hexadecenoic Palmitoleic
9-18:1 / 18:l(n-9) cis-9-Octadecenoic Oleic
11-18:1 / 18:l(n-7) cis-11-Octadecenoic cis-Vaccenic
11-20:1 / 20:1 (n-9) cis-ll-Eicosenoic Gondoic
14-20:1 /20:l(n-6) cis- 14-Eico saenoic
13-22:1 /22:l(n-9) cis-13-Docosenoic Erucic
15-24:1 / 24:1 (n-9) cis-15-Tetracosenoic Nervoni
3t-18:l trans-3 -Hexadecenoi
9t-18:l trans-9-Octadecenoic Elaidic
llt-18:l trans- 11-Octadecenoic Vaccenic
Table 4: The (most) preferred dienoic and polyenoic fatty chain residues
Shorthand designation Systematic name Trivial name
10,13c-16:2/ 16:2(n-3) 10-cis,13-cis-Hexadecadienoic
7,10c-16:2/ 16:3(n-6) 7-cis,10-cis -Hexadecadienoic
7,10,13c-16:3/16:3(n-3) 7- cis,10-cis,13-cis-Hexadecatrienoic
12,15c-18:2/ 18:2(n-3) 12-cis, 15-cis-Octadecadienoic a-Linoleic
10,12t-18:2/ 18:2(n-6) trans- 10,trans- 12-Octadecadienoic
9,12c-18:2/ 18:2(n-6) 9-cis,12-cis-Octadecadienoic γ-Linoleic
9,12,15c-18:3/18:3(n-3) 9-cis, 12-cis, 15-cis-Octadecatrienoic a-Linolenic
6,9,12c-18:3/18:3(n-6) 6-cis,9-cis,12-cis-Octadecatrienoic γ-Linolenic
9c,llc,13t-18:3 9-cis, 11 -trans, 13 -trans-Octadecatrienoic a-Eleostearic
8t,10t,12c-18:3 8- trans, 10-trans, 12-cis-Octadecatrienoic Calendic
6,9,12,15c-18:4/ 18:4(n-3) 6,9, 12, 15-Octadecatetraenoic Stearidonic
3,6,9,12c-18:4/ 18:4(n-6) 3,6,9, 12-Octadecatetraenoic
3,6,9,12,15c-18:5/18:5(n-3) 3,6,9, 12, 15-Octadecapentaenoic
14,17c-20:2/20:2(n-3) 14-cis,17-cis-Eicosadienoic
ll,14c-20:2/20:2(n-6) 1 l-cis,14-cis-Eicosadienoic
ll,14,17c-20:3 /20:3(n-3) 8-cis, 11 -cis, 14-cis-Eicosatrienoic Dihomo-a-linolenic 8,ll,14c-20:3 /20:3(n-6) 8-cis, 11 -cis, 14-cis-Eicosatrienoic Dihomo-y-linolenic 5,8,llc-20:320:3(n-9) 5,8,11 all-cis-Eicosatrienoic 'Mead's'
5,8,1 l,14c-20:4/20:4(n-6) 5,8, 11 ; 14-all-cis-Eicosatetraenoic Arachidonic
8,ll,14,17c-20:4/20:4(n-3) 8,11,14,17-all-cis-Eicosatetraenoic
5,8,11, 14,17c-20:5 5,8, 11 , 14, 17-all-cis-Eicosapentaenoic
or 20:5(n-3)
13,16c-22:2 13,16-Docosadienoic
13,16,19c-22:3 /22:3(n-3) 13,16,19-Docosatrienoic
10,13, 16c-22:3 /22:3(n-6) 10,13,16-Docosatrienoic
7,10,13,16c-22:4/22:4(n-6) 7, 10, 13 , 16-Docosatetraenoic Adrenic
4,7,10,13,16c-22:5 4,7, 10,13,16-Docosapentaenoic
or 22:5(n-6)
4,7,10,13, 16,19c-22:5 4,7,10,13,16,19-Docosahexaenoic
or 22:6(n-3)
[0063] Other double bond combinations or positions are possible as well.
[0064] Suitable fatty residues can furthermore be branched, for example, can contain a methyl group in an iso or anteiso position of the fatty acid chain, or else closer to the chain middle, as in 10-i?-methyloctadecanoic acid or tuberculostearic chain. Relatively important amongst branched fatty acids are also isoprenoids, many of which are derived from
3,7,1 l,15-tetramethylhexadec-trans-2-en-l-ol, the aliphatic alcohol moiety of chlorophyll. Examples include 5,9,13,17-tetramethyloctadecanoic acid and especially 3,7,11,15- tetramethylhexadecanoic (phytanic) and 2,6,10,14-tetramethylpentadecanoic (pristanic) acids. A good source of 4,8,12-trimethyltridecanoic acid are marine organisms. Combination of double bonds and side chains on a fatty residue are also possible.
[0065] Alternatively, suitable fatty residues may carry one or a few oxy- or cyclic groups, especially in the middle or towards the end of a chain. The most prominent amongst the later, alicyclic fatty acids, are those that include a cyclopropane (and sometimes
cyclopropene) ring, but cyclohexyl and cycloheptyl rings can also be found and might be useful for purposes of this disclosure. 2-(D)-Hydroxy fatty acids are more ubiquitous than alicyclic fatty acids, and are also important constituents of sphingolipids. Also interesting are 15-hydroxy-hexadecanoic and 17-hydroxy-octadecanoic acids, and maybe 9-hydroxy- octadeca-tra/?s-10,tra/?s-12-dienoic (dimorphecolic) and 13-hydroxy-octadeca-czs-9,zra/?s-l 1- dienoic (coriolic) acid. Arguably the most prominent hydroxyl-fatty acid in current pharmaceutical use is ricinoleic acid, (D-(-)12-hydroxy-octadec-cz's-9-enoic acid, which includes up to 90% of castor oil, which is also often used in hydrogenated form. Epoxy-, methoxy-, and furanoid-fatty acids are of only limited practical interest in the context of this disclosure.
[0066] Generally speaking, unsaturation, branching or any other kind of derivatization of a fatty acid is best compatible with the intention of present disclosure of the site of such modification is in the middle or terminal part of a fatty acid chain. The cz's -unsaturated fatty acids are also more preferable than trans -unsaturated fatty acids and the fatty radicals with fewer double bonds are preferred over those with multiple double bonds, due to oxidation sensitivity of the latter. Moreover, symmetric chain lipids are generally better suited than asymmetric chain lipids.
[0067] A preferred lipid of the Formula II is, for example, a natural phosphatidylcholine, which used to be called lecithin. It can be obtained from egg (rich in palmitic, Ci6:o, and oleic, Ci8:i, but also including stearic,Ci8:o, palmitoleic, Ci6:i, linolenic, C18:2, and
arachidonic, C2o:4, radicals), soybean (rich in unsaturated Cig chains, but also containing some palmitic radical, amongst a few others), coconut (rich in saturated chains), olives (rich in monounsaturated chains), saffron (safflower) and sunflowers (rich in n-6 linoleic acid), linseed (rich in n-3 linolenic acid), from whale fat (rich in monounsaturated n-3 chains), from primrose or primula (rich in n-3 chains). Preferred, natural phosphatidyl ethanolamines (used
to be called cephalins) frequently originate from egg or soybeans. Preferred sphingomyelins of biological origin are typically prepared from eggs or brain tissue. Preferred
phosphatidylserines also typically originate from brain material whereas phosphatidylglycerol is preferentially extracted from bacteria, such as E. Coli, or else prepared by way of transphosphatidylation, using phospholipase D, starting with a natural phosphatidylcholine. The preferably used phosphatidylinositols are isolated from commercial soybean
phospholipids or bovine liver extracts. The preferred phosphatidic acid is either extracted from any of the mentioned sources or prepared using phospholipase D from a suitable phosphatidylcholine.
[0068] Furthermore, synthetic phosphatidyl cholines (R4 in Formula II corresponds to 2-
1 2
trimethylammonium ethyl), and R and R are aliphatic chains, as defined in the preceding paragraph with 12 to 30 carbon atoms, preferentially with 14 to 22 carbon atoms, and even more preferred with 16 to 20 carbon atoms, under the proviso that the chains must be chosen so as to ensure that the resulting ESAs include fluid lipid bilayers. This typically means use of relatively short saturated and of relatively longer unsaturated chains. Synthetic
sphingomyelins (R4 in Formula IIB corresponds to 2-trimethylammonium ethyl), and R1 is an aliphatic chain, as defined in the preceding paragraph, with 10 to 20 carbon atoms, preferentially with 10 to 14 carbon atoms per fully saturated chain and with 16-20 carbon atoms per unsaturated chain.
[0069] Synthetic phosphatidyl ethanolamines (R4 is 2-aminoethyl), synthetic phosphatidic acids (R4 is a proton) or its ester (R4 corresponds, for example, to a short-chain alkyl, such as methyl or ethyl), synthetic phosphatidyl serines (R4 is L- or D-serine), or synthetic
phosphatidyl (poly)alcohols, such as phosphatidyl inositol, phosphatidyl glycerol (R4 is L- or
1 2
D-glycerol) are preferred as lipids, wherein R and R are fatty residues of identical or moderately different type and length, especially such as given in the corresponding tables given before in the text. Moreover, R 1 can represent alkenyl and R 2 identical hydroxyalkyl groups, such as tetradecylhydroxy or hexadecylhydroxy, for example, in ditetradecyl or
1 2 dihexadecylphosphatidyl choline or ethanolamine, R can represent alkenyl and R
hydroxyacyl, such as a plasmalogen (R4 trimethylammonium ethyl), or R1 can be acyl, such as lauryl, myristoyl or palmitoyl and R can represent hydroxy as, for example, in natural or synthetic lysophosphatidyl cholines or lysophosphatidyl glycerols or lysophosphatidyl ethanolamines, such as 1 -myristoyl or 1-palmitoyllysophosphatidyl choline or -phosphatidyl ethanolamine; frequently, R represents hydrogen.
[0070] A lipid of Formula IIB is also a suitable lipid within the sense of this disclosure. In Formula IIB, n=l, R1 is an alkenyl group, R2 is an acylamido group, R3 is hydrogen and R4 represents 2-trimethylammonium ethyl (choline group). Such a lipid is known under the name of sphingomyelin.
[0071] Suitable lipids furthermore are a lysophosphatidyl choline analog, such as 1- lauroyl-l,3-dihydroxypropane-3-phosphoryl choline, a monoglyceride, such as monoolein or monomyristin, a cerebroside, ceramide polyhexoside, sulfatide, sphingoplasmalogen, a ganglioside or a glyceride, which does not contain a free or esterified phosphoryl or phosphono or phosphino group in the 3 position. An example of such a glyceride is diacylglyceride or 1 -alkenyl- l-hydroxy-2-acyl glyceride with any acyl or alkenyl groups, wherein the 3 -hydroxy group is etherified by one of the carbohydrate groups named, for example, by a galactosyl group such as a monogalactosyl glycerin.
[0072] Lipids with desirable head or chain group properties can also be formed by biochemical means, for example, by means of phospholipases (such as phospholilpase Al, A2, B, C and, in particular, D), desaturases, elongases, acyl transferases, etc., from natural or synthetic precursors.
[0073] Furthermore, a suitable lipid is any lipid, which is contained in biological membranes and can be extracted with the help of apolar organic solvents, such as chloroform. Aside from the lipids already mentioned, such lipids also include, for example, steroids, such as estradiol, or sterols, such as cholesterol, beta-sitosterol, desmosterol, 7-keto-cholesterol or beta-cholestanol, fat-soluble vitamins, such as retinoids, vitamins, such as vitamin Al or A2, vitamin E, vitamin K, such as vitamin Kl or K2 or vitamin Dl or D3, etc.
[0074] The less soluble amphiphilic components include or preferably include a synthetic lipid, such as myristoleoyl, palmitoleoyl, petroselinyl, petroselaidyl, oleoyl, elaidyl, cis- or trans-vaccenoyl, linolyl, linolenyl, linolaidyl, octadecatetraenoyl, gondoyl, eicosaenoyl, eicosadienoyl, eicosatrienoyl, arachidoyl, cis- or trans-docosaenoyl, docosadienoyl, docosatrienoyl, docosatetraenoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, heptadecanoyl, stearoyl or nonadecanoyl, glycerophospholipid or corresponding derivatives with branched chains or a corresponding dialkyl or sphingosin derivative, glycolipid or other diacyl or dialkyl lipid.
[0075] The more soluble amphiphilic components(s) is/are frequently derived from the less soluble components listed above and, to increase the solubility, substituted and/or
complexed and/or associated with a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl or undecanoyl substituent or several, mutually independent, selected substituents or with a different material for improving the solubility.
[0076] A further suitable lipid is a diacyl- or dialkyl-glycerophosphoetha- nolamine azo polyethoxylene derivative, a didecanoylphosphatidyl choline or a
diacylphosphoolligomaltobionamide.
[0077] In certain embodiments, the amount of lipid in the formulation is from about 1% to about 12%, about 1% to about 10%>, about 1% to about 4%, about 4% to about 7% or about 7%) to about 10%) by weight. In a specific embodiment, the lipid is a phospholipid. In another specific embodiment, the phospholipid is a phosphatidylcholine.
[0078] In some embodiments, the lipid in the formulation does not include an alkyl- lysophospholipid. In some embodiments, the lipid in the formulation does not include a polyeneylphosphatidylcholine .
4.2. SURFACTANT
[0079] The term "surfactant" has its usual meaning. A list of relevant surfactants and surfactant related definitions is provided in EP 0 475 160 Al (see, e.g., p. 6, 1. 5 to p.14. 1.17)and U.S. Pat. No. 6,165,500 (see, e.g., col. 7, 1. 60 to col. 19, 1. 64), each herein incorporated by reference in their entirety, and in appropriate surfactant or pharmaceutical Handbooks, such as Handbook of Industrial Surfactants or US Pharmacopoeia, Pharm. Eu. In some embodiments, the surfactants are those described in Tables 1-18 of U.S. Patent Application Publication No. 2002/0012680 Al, published January 31, 2002, the disclosure of which is herein incorporated by reference in its entirety. The following list therefore only offers a selection, which is by no means complete or exclusive, of several surfactant classes that are particularly common or useful in conjunction with present patent application.
Preferred surfactants to be used in accordance with the disclosure include those with an HLB greater than 12. The list includes ionized long-chain fatty acids or long chain fatty alcohols, long chain fatty ammonium salts, such as alkyl- or alkenoyl-trimethyl-, -dimethyl- and - methyl-ammonium salts, alkyl- or alkenoyl-sulphate salts, long fatty chain dimethyl- aminoxides, such as alkyl- or alkenoyl-dimethyl-aminoxides, long fatty chain, for example alkanoyl, dimethyl-aminoxides and especially dodecyl dimethyl-aminoxide, long fatty chain, for example alkyl-N-methylglucamide- s and alkanoyl-N-methylglucamides, such as MEGA- 8, MEGA-9 and MEGA- 10, N-long fatty chain-N,N-dimethylglycines, for example N-alkyl- Ν,Ν-dimethylglycines, 3-(long fatty chain-dimethylammonio)-alkane- sulphonates, for
example 3-(acyidimethylammonio)-alkanesulphonates, long fatty chain derivatives of sulphosuccinate salts, such as bis(2-ethylalkyl) sulphosuccinate salts, long fatty chain- sulphobetaines, for example acyl-sulphobetaines, long fatty chain betaines, such as
EMPIGEN BB or ZWITTERGENT-3-16, -3-14, -3-12, -3-10, or -3-8, or polyethylen-glycol- acylphenyl ethers, especially nonaethylen-glycol-octyl- phenyl ether, polyethylene-long fatty chain-ethers, especially polyethylene-acyl ethers, such as nonaethylen-decyl ether, nonaethylen-dodecyl ether or octaethylene-dodecyl ether, polyethyleneglycol-isoacyl ethers, such as octaethyleneglycol-isotridecyl ether, polyethyleneglycol-sorbitane-long fatty chain esters, for example polyethyleneglycol-sorbitane-acyl esters and especially polyoxyethylene- monolaurate (e.g. polysorbate 20 or Tween 20), polyoxyethylene-sorbitan-monooleate (e.g. polysorbate 80 or Tween 80), polyoxyethylene-sorbitan-monolauroleylate, polyoxyethylene - sorbitan-monopetroselinate, polyoxyethylene -sorbitan— monoelaidate, polyoxyethylene - sorbitan-myristoleylate, polyoxyethylene -sorbitan-palmitoleinylate, polyoxyethylene- sorbitan-p- etroselinylate, polyhydroxyethylene-long fatty chain ethers, for example polyhydroxyethylene-acyl ethers, such as polyhydroxyethylene-lauryl ethers,
polyhydroxyethylene-myristoyl ethers, polyhydroxyethylene-cetylst- earyl, polyhyd roxyethylene-palmityl ethers, polyhyd roxyethylene-oleoyl ethers, polyhydroxyethylene- palmitoleoyl ethers, polyhydroxyethylene-lino- leyl, polyhydroxyethylen-4, or 6, or 8, or 10, or 12-lauryl, miristoyl, palmitoyl, palmitoleyl, oleoyl or linoeyl ethers (Brij series), or in the corresponding esters, polyhydroxyethylen-laurate, -myristate, -palmitate, -stearate or -oleate, especially polyhydroxyethylen-8 -stearate (Myrj 45) and polyhydroxyethylen-8-oleate, polyethoxylated castor oil 40 (Cremophor EL), sorbitane-mono long fatty chain, for example alkylate (Arlacel or Span series), especially as sorbitane-monolaurate (Arlacel 20, Span 20), long fatty chain, for example acyl-N-methylglucamides, alkanoyl-N-methylglucamides, especially decanoyl-N-methylglucamide, dodecanoyl-N-methylglucamide, long fatty chain sulphates, for example alkyl-sulphates, alkyl sulphate salts, such as lauryl-sulphate (SDS), oleoyl-sulphate; long fatty chain thioglucosides, such as alkylthioglucosides and especially heptyl-, octyl- and nonyl-beta-D-thioglucopyranoside; long fatty chain derivatives of various carbohydrates, such as pentoses, hexoses and disaccharides, especially alkyl-glucosides and maltosides, such as hexyl-, heptyl-, octyl-, nonyl- and decyl-beta-D-glucopyranoside or D- maltopyranoside; further a salt, especially a sodium salt, of cholate, deoxycholate, glycocholate, glycodeoxycholate, taurodeoxycholate, taurocholate, a fatty acid salt, especially oleate, elaidate, linoleate, laurate, or myristate, most often in sodium form,
lysophospholipids, n-octadecylene-glycerophosphatidic acid, octadecylene-
phosphorylglycerol, octadecylene-phosphorylserine, n-long fatty chain-glycero-phosphatidic acids, such as n-acyl-glycero-phosphatidic acids, especially lauryl glycero-phosphatidic acids, oleoyl-glycero-phosphatidic acid, n-long fatty chain-phosphorylglycerol, such as n- acyl-phosphorylglycerol, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl- phosphorylglycerol, n-long fatty chain-phosphorylserine, such as n-acyl-phosphorylserine, especially lauryl-, myristoyl-, oleoyl- or palmitoeloyl-phosphorylserine, n-tetradecyl-glycero- phosphatidic acid, n-tetradecyl-phosphorylglycerol, n-tetradecyl-phosphorylserine, corresponding-, elaidoyl-, vaccenyl-lysophospholipids, corresponding short-chain
phospholipids, as well as all surface active and thus membrane destabilising polypeptides. Surfactant chains are typically chosen to be in a fluid state or at least to be compatible with the maintenance of fluid-chain state in carrier aggregates.
[0080] Table 5 lists preferred surfactants in accordance with the disclosure.
Table 5
Preferred surfactants
Nonionic surfactants (S)
chain
Name(s) Length: POE- nr. of double P( )l -soibit:in- POk- POI:- phenoxy- bonds o.Nior ci her orer ether
Brij, Myrj, Selected
Tween Macrogol Nonex Triton brandnames
C24
Behen(o)yl C22
Eruca(o)yl C22:l-13cis
Arachin(o)yl C20
Gadolen(o)yl C20:l-llcis
Arachidon(o)yl C20:4-5,8,ll,14cis
Siniiilsol-
01e(o)yl C18:l-9cis Tween SO Brij *JS 25W TritonXitH)**
Stear(o)yl C18 Tw et ii 60 M> r j-52
Linol(o)yl C18:2-9,12cis
Linole(n/o)yl C18:3-9,12,15cis
Palmitole(o)yl C18:l-9cis
Palmit(o)yl C16 1 «ei n 40
Myrist(o)yl C14
Laur(o)yl C12 Tween 20 Brij 35
Capr(o)yl CIO iiiiiititiiititiiitii
Rel. concentration range L/S (M/M) 5/1 - 1/1 5/1 - 1/1 4/1 - 3/2
N : not readily
available in the
market
but in principle
suitable
**Triton is not an oleate, but an octylphenoxy-POE derivative
Myrj-45: Stearoyl-E08; Myrj-49: Stearoyl-EO20 (not in the market); Myrj-59: Stearoyl- EO100; Myrj-52: Stearoyl-EO40;
Simulsol-2599 = Macrogol-10-oleate
Brij-98: Oleoyl-EO20
Brij-35: Lauryl-E023
[0081] In certain embodiments, the surfactant is a nonionic surfactant. The surfactant may be present in the formulation in about 1% to about 10%, about 1% to about 4%, about 4% to about 7% or about 7% to about 10% by weight. In some embodiments, the amount of surfactants in the formulation is from about 0.2% to about 0.5%. In certain embodiments, the nonionic surfactant is selected from the group consisting of: polyoxyethylene sorbitans (polysobate surfactants), polyhydroxyethylene stearates or polyhydroxyethylene laurylethers (Brij surfactants). In a specific embodiment, the surfactant is a polyoxyethylene-sorbitan- monooleate (e.g. polysorbate 80 or Tween 80). In certain embodiments, the polysorbate can have any chain with 12 to 20 carbon atoms. In certain embodiments, the polysorbate is fluid in the formulation, which may contain one or more double bonds, branching, or cyclo-groups.
4.3. FORMULATIONS
[0082] In some embodiments, the formulations include only one lipid and only one surfactant. In other embodiments, the formulations include more than one lipid and only one surfactant, e.g., two, three, four, or more lipids and one surfactant. In other embodiments, the formulations include only one lipid and more than one surfactant, e.g., two, three, four, or more surfactants and one lipid. In other embodiments, the formulations include more than one lipid and more than one surfactant, e.g., two, three, four, or more lipids and two, three, four, or more surfactants.
[0083] The formulations disclosed herein may have a range of lipid to surfactant ratios. The ratios may be expressed in terms of molar terms (mol lipid /mol surfactant). The molar ratio of lipid to surfactant in the formulations may be from about 1 :3 to about 30: 1, from about 1 :2 to about 30: 1, from about 1 : 1 to about 30:1, from about 5: 1 to about 30: 1, from about 10:1 to about 30: 1, from about 15: 1 to about 30:1, or from about 20: 1 to about 30: 1. In certain embodiments, the molar ratio of lipid to surfactant in the formulations disclosed herein may be from about 1 :2 to about 10: 1. In certain embodiments, the ratio is from about 1 : 1 to about 2: 1, from about 2 : 1 to about 3: 1, from about 3 : 1 to about 4: 1, from about 4 : 1 to about 5:1 or from about 5: 1 to about 10: 1. In specific embodiments, the lipid to surfactant ratio is about 1.0: 1.0, about 1.25:1.0, about 1.5/1.0, about 1.75/1.0, about 2.0/1.0, about 2.5/1.0, about 3.0/1.0 or about 4.0/1.0.
[0084] The formulations disclosed herein may also have varying amounts of total amount of the following components: lipid and surfactant combined (TA). The TA amount may be stated in terms of weight percent of the total composition. In one embodiment, the TA is
from about 1% to about 40%, about 5% to about 30%>, about 7.5% to about 15%, about 5% to about 10%), about 10% to about 20% or about 20% to about 30%. In specific embodiments, the TA is 8%, 9%, 10%, 15% or 20%.
[0085] In certain agricultural embodiments, for example in emodiments where the formulations are applied directly to the surface of the leaf, or where the formulations have an insecticide effect, the TA will be substantially smaller than the TA for pharmaceutical embodiments. For example, the TA may be from about 0.1% to about 10%, from about 0.1% to about 5%, from about 0.1% to about 3%, or from about 0.1% to about 1%. It will be understood that such a "dilution" would be useful in agricultural applications in order to avoid waste (because the delivery occurs over a large and sparse area, e.g., a forest), and because such a "dilution" would not be expected to reduce the efficacy on a leaf surface, as the leaf surfact would disperse the water carrier, leaving behind the as residue the vesicles. Such "dilution" may be particularly advantageous because of the reduced environmental impact: less active need to be used because of the direct and targeted treatment.
[0086] Selected ranges for total lipid amounts and lipid/surfactant ratios (mol/mol) for the formulations disclosed herein are described in Table 6 below:
Table 6: Total Amount and Lipid to Surfactant Ratios
[0087] In some embodiments, the formulations disclosed herein do not include a pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or any other disorder listed above. In some embodiments, the formulations disclosed herein include one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
[0088] The formulations disclosed herein may optionally contain one or more of the following ingredients: co-solvents, chelators, buffers, antioxidants, preservatives,
microbicides, emollients, humectants, lubricants and thickeners. Preferred amounts of optional components are described in Table 7.
[0089] The formulations disclosed herein may include a buffer to adjust the pH of the aqueous solution to a range from pH 3.5 to pH 9, pH 4 to pH 7.5, or pH 4 to pH 6.5.
Examples of buffers include, but are not limited to, acetate buffers, lactate buffers, phosphate buffers, and propionate buffers.
[0090] The formulations disclosed herein are typically formulated in aqueous media. The formulations may be formulated with or without co-solvents, such as lower alcohols
[0091] A "microbicide" or "antimicrobial" agent is commonly added to reduce the bacterial count in pharmaceutical formulations. Some examples of microbicides are short chain alcohols, including ethyl and isopropyl alcohol, chlorbutanol, benzyl alcohol, chlorbenzyl alcohol, dichlorbenzylalcohol, hexachlorophene; phenolic compounds, such as cresol, 4-chloro-m-cresol, p-chloro-m-xylenol, dichlorophene, hexachlorophene, povidon- iodine; parabenes, especially alkyl-parabenes, such as methyl-, ethyl-, propyl-, or butyl- paraben, benzyl paraben; acids, such as sorbic acid, benzoic acid and their salts; quaternary ammonium compounds, such as alkonium salts, e.g., a bromide, benzalkonium salts, such as a chloride or a bromide, cetrimonium salts, e.g., a bromide, phenoalkecinium salts, such as phenododecinium bromide, cetylpyridinium chloride and other salts; furthermore, mercurial compounds, such as phenylmercuric acetate, borate, or nitrate, thiomersal, chlorhexidine or its gluconate, or any antibiotically active compounds of biological origin, or any suitable mixture thereof.
[0092] Examples of "antioxidants" are butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT) and di-tert-butylphenol (LY178002, LY256548, HWA-131, BF-389,
CI-986, PD-127443, E-51 19, BI-L-239XX, etc.), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), l-0-hexyl-2,3,5-trimethylhydroquinone (HTHQ); aromatic amines
(diphenylamine, p-alkylthio-o-anisidine, ethylenediamine derivatives, carbazol,
tetrahydroindenoindol); phenols and phenolic acids (guaiacol, hydroquinone, vanillin, gallic acids and their esters, protocatechuic acid, quinic acid, syringic acid, ellagic acid, salicylic acid, nordihydroguaiaretic acid (NDGA), eugenol); tocopherols (including tocopherols (alpha, beta, gamma, delta) and their derivatives, such as tocopheryl-acylate (e.g., -acetate, - laurate, myristate, -palmitate, -oleate, -linoleate, etc., or an y other suitable tocopheryl- lipoate), tocopheryl-POE-succinate; trolox and corresponding amide and thiocarboxamide analogues; ascorbic acid and its salts, isoascorbate, (2 or 3 or 6)-o-alkylascorbic acids, ascorbyl esters (e.g., 6-o-lauroyl, myristoyl, palmitoyl-, oleoyl, or linoleoyl-L-ascorbic acid, etc.). Also useful are the preferentially oxidised compounds, such as sodium bisulphite, sodium metabisulphite, thiourea; chellating agents, such as EDTA, GDTA, desferral;
miscellaneous endogenous defence systems, such as transferrin, lactoferrin, ferritin, cearuloplasmin, haptoglobion, heamopexin, albumin, glucose, ubiquinol-10); enzymatic antioxidants, such as superoxide dismutase and metal complexes with a similar activity, including catalase, glutathione peroxidase, and less complex molecules, such as beta- carotene, bilirubin, uric acid; flavonoids (flavones, flavonols, flavonones, flavanonals, chacones, anthocyanins), N-acetylcystein, mesna, glutathione, thiohistidine derivatives, triazoles; tannines, cinnamic acid, hydroxycinnamatic acids and their esters (coumaric acids and esters, caffeic acid and their esters, ferulic acid, (iso-) chlorogenic acid, sinapic acid); spice extracts (e.g., from clove, cinnamon, sage, rosemary, mace, oregano, allspice, nutmeg); carnosic acid, carnosol, carsolic acid; rosmarinic acid, rosmaridiphenol, gentisic acid, ferulic acid; oat flour extracts, such as avenanthramide 1 and 2; thioethers, dithioethers, sulphoxides, tetralkylthiuram disulphides; phytic acid, steroid derivatives (e.g., U74006F); tryptophan metabolites (e.g., 3-hydroxykynurenine, 3-hydroxyanthranilic acid), and
organochalcogenides.
[0093] "Thickeners" are used to increase the viscosity of pharmaceutical formulations to and may be selected from selected from pharmaceutically acceptable hydrophilic polymers, such as partially etherified cellulose derivatives, including carboxymethyl-, hydroxyethyl-, hydroxypropyl-, hydroxypropylmethyl- or methyl-cellulose; completely synthetic hydrophilic polymers including polyacrylates, polymethacrylates, poly(hydroxyethyl)-,
poly(hydroxypropyl)-, poly(hydroxypropylmethyl)methacrylate, polyacrylonitrile, methallyl-
sulphonate, polyethylenes, polyoxiethylenes, polyethylene glycols, polyethylene glycol- lactide, polyethylene glycol-diacrylate, polyvinylpyrrolidone, polyvinyl alcohols, poly(propylmethacrylamide), poly(propylene fumarate-co-ethylene glycol), poloxamers, polyaspartamide, (hydrazine cross-linked) hyaluronic acid, silicone; natural gums including alginates, carrageenan, guar-gum, gelatine, tragacanth, (amidated) pectin, xanthan, chitosan collagen, agarose; mixtures and further derivatives or co-polymers thereof and/or other pharmaceutically, or at least biologically, acceptable polymers.
[0094] The formulations disclosed herein may also include a polar liquid medium. The formulations disclosed herein may be administered in an aqueous medium. The formulations disclosed herein may be in the form of a solution, suspension, emulsion, cream, lotion, ointment, gel, spray, film forming solution or lacquer.
[0095] In some embodiments, the compositions and methods disclosed herein relate to the use of a vesicular formulation as described above for the preparation of a pharmaceutical composition for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia. In some embodiments, a vesicular formulation or pharmaceutical composition includes at least one phospholipid and one nonionic surfactant for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia wherein the formulation or pharmaceutical composition is formulated for subcutaneous, topical or intravenous delivery.
[0096] Table 7 lists preferred excipients for the formulation.
Table 7
Preferred excipients for use in the formulations disclosed
Primary
*As percentage of Total Lipid quantity
EGTA= Ethylene glycol-bis-(2-aminoethyl)-N,N,N', N'-tetraacetic acid
EDTA = Ethylenedioxy-diethylene-dinitrilo-tetraacetic acid
4.4. VESICULAR FORMULATIONS
[0097] While not to be limited to any mechanism of action or any theory, the
formulations disclosed herein may form vesicles or ESAs characterized by their adaptability, deformability, or penetrability.
[0098] The term vesicle or aggregate "adaptability" which governs the "tolerable surface curvature" is defined as the ability of a given vesicle or aggregate to change easily its properties, such as shape, elongation ratio, and surface to volume ratio. The vesicles disclosed herein may be characterized by their ability to adjust the aggregates' shape and properties to the anisotropic stress caused by pore crossing. Sufficient adaptability implies that a vesicle or an aggregate can sustain different unidirectional forces or stress, such as one caused by pressure, without extensive fragmentation, which defines a "stable" aggregate. If an aggregate passes through a barrier fulfilling this condition the terms "adaptability" and (shape) "deformability" plus "permeability" are essentially equivalent. As used herein, a "barrier" is (as in, for example, EP 0 475 160 and WO 98/17255) a body with through- extending narrow pores, such narrow pores having a radius which is at least 25% smaller than the radius of the ESAs (considered as spherical) before the ESAs permeate through such pores.
[0099] The term "narrow" used in connection with a pore implies that the pore radius is significantly, typically at least 25%, smaller than the radius of the entity tested with regard to its ability to cross the pore. The necessary difference typically should be greater for the narrower pores. Using 25% limit is therefore quite suitable for >150 nm diameter whereas >100% difference requirement is more appropriate for the smaller systems, e.g., with <50 nm diameter. For diameters around 20 nm, aggregate diameter difference of at least 200% is often required.
[00100] The term "semipermeable" used in connection with a barrier implies that a solution can cross transbarrier openings whereas a suspension of non-adaptable aggregates (large enough for the above definition of "narrow" pores to apply) cannot. Conventional lipid vesicles (liposomes) made from any common phosphatidylcholine in the gel lamellar phase or else from any biological phosphatidylcholine/cholesterol 1/1 mol/mol mixture or else comparably large oil droplets, all having the specified relative diameter, are three examples for such non-adaptable aggregates.
[0100] The term "stable" means that the tested aggregates do not change their diameter spontaneously or under the transport related mechanical stress (e.g. during passage through a semipermeable barrier) unacceptably, which most often means only to a pharmaceutically acceptable degree. A 20-40% change is normally considered acceptable; the halving or doubling of aggregate diameter is borderline and a greater change in diameter is typically unacceptable. Alternatively and very conveniently, the change in aggregate diameter resulting from pore crossing under pressure is used to assess system stability; the same criteria are then applied as for "narrow" pores, mutatis mutandis. To obtain the correct value for aggregate diameter change, a correction for flux/vortex effects may be necessary. These procedures are described in greater detail in the publications of the applicant in Cevc et. al., Biochim. Biophys. Acta 2002; 1564:21-30.
[0101] Non-destructing passage of ultradeformable, mixed lipid aggregates through narrow pores in a semi-permeable barrier is thus diagnostic of high aggregate adaptability. If pore radius is two times smaller than the average aggregate radius the aggregate must change its shape and surface-to-volume ratio at least 100% to pass without fragmentation through the barrier. An easy and reversible change in aggregate shape inevitably implies high aggregate deformability and requires large surface-to-volume ratio adaptation. A change in surface-to- volume ratio per se implies: a) high volume compressibility, e.g. in the case of compact droplets containing material other than, and immiscible with, the suspending fluid; b) high aggregate membrane permeability, e.g. in the case of vesicles that are free to exchange fluid between inner and outer vesicle volume.
[0102] The vesicles or ESAs disclosed herein have "adaptability" that can be assessed using the following method: 1) measure the flux ja) of the aggregate or ESA suspension through a semi-permeable membrane (e.g. , gravimetrically) for different transport-driving trans barrier pressures (Δρ); 2) calculate the pressure dependence of barrier penetratability P for the suspension by dividing each measured flux value by the corresponding pressure value: Ρ(Δρ) = ja(Ap)/Ap; 3) monitor the ratio of final and starting vesicle diameter 2 rves(Ap)/2 rves,o (e.g. by dynamic light scattering), wherein 2 rves(Ap) is the vesicle diameter after semipermeable barrier passage driven by Δρ and 2 rveS;0 is the starting vesicle diameter, and if necessary make corrections for the flow-effects; and 4) aligh both data sets Ρ(Δρ) vs.
rves(Ap)/rveS;0 to determine the co-existence range for high aggregate adaptability and stability.
[0103] It is also useful, but not essential, to parameterize experimental penetratability data within the framework of Maxwell-approximation in terms of the necessary pressure value p* and in terms of maximum penetratability value Pmax- It is plausible to sum-up all the contributions to a moving aggregate energy (deformation energy/ies, thermal energy, the shearing work, etc.) into a single, total energy. The equilibrium population density of aggregate's energetic levels then may be taken to correspond to Maxwell's distribution. All aggregates with a total energy greater than the activation energy, E/EA, are finally concluded to penetrate the barrier. The pore-crossing probability for such aggregates is then given by the following formula, where e is dimensionless aggregate energy units of the activation energy EA:
[0104] It is therefore plausible to represent barrier penetratibility of a given suspension as a function of transport driving pressure by the following formula, where Pmax is the maximum possible penetratability of a given barrier (for the aggregates with zero transport resistance this penetrability is identical to the penetrability of the suspending medium flux), and p* is an adjustable parameter that describes the pressure sensitivity, and thus the transport resistance, of the tested system (for barriers with a fixed pore radius this sensitivity is a function of aggregate properties solely; for non-interacting particles the sensitivity is dominated by aggregate adaptability, allowing to make the assumption: aa proportional to 1/p*
[0105] Other methods of testing deformability and adaptability which may be used to characterize the compsitions disclosed herein are set forth, for example, in U.S. Patent Application Publication Nos. 2004/0071767 and 2004/0105881 , each herein incorporated by reference as if set forth herein in their entirety.
4.5. METHODS OF ADMINISTRATION / TREATMENT
[0106] Provided are methods of treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypolididemia, hypertriglyceridemia and hypercholesterolemia including administering to a subject in need thereof a pharmaceutical composition including at least one phospholipid and one nonionic surfactant. In another embodiment, provided are methods of treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypolididemia, hypertriglyceridemia and hypercholesterolemia including administering to a subject in need thereof a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners. In another embodiment, provided are methods of treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypolididemia, hypertriglyceridemia and hypercholesterolemia including administering to a subject in need thereof a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners.
[0107] In another embodiment, provided are methods of treating disorders related to inflammation, asthma, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, dysmenorrheal, hypercholesterolemia, hypertriglyceridemia, fatty acid metabolism, metal or other toxicity, Alzheimers disease, gout or macular degeneration, such as AMD, or fungal infection, including administering to a subject in need thereof a pharmaceutical composition including at least one phospholipid and one nonionic surfactant, wherein the pharmaceutical composition sequesters organic matter upon administration. In another embodiment, provided are methods of treating disorders related to inflammation, asthma, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, dysmenorrheal, hypercholesterolemia, hypertriglyceridemia, fatty acid metabolism, metal or other toxicity, Alzheimers disease, gout or macular degeneration, such as AMD, or fungal infection including administering to a subject in need thereof a pharmaceutical composition consisting essentially of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and optionally buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and/or thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration. In another embodiment, provided are methods of treating disorders related to
inflammation, asthma, bronchospasm, atherothrombatic cardiovascular disorders, venous thrombatic disorders, pain, dysmenorrhea!, hypercholesterolemia, hypertriglyceridemia, fatty acid metabolism, metal or other toxicity, Alzheimers disease, gout or macular degeneration, such as AMD, or fungal infection including administering to a subject in need thereof a pharmaceutical composition consisting of at least one phospholipid and one nonionic surfactant, a pharmaceutically acceptable carrier, and one or more of the following: buffers, antioxidants, preservatives, microbicides, antimicrobials, emollients, co-solvents, and thickeners, wherein the pharmaceutical composition sequesters organic matter upon administration.
4.6. PACKAGES
[0108] In another embodiment provide is a pharmaceutical package or kit including one or more containers filled with the formulation disclosed herein, and instructions for administration of the formulation to a patient or subject in need thereof for treating disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and
hypercholesterolemia. In certain embodiments, the formulation includes one or more phospholipids and one or more surfactants. In certain embodiments, the formulation does not include a non-lipid non-surfactant pharmaceutically active agent that has received marketing or regulatory approval in any country for the treatment of disorders related to fatty acid deficiencies, fatty acid metabolism, hypertriglyceridemia and hypercholesterolemia, or other disorder listed above. In various embodiments, the container includes a formulation formulated as a suspension, emulsion, gel, cream, lotion, spray, film forming solution or lacquer. Also provided are packages or kits that can be used in any of the methods disclosed herein.
4.5. AGRICULTURAL APPLICATIONS
[0109] In various aspects and embodiments, the formulations as described herein are used for agricultrural puposeses and applications. For example, provided are methods that include administering a formulation as described herein to a plant, seed or soil.
[0110] In certain embodiments, the formulation may be effective as an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and/or a synergist.
[0111] In certain aspects and embodiments of the methods and compositions as disclosed herein, a formulation as described herein is applied in any desirable application such as in agricultural applications. For instance, the formulation may be applied to control weeds, insects, and/or fungi. In addition, the formulation may be applied to insects, crops, soils, and the like. The pesticide composition may be applied by any suitable method.
[0112] In certain embodiments, the formulations may facilitate the transport of different agents into plant tissues, for example, the formulations may facilitate the penetration of cuticular wax layers. In certain aspects and embodiments, improved penetration into or through the cuticle could reduce the concentration of active agent required for a given application and thus significantly diminish pollution problems (Price, C. E. (1981) In: The plant cuticle (D. F. Cutler, K. L. Alvin, C. E. Price, Edits.), Academic, New York, pp. 237- 252).
[0113] In certain embodiments of the methods, formulations as described herein are applied to plants, crops, fields and the like and are applied such that the active agent is applied at a rate of 1 g/hectar to 500 g/hectar; or at a rate of 1 g/hectar to 200 g/hectar; at a rate of 100 g/hectar to 350 g/hectar; or at a rate of 30 g/hectar to 100 g/hectar.
[0114] According to some embodiments, the formulations are used to prepare a tank mix which may then be applied via spraying to the area, plant matter or crop needing treatment. The active agent concentration in the tank mix is adjusted to the particular application, depending on agricultural or non-agricultural application, the crop and the pest. Although various methods of application may be employed as the skilled artisan may appreciate, spraying may be the preferred method of application. Various methods of application can also be employed when necessary. For example, in field crops systemic application via an irrigation system can be combined with foliar application.
[0115] In certain embodiments, provided are a package, bag or kit that includes a formulation such as described herein, and instructions for indicating that the formulation is suitable for application to a plant, seed or soil. In certain embodiments the instructions indicate that the formulation is suitable for use as one or more selected from the group consisting of consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird
repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
Formulations with Active Ingredients
[0116] In some embodiments, the formulation may include an active agent, for example, the active agent may be an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, plant activator, and/or a synergist. In certain embodiments, the formulation includes one or more active agents selected from the agents listed on Table 9. In some embodiments, the formulation does not include any of the active agents listed on Table 9.
Table 9: Active Agents
fentrifanil
fluorbenside
proclonol
tetradifon
tetrasul
Carbamate Acaricides
benomyl
carbanolate
carbaryl
carbofuran
methiocarb
metolcarb
promacyl
propoxur
Oxime Carbamate Acaricides aldicarb
butocarboxim
oxamyl
thiocarboxime
thiofanox
Carbazate Acaricides
bifenazate
Dinitrophenol Acaricides
binapacryl
dinex
dinobuton
dinocap
dinocap-4
dinocap-6
dinocton
dinopenton
dinosulfon
dinoterbon
DNOC
Formamidine Acaricides
amitraz
chlordimeform
chloromebuform
formetanate
formparanate
Mite Growth Regulators
clofentezine
cyromazine
diflovidazin
dofenapyn
fluazuron
flubenzimine
flucycloxuron
flufenoxuron
hexythiazox
Organochlorine Acaricides
bromocyclen
camphechlor
DDT
dienochlor
endosulfan
lindane
Organophosphorus Acaricides
Organophosphate Acaricides chlorfenvinphos
crotoxyphos
dichlorvos
heptenophos
mevinphos
monocrotophos
naled
TEPP
tetrachlorvinphos
Organothiophosphate Acaricides amidithion
amiton
azinphos-ethyl
azinphos-methyl
azothoate
benoxafos
bromophos
bromophos-ethyl
carbophenothion
chlorpyrifos
chlorthiophos
coumaphos
cyanthoate
demeton
demeton-0
demeton-S
demeton-methyl
demeton-O-methyl
demeton-S-methyl
demeton-S-methylsulphon
dialifos
diazinon
dimethoate
dioxathion
disulfoton
endothion
ethion
ethoate-methyl
formothion
malathion
mecarbam
methacrifos
omethoate
oxydeprofos
oxydisulfoton
parathion
phenkapton
phorate
phosalone
phosmet
phoxim
pirimiphos-methyl
prothidathion
prothoate
pyrimitate
quinalphos
quintiofos
sophamide
sulfotep
thiometon
triazophos
trifenofos
vamidothion
Phosphonate Acaricides
trichlorfon
Phosphoramidothioate Acaricides isocarbophos
methamidophos
propetamphos
Phosphorodiamide Acaricides dimefox
mipafox
schradan
Organotin Acaricides
azocyclotin
cyhexatin
fenbutatinoxide
Phenylsulfamide Acaricides
dichlofluanid
Phthalimideac Acaricides
dialifos
phosmet
Pyrazole Acaricides
cyenopyrafen
fenpyroximate
tebufenpyrad
Phenylpyrazole Acaricides acetoprole
fipronil
vaniliprole
Pyrethroid Acaricides
Pyrethroid Ester Acaricides acrinathrin
bifenthrin
cyhalothrin
cypermethrin
alpha-cyp ermethrin
fenpropathrin
fenvalerate
flucythrinate
flumethrin
fluvalinate
tau-fluvalinate
permethrin
Pyrethroid Ether Acaricides halfenprox
Pyrimidinamine Acaricides pyrimidifen
Pyrrole Acaricides
chlorfenapyr
Ouinoxaline Acaricides
chinomethionat
thioquinox
Sulfite Ester Acaricides
propargite
Tetronic Acid Acaricides
spirodiclofen
Tetrazine Acaricides
clofentezine
diflovidazin
Thiazolidine Acaricides
flubenzimine
hexythiazox
Thiocarbamate Acaricides
fenothiocarb
Thiourea Acaricides
chloromethiuron
diafenthiuron
Other Acaricides
acequinocyl
amidoflumet
arsenousoxide
closantel
crotamiton
cymiazole
disulfiram
etoxazole
fenazaflor
fenazaquin
fluacrypyrim
fluenetil
mesulfen
MNAF
nifluridide
pyridaben
sulfiram
sulfluramid sulfur
triarathene
Algicides benzalkonium chloride bethoxazin
copper sulfate cybutryne
dichlone
dichlorophen diuron
endothal
fentin
hydrated lime methabenzthiazuron nabam
oxyfluorfen quinoclamine quinonamid simazine
terbutryn
Antibiotics carbenicillin
cefotaxime chloramphenicol
G 418
gentamicin
hygromycin kanamycin
paromomycin penicillin G puromycin
rifampicin
spectinomycin streptomycin vancomycin
Antifeedants chlordimeform
fentin
guazatine
pymetrozine
Avicides 4-aminopyridine
chloralose
endrin
fenthion
strychnine
Bactericides bronopol
copper hydroxide
cresol
dichlorophen
dipyrithione
dodicin
fenaminosulf
formaldehyde
hydrargaphen
8-hydroxyquinoline sulfate kasugamycin
nitrapyrin
octhilinone
oxolinic acid
oxytetracycline
probenazole
streptomycin
tecloftalam
thiomersal
Bird Repellants anthraquinone
chloralose
copper oxychloride
diazinon
guazatine
methiocarb
thiram
trimethacarb
ziram
Chemosterilants apholate
bisazir
busulfan
diflubenzuron
dimatif
hemel
hempa
metepa
methiotepa
methyl apholate
morzid
penfluron
tepa
thiohempa
thiotepa
tretamine
uredepa
Fungicides Aliphatic Nitrogen Fungicides
butylamine
cymoxanil
dodicin
dodine
guazatine
iminoctadine
Amide Fungicides
carpropamid
chloraniformethan
cyflufenamid
diclocymet
ethaboxam
fenoxanil
flumetover
furametpyr
isopyrazam
mandipropamid
penthiopyrad
prochloraz
quinazamid
silthiofam
triforine
Acvlamino Acid Fungicides benalaxyl
benalaxyl-M
furalaxyl
metalaxyl
metalaxyl-M
pefurazoate
valifenalate
Anilide Fungicides
benalaxyl
benalaxyl-M
bixafen
boscalid
carboxin
fenhexamid
fluxapyroxad
isotianil
metalaxyl
metalaxyl-M
metsulfovax
ofurace
oxadixyl
oxycarboxin
penflufen
pyracarbolid
sedaxane
thifluzamide
tiadinil
Benzanilide Fungicides benodanil
flutolanil
mebenil
mepronil
salicylanilide
tecloftalam
Furanilide Fungicides fenfuram
furalaxyl
furcarbanil
methfuroxam
Sulfonanilide Fungicides flusulfamide
Benzamide Fungicides
benzohydroxamic acid
fluopicolide
fluopyram
tioxymid
trichlamide
zarilamid
zoxamide
Furamide Fungicides
cyclafuramid
furmecyclox
Phenylsulfamide Fungicides dichlofluanid
tolylfluanid
Sulfonamide Fungicides amisulbrom
cyazofamid
Valinamide Fungicides
benthiavalicarb
iprovalicarb
Antibiotic Fungicides
aureofungin
blasticidin-S
cycloheximide
griseofulvin
kasugamycin
natamycin
polyoxins
polyoxorim
streptomycin
validamycin
Strobilurin Fungicides
azoxystrobin
dimoxystrobin
fluoxastrobin
kresoxim-methyl
metominostrobin
orysastrobin
picoxystrobin
pyraclostrobin
pyrametostrobin
pyraoxystrobin
trifloxystrobin
Aromatic Fungicides
biphenyl
chlorodinitronaphthalenes
chloroneb
chlorothalonil
cresol
dicloran
hexachlorobenzene
pentachlorophenol
quintozene
sodium pentachlorophenoxide
tecnazene
Benzimidazole Fungicides
benomyl
carbendazim
chlorfenazole
cypendazole
debacarb
fuberidazole
mecarbinzid
rabenzazole
thiabendazole
Benzimidazole Precursor Fungicides furophanate
thiophanate
thiophanate-methyl
Benzothiazole Fungicides
bentaluron
benthiavalicarb
chlobenthiazone
probenazole
TCMTB
Bridged Diphenyl Fungicides
bithionol
dichlorophen
diphenylamine
Carbamate Fungicides
benthiavalicarb
furophanate
iprovalicarb
propamocarb
pyribencarb
thiophanate
thiophanate-methyl
Benzimidazolylcarbamate Fungicides benomyl
carbendazim
cypendazole
debacarb
mecarbinzid
Carbanilate Fungicides
diethofencarb
pyraclostrobin
pyrametostrobin
Conazole Fungicides
Conazole Fungicides (Imidazoles) climbazole
clotrimazole
imazalil
oxpoconazole
prochloraz
triflumizole
Conazole Fungicides (Triazoles) azaconazole
bromuconazole
cyproconazole
diclobutrazol
difenoconazole
diniconazole
diniconazole-M
epoxiconazole
etaconazole
fenbuconazole
fluquinconazole
flusilazole
flutriafol
furconazole
furconazole-cis
hexaconazole
imibenconazole
ipconazole
metconazole
myclobutanil
penconazole
propiconazole
prothioconazole
quinconazole
simeconazole
tebuconazole
tetraconazole
triadimefon
triadimenol
triticonazole
uniconazole
uniconazole-P
Copper Fungicides
Bordeaux mixture
Burgundy mixture
Cheshunt mixture
copper acetate
copper carbonate, basic
copper hydroxide
copper naphthenate
copper oleate
copper oxychloride
copper silicate
copper sulfate
copper sulfate, basic
copper zinc chromate
cufraneb
cuprobam
cuprous oxide
mancopper
oxine-copper
Dicarboximide Fungicides
famoxadone
fluoroimide
Dichlorophenyl Dicarboximide Fungicides chlozolinate
dichlozoline
iprodione
isovaledione
myclozolin
procymidone
vinclozolin
Phthalimide Fungicides
captafol
captan
ditalimfos
folpet
thio chlorfenphim
Dinitrophenol Fungicides
binapacryl
dinobuton
dinocap
dinocap-4
dinocap-6
meptyldinocap
dinocton
dinopenton
dinosulfon
dinoterbon
DNOC
Dithiocarbamate Fungicides
azithiram
carbamorph
cufraneb
cuprobam
disulfiram
ferbam
metam
nabam
tecoram
thiram
ziram
Cyclic Dithiocarbamate Fungicides dazomet
etem
milneb
Polymeric Dithiocarbamate Fungicides mancopper
mancozeb
maneb
metiram
polycarbamate
propineb
zineb
Imidazole Fungicides
cyazofamid
fenamidone
fenapanil
glyodin
iprodione
isovaledione
pefurazoate
triazoxide
Inorganic Fungicides
potassium azide
potassium thiocyanate
sodium azide
sulfur
see also copper fungicides
see also inorganic mercury fungicides
Mercury Fungicides
Inorganic Mercury Fungicides
mercuric chloride
mercuric oxide
mercurous chloride
Organomercury Fungicides
(3-ethoxypropyl)mercury bromide
ethylmercury acetate
ethylmercury bromide
ethylmercury chloride
ethylmercury 2,3-dihydroxypropyl mercaptide ethylmercury phosphate
N-(ethylmercury)-p-toluenesulphonanilide hydrargaphen
2-methoxyethylmercury chloride
methylmercury benzoate
methylmercury dicyandiamide methylmercury pentachlorophenoxide
8-phenylmercurioxyquinoline
phenylmercuriurea
phenylmercury acetate
phenylmercury chloride
phenylmercury derivative of pyrocatechol phenylmercury nitrate
phenylmercury salicylate
thiomersal
tolylmercury acetate
Morpholine Fungicides
aldimorph
benzamorf
carbamorph
dimethomorph
dodemorph
fenpropimorph
flumorph
tridemorph
Organophosphorus Fungicides
ampropylfos
ditalimfos
edifenphos
fosetyl
hexylthiofos
iprobenfos
phosdiphen
pyrazophos
tolclofos-methyl
triamiphos
Organotin Fungicides
decafentin
fentin
tributyltin oxide
Oxathiin Fungicides
carboxin
oxycarboxin
Oxazole Fungicides
chlozolinate
dichlozoline
drazoxolon
famoxadone
hymexazol
metazoxolon
myclozolin
oxadixyl
vinclozolin
Polvsulfide Fungicides
barium polysulfide
calcium polysulfide
potassium polysulfide
sodium polysulfide
Pvrazole Fungicides
bixafen
fluxapyroxad
furametpyr
isopyrazam
penflufen
penthiopyrad
pyraclostrobin
pyrametostrobin
pyraoxystrobin
rabenzazole
sedaxane
Pyridine Fungicides
boscalid
buthiobate
dipyrithione
fluazinam
fluopicolide
fluopyram
pyribencarb
pyridinitril
pyrifenox
pyroxychlor
pyroxyfur
Pvrimidine Fungicides
bupirimate
diflumetorim
dimethirimol
ethirimol
fenarimol
ferimzone
nuarimol
triarimol
Anilinopvrimidine Fungicides cyprodinil
mepanipyrim
pyrimethanil
Pyrrole Fungicides
fenpiclonil
fludioxonil
fluoroimide
Ouinoline Fungicides
ethoxyquin
halacrinate
8-hydroxyquinoline sulfate
quinacetol
quinoxyfen
tebufloquin
Ouinone Fungicides
benquinox
chloranil
dichlone
dithianon
Ouinoxaline Fungicides chinomethionat
chlorquinox
thioquinox
Thiazole Fungicides
ethaboxam
etridiazole
isotianil
metsulfovax
octhilinone
thiabendazole
thifluzamide
Thiazolidine Fungicides flutianil
thiadifluor
Thiocarbamate Fungicides methasulfocarb
prothiocarb
Thiophene Fungicides
ethaboxam
silthiofam
Triazine Fungicides
anilazine
Triazole Fungicides
amisulbrom
bitertanol
fluotrimazole
triazbutil
Triazolopvrimidine Fungicides ametoctradin
Urea Fungicides
bentaluron
pencycuron
quinazamid
Other Fungicides
acibenzolar
acypetacs
allyl alcohol
benzalkonium chloride benzamacril
bethoxazin
carvone
chloropicrin
DBCP
dehydroacetic acid diclomezine
diethyl pyrocarbonate fenaminosulf
fenitropan
fenpropidin
formaldehyde
furfural
hexachlorobutadiene iodomethane
isoprothiolane
methyl bromide
methyl isothiocyanate metrafenone
nitrostyrene
nitrothal-isopropyl nystatin
OCH
pentachloronitrobenzene
2-phenylphenol
phthalide
piperalin
proquinazid
pyroquilon
sodium orthophenylphenoxide spiroxamine
sultropen
terbinafme
terbinafme hydrochloride thiabendazole
thicyofen
tricyclazole
zinc naphthenate
Herbicide safeners benoxacor
cloquintocet
cyometrinil
cyprosulfamide
dichlormid
dicyclonon
dietholate
fenchlorazole
fenclorim
flurazole
fluxofenim
furilazole
isoxadifen
mefenpyr
mephenate
naphthalic anhydride
oxabetrinil
Herbicides Amide Herbicides
allidochlor
amicarbazone
beflubutamid
benzadox
benzipram
bromobutide
cafenstrole
CDEA
cyprazol
dimethenamid
dimethenamid-P diphenamid
epronaz
etnipromid
fentrazamide
flucarbazone
flupoxam
fomesafen
halosafen
isocarbamid
isoxaben
napropamide
naptalam
pethoxamid
propyzamide
quinonamid
saflufenacil
tebutam
Anilide Herbicides chloranocryl
cisanilide
clomeprop
cypromid
diflufenican
etobenzanid
fenasulam
flufenacet
flufenican
ipfencarbazone
mefenacet
mefluidide
metamifop
monalide
naproanilide
pentanochlor
picolinafen
propanil
sulfentrazone
Arvlalanine Herbicides benzoylprop
flamprop
flamprop-M
Chloroacetanilide Herbicides acetochlor
alachlor
butachlor
butenachlor
delachlor
diethatyl
dimethachlor
metazachlor
metolachlor
S-metolachlor
pretilachlor
propachlor
propisochlor
prynachlor
terbuchlor
thenylchlor
xylachlor
Sulfonanilide Herbicides benzofluor
cloransulam
diclosulam
florasulam
flumetsulam
metosulam
perfluidone
pyrimisulfan
profluazol
Sulfonamide Herbicides
asulam
carbasulam
fenasulam
oryzalin
penoxsulam
pyroxsulam
Thioamide Herbicides
bencarbazone
chlorthiamid
Antibiotic Herbicides
bilanafos
Aromatic Acid Herbicides
Benzoic Acid Herbicides
chloramben
dicamba
2,3,6-TBA
tricamba
Pvrimidinvloxvbenzoic AcidHerbicides bispyribac
pyriminobac
Pvrimidinvlthiobenzoic AcidHerbicides pyrithiobac
Phthalic Acid Herbicides
chlorthal
Picolinic Acid Herbicides
aminopyralid
clopyralid
picloram
Ouinolinecarboxvlic Acid Herbicides
quinclorac
quinmerac
Arsenical Herbicides
cacodylic acid
CMA
DSMA
hexaflurate
MAA
MAMA
MSMA
potassium arsenite
sodium arsenite
Benzovlcvclohexanedione Herbicides
ketospiradox
mesotrione
sulcotrione
tefuryltrione
tembotrione
Benzofuranyl Alkylsulfonate Herbicides
benfuresate
ethofumesate
Benzothiazole Herbicides
benazolin
benzthiazuron
fenthiaprop
mefenacet
methabenzthiazuron
Carbamate Herbicides
asulam
carboxazole
chlorprocarb
dichlormate
fenasulam
karbutilate
terbucarb
Carbanilate Herbicides
barban
BCPC
carbasulam
carbetamide
CEPC
chlorbufam
chlorpropham
CPPC
desmedipham
phenisopham
phenmedipham
phenmedipham-ethyl
propham
swep
Cyclohexene Oxime Herbicides alloxydim
butroxydim
clethodim
cloproxydim
cycloxydim
profoxydim
sethoxydim
tepraloxydim
tralkoxydim
Cvclopropvlisoxazole Herbicides isoxachlortole
isoxaflutole
Dicarboximide Herbicides cinidon-ethyl
flumezin
flumiclorac
flumioxazin
flumipropyn
Dinitroaniline Herbicides benfluralin
butralin
dinitramine
ethalfluralin
fluchloralin
isopropalin
methalpropalin
nitralin
oryzalin
pendimethalin
prodiamine
profluralin
trifluralin
Dinitrophenol Herbicides dinofenate
dinoprop
dinosam
dinoseb
dinoterb
DNOC
etinofen
medinoterb
Diphenvl Ether Herbicides
ethoxyfen
Nitrophenyl Ether Herbicides acifluorfen
aclonifen
bifenox
chlomethoxyfen
chlornitrofen
etnipromid
fluorodifen
fluoroglycofen
fluoronitrofen
fomesafen
furyloxyfen
halosafen
lactofen
nitrofen
nitrofluorfen
oxyfluorfen
Dithiocarbamate Herbicides
dazomet
metam
Halosenated Aliphatic Herbicides alorac
chloropon
dalapon
flupropanate
hexachloroacetone
iodomethane
methyl bromide
monochloroacetic acid
SMA
TCA
Imidazolinone Herbicides
imazamethabenz
imazamox
imazapic;imazapyr;imazaquin;imazethapyr
Inorganic Herbicides
ammonium sulfamate
borax
calcium chlorate
copper sulfate
ferrous sulfate
potassium azide
potassium cyanate
sodium azide
sodium chlorate
sulfuric acid
Nitrile Herbicides
bromobonil
bromoxynil
chloroxynil
dichlobenil
iodobonil
ioxynil
pyraclonil
Organophosphorus Herbicides amiprofos-methyl
anilofos
bensulide
bilanafos
butamifos
2,4-DEP
DMPA
EBEP
fosamine
glufosinate
glufosinate-P
glyphosate
piperophos
Oxadiazolone Herbicides dimefuron
methazole
oxadiargyl
oxadiazon
Oxazole Herbicides
carboxazole
fenoxasulfone
isouron
isoxaben
isoxachlortole
isoxaflutole
methiozolin
monisouron
pyroxasulfone
topramezone
Phenoxv Herbicides
bromofenoxim
clomeprop
2,4-DEB
2,4-DEP
difenopenten
disul
erbon
etnipromid
fenteracol
trifopsime
Phenoxvacetic Herbicides
4-CPA
2,4-D
3,4-DA
MCPA ((4-chloro-2-methylphenoxy)acetic acid)
MCPA-thioethyl
2,4,5-T
Phenoxvbutvric Herbicides
4-CPB
2,4-DB
3,4-DB
MCPB
2,4,5-TB
Phenoxvpropionic Herbicides
cloprop
4-CPP
dichlorprop
dichlorprop-P
3,4-DP
fenoprop
mecoprop
mecoprop-P
Arvloxvphenoxvpropionic Herbicides chlorazifop
clodinafop
clofop
cyhalofop
diclofop
fenoxaprop
fenoxaprop-P
fenthiaprop
fluazifop
fluazifop-P
haloxyfop
haloxyfop-P
isoxapyrifop
metamifop
propaquizafop
quizalofop
quizalofop-P
quizalofop-P-ethyl
trifop
Phenylenediamine Herbicides
dinitramine
prodiamine
Pvrazole Herbicides
azimsulfuron
difenzoquat
halosulfuron
metazachlor
metazosulfuron
pyrazosulfuron
pyroxasulfone
Benzovlpvrazole Herbicides benzofenap
pyrasulfotole
pyrazolynate
pyrazoxyfen
topramezone
Phenylpyrazole Herbicides fluazolate
nipyraclofen
pinoxaden
pyraflufen
Pvridazine Herbicides
credazine
pyridafol
pyridate
Pvridazinone Herbicides
brompyrazon
chloridazon
dimidazon
flufenpyr
metflurazon
norflurazon
oxapyrazon
pydanon
Pyridine Herbicides
aminopyralid
cliodinate
clopyralid
diflufenican
dithiopyr
flufenican
fluroxypyr
haloxydine
picloram
picolinafen
pyriclor
pyroxsulam
thiazopyr
triclopyr
Pyrimidinediamine Herbicides iprymidam
tioclorim
Quaternary Ammonium Herbicides cyperquat
diethamquat
difenzoquat
diquat
morfamquat
paraquat
Thiocarbamate Herbicides
butylate
cycloate
di-allate
EPTC
esprocarb
ethiolate
isopolinate
methiobencarb
molinate
orbencarb
pebulate
prosulfocarb
pyributicarb
sulfallate
thiobencarb
tiocarbazil
tri-allate
vernolate
Thiocarbonate Herbicides
dimexano
EXD
proxan
Thiourea Herbicides
methiuron
Triazine Herbicides
dipropetryn
trihydroxytriazine
Chlorotriazine Herbicides atrazine
chlorazine
cyanazine
cyprazine
eglinazine
ipazine
mesoprazine
procyazine
proglinazine
propazine
sebuthylazine
simazine
terbuthylazine
trietazine
Gluoroalkvltriazine Herbicides indaziflam
triaziflam
Methoxvtriazine Herbicides
atraton
methometon
prometon
secbumeton
simeton
terbumeton
Methvlthiotriazine Herbicides ametryn
aziprotryne
cyanatryn
desmetryn
dimethametryn
methoprotryne
prometryn
simetryn
terbutryn
Triazinone Herbicides
ametridione
amibuzin
hexazinone
isomethiozin
metamitron
metribuzin
Triazole Herbicides
amitrole
cafenstrole
epronaz
flupoxam
Triazolone Herbicides
amicarbazone
bencarbazone
carfentrazone
flucarbazone
ipfencarbazone
propoxycarbazone
sulfentrazone
thiencarbazone
Triazolopvrimidine Herbicides cloransulam
diclosulam
florasulam
flumetsulam
metosulam
penoxsulam
pyroxsulam
Uracil Herbicides
benzfendizone
bromacil
butafenacil
flupropacil
isocil
lenacil
saflufenacil
terbacil
Urea Herbicides
benzthiazuron
cumyluron
cycluron
dichloralurea
diflufenzopyr
isonoruron
isouron
methabenzthiazuron
monisouron
noruron
Phenylurea Herbicides
anisuron
buturon
chlorbromuron
chloreturon
chlorotoluron
chloroxuron
daimuron
difenoxuron
dimefuron
diuron
fenuron
fluometuron
fluothiuron
isoproturon
linuron
methiuron
methyldymron
metobenzuron
metobromuron
metoxuron
monolinuron
monuron
neburon
parafluron
phenobenzuron
siduron
tetrafluron
thidiazuron
Sulfonylurea Herbicides
Pynmidinylsulfonylurea Herbicides amidosulfuron
azimsulfuron
bensulfuron
chlorimuron
cyclosulfamuron
ethoxysulfuron
flazasulfuron
flucetosulfuron
flupyrsulfuron
foramsulfuron
halosulfuron
imazosulfuron
mesosulfuron
metazosulfuron
nicosulfuron
orthosulfamuron
oxasulfuron
primisulfuron
propyrisulfuron
pyrazosulfuron
rimsulfuron
sulfometuron
sulfosulfuron
trifloxysulfuron
Triazinvlsulfonvlurea Herbicides chlorsulfuron
cinosulfuron
ethametsulfuron
iodosulfuron
metsulfuron
prosulfuron
thifensulfuron
triasulfuron
tribenuron
triflusulfuron
tritosulfuron
Thiadiazolylurea Herbicides
buthiuron
ethidimuron
tebuthiuron
thiazafluron
thidiazuron
Other Herbicides
acrolein
allyl alcohol
altrazine
aminocyclopyrachlor
aminotriazole
azafenidin
benefm
bentazone
benzobicyclon
bicyclopyrone
buthidazole
calcium cyanamide
cambendichlor carbetamide
chlorfenac
chlorfenprop
chlorflurazole
chlorflurenol
chlortoluron
cinmethylin
clomazone
CPMF
cresol
cyanamide
ortho-dichlorobenzene propaquizafop
dimepiperate
endothal
fluoromidine
fluridone
flurochloridone flurtamone
fluthiacet
indanofan
loxynil
MCPP
MCPP-P
methyl isothiocyanate metsulfuron-methyl
OCH
oxaziclomefone pelargonic acid pendimethalin
pentachlorophenol pentoxazone
phenylmercury acetate prosulfalin
pyribenzoxim
pyriftalid
quinoclamine
rhodethanil
sulglycapin
thidiazimin
tridiphane
trimeturon
tripropindan
tritac
Insect Attractants Coleopteran Attractants
brevicomin
dominicalure
frontalin
grandlure
ipsdienol
ipsenol
japonilure
lineatin
megatomoic acid
a-multistriatin
oryctalure
sulcatol
trunc-call
Dipteran Attractants
ceralure
cue-lure
latilure
medlure
muscalure
trimedlure
Lepidopteran Attractants
disparlure
Straight Chain Lepidopteran Pheromones codlelure
gossyplure
hexalure
litlure
looplure
orfralure
ostramone
Other Insect Attractants
eugenol
methyl eugenol
siglure
Insect Repellents acrep
butopyronoxyl
carboxide
dibutyl phthalate
diethyltoluamide
dimethyl carbate
dimethyl phthalate
ethohexadiol
hexamide
icaridin
methoquin-butyl
methylneodecanamide
oxamate
rebemide
Insecticides Antibiotic Insecticides
allosamidin
thuringiensin
Macrocyclic Lactone Insecticides
Avermectin Insecticides
abamectin
doramectin
emamectin
eprinomectin
ivermectin
selamectin
Milbemycin Insecticides lepimectin
milbemectin
milbemycin oxime
moxidectin
Spinosvn Insecticides
spinetoram
spinosad
Arsenical Insecticides
calcium arsenate
copper acetoarsenite
copper arsenate
lead arsenate
potassium arsenite
sodium arsenite
Botanical Insecticides
anabasine
azadirachtin
d-limonene
nicotine
pyrethrins
cinerins
cinerinl
cinerinll
jasmolinl
jasmolinll
pyrethrinl
pyrethrinll
quassia
rotenone
ryania
sabadilla
Carbamate Insecticides
bendiocarb
carbaryl
Benzofuranyl Methylcarbamate Insecticides benfuracarb
carbofuran
carbosulfan
decarbofuran
furathiocarb
Dimethylcarbamate Insecticides dimetan
dimetilan
hyquincarb
pirimicarb
Oxime Carbamate Insecticides alanycarb
aldicarb
aldoxycarb
butocarboxim
butoxycarboxim
methomyl
nitrilacarb
oxamyl
tazimcarb
thiocarboxime
thiodicarb
thiofanox
Phenyl Methylcarbamate Insecticides allyxycarb
aminocarb
bufencarb
butacarb
carbanolate
cloethocarb
dicresyl
dioxacarb
EMPC
ethiofencarb
fenethacarb
fenobucarb
isoprocarb
methiocarb
metolcarb
mexacarbate
promacyl
promecarb
propoxur
trimethacarb
XMC
xylylcarb
Desiccant Insecticides
boric acid
diatomaceous earth
silica gel
Diamide Insecticides
chlorantraniliprole
cyantraniliprole
flubendiamide
Dinitrophenol Insecticides
dinex
dinoprop
dinosam
DNOC
Fluorine Insecticides
barium hexafluorosilicate cryolite
sodium fluoride
sodium hexafluorosilicate sulfluramid
Formamidine Insecticides amitraz
chlordimeform
formetanate
formparanate
Fumigant Insecticides
acrylonitrile
carbon disulfide
carbon tetrachloride
chloroform
chloropicrin
para-dichlorobenzene
1 ,2-dichloropropane
ethyl formate
ethylene dibromide
ethylene dichloride
ethylene oxide
hydrogen cyanide
iodomethane
methyl bromide
methylchloroform
methylene chloride
naphthalene
phosphine
sulfuryl fluoride
tetr achloro ethane
Inorganic Insecticides
borax
boric acid
calcium polysulfide
copper oleate
diatomaceous earth
mercurous chloride
potassium thiocyanate
silica gel
sodium thiocyanate
see also arsenical insecticides see also fluorine insecticides
Insect Growth Regulators
Chitin Synthesis Inhibitors bistrifluron
buprofezin
chlorfluazuron
cyromazine
diflubenzuron
flucycloxuron
flufenoxuron
hexaflumuron
lufenuron
novaluron
noviflumuron
penfluron
teflubenzuron
triflumuron
Juvenile Hormone Mimics epofenonane
fenoxycarb
hydroprene
kinoprene
methoprene
pyriproxyfen
triprene
Juvenile Hormones
juvenile hormone I
juvenile hormone II
juvenile hormone III
Moulting Hormone Agonists chromafenozide
halofenozide
methoxyfenozide
tebufenozide
Moulting Hormones
a-ecdysone
ecdysterone
Moulting Inhibitors
diofenolan
Precocenes
precocene I
precocene II
precocene III
Other Insect Growth Regulators dicyclanil
Nereistoxin Analogue Insecticides bensultap
cartap
thiocyclam
thiosultap
Nicotinoid Insecticides
flonicamid
Nitroguanidine Insecticides
clothianidin
dinotefuran
imidacloprid
thiamethoxam
Nitromethvlene Insecticides
nitenpyram
nithiazine
Pvridvlmethvlamine Insecticides acetamiprid
imidacloprid
nitenpyram
thiacloprid
Organochlorine Insecticides
bromo-DDT
camphechlor
DDT
pp'-DDT
ethyl-DDD
HCH
gamma-HCH
lindane
methoxychlor
pentachlorophenol
TDE
Cvclodiene Insecticides
aldrin
bromocyclen
chlorbicyclen
chlordane
chlordecone
dieldrin
dilor
endosulfan
alpha-endosulfan
endrin
HEOD
heptachlor
HHDN
isobenzan
isodrin
kelevan
mirex
Organophosphorus Insecticides
Organophosphate Insecticides bromfenvinfos
chlorfenvinphos
crotoxyphos
dichlorvos
dicrotophos
dimethylvinphos
fospirate
heptenophos
methocrotophos
mevinphos
monocrotophos
naled
naftalofos
phosphamidon
propaphos
TEPP
tetrachlorvinphos
Organothiophosphate Insecticides
dioxabenzofos
fosmethilan
phenthoate
Aliphatic Organothiophosphate Insecticides acethion
amiton
cadusafos
chlorethoxyfos
chlormephos
demephion
demephion-0
demephion-S
demeton
demeton-0
demeton-S
demeton-methyl
demeton-O-methyl
demeton-S-methyl
demeton-S-methylsulphon
disulfoton
ethion
ethoprophos
IPSP
isothioate
malathion
methacrifos
oxydemeton-methyl
oxydeprofos
oxydisulfoton
phorate
sulfotep
terbufos
thiometon
Aliphatic Amide Organothiophosphate Insecticides amidithion
cyanthoate
dimethoate
ethoate-methyl
formothion
mecarbam
omethoate
prothoate
sophamide
vamidothion
Oxime Organothiophosphate Insecticides chlorphoxim
phoxim
phoxim-methyl
Heterocyclic Organothiophosphate Insecticides azamethiphos
coumaphos
coumithoate
dioxathion
endothion
menazon
morphothion
phosalone
pyraclofos
pyridaphenthion
quinothion
Benzothiopyran Organothiophosphate Insecticides dithicrofos
thicrofos
Benzotriazine Organothiophosphate Insecticides azinphos-ethyl
azinphos-methyl
Isoindole Organothiophosphate Insecticides
dialifos
phosmet
Isoxazole Organothiophosphate Insecticides
isoxathion
zolaprofos
Pyrazolopvrimidine Organothiophosphate Insecticides chlorprazophos
pyrazophos
Pyridine Organothiophosphate Insecticides
chlorpyrifos
chlorpyrifos-methyl
Pyrimidine Organothiophosphate Insecticides
butathiofos
diazinon
etrimfos
lirimfos
pirimiphos-ethyl
pirimiphos-methyl
primidophos
pyrimitate
tebupirimfos
Ouinoxaline Organothiophosphate Insecticides quinalphos
quinalphos-methyl
Thiadiazole Organothiophosphate Insecticides athidathion
lythidathion
methidathion
prothidathion
Triazole Organothiophosphate Insecticides isazofos
triazophos
Phenyl Organothiophosphate Insecticides azothoate
bromophos
bromophos-ethyl
carbophenothion
chlorthiophos
cyanophos
cythioate
dicapthon
dichlofenthion
etaphos
famphur
fenchlorphos
fenitrothion
fensulfothion
fenthion
fenthion-ethyl
heterophos
jodfenphos
mesulfenfos
parathion
parathion-methyl
phenkapton
phosnichlor
profenofos
prothiofos
sulprofos
temephos
trichlormetaphos-3
trifenofos
Phosphonate Insecticides
butonate
trichlorfon
Phosphonothioate Insecticides
mecarphon
Phenyl Ethylphosphonothioate Insecticides fonofos
trichloronat
Phenyl Phenylphosphonothioate Insecticides cyanofenphos
EPN
leptophos
Phosphoramidate Insecticides crufomate
fenamiphos
fosthietan
mephosfolan
phosfolan
pirimetaphos
Phosphoramidothioate Insecticides acephate
isocarbophos
isofenphos
isofenphos-methyl
methamidophos
propetamphos
Phosphorodiamide Insecticides dimefox
mazidox
mipafox
schradan
Oxadiazine Insecticides
indoxacarb
Oxadiazolone Insecticides
metoxadiazone
Phthalimide Insecticides
dialifos
phosmet
tetramethrin
Pvrazole Insecticides
chlorantraniliprole
cyantraniliprole
dimetilan
tebufenpyrad
tolfenpyrad
Phenvlpvrazole Insecticides acetoprole
ethiprole
fipronil
pyraclofos
pyrafluprole
pyriprole
vaniliprole
Pvrethroid Insecticides
Pvrethroid Insecticides
acrinathrin
allethrin
bioallethrin
esdepallethrine
barthrin
bifenthrin
bioethanomethrin
cyclethrin
cycloprothrin
cyfluthrin
beta-cyfluthrin
cyhalothrin
gamma-cyhalothrin
lambda-cyhalothrin
cypermethrin
alpha-cyp ermethrin
beta-cypermethrin
theta-cypermethrin
zeta-cypermethrin
cyphenothrin
deltamethrin
dimefluthrin
dimethrin
empenthrin
fenfluthrin
fenpirithrin
fenpropathrin
fenvalerate
esfenvalerate
flucythrinate
fluvalinate
tau-fluvalinate
furethrin
imiprothrin
meperfluthrin
methothrin
metofluthrin
permethrin
biopermethrin
tr ansp ermethrin
phenothrin
prallethrin
profluthrin
pyresmethrin
resmethrin
bioresmethrin
cismethrin
tefluthrin
terallethrin
tetramethrin
tetramethylfluthrin
tralomethrin
transfluthrin
Pyrethroidether Insecticides etofenprox
flufenprox
halfenprox
protrifenbute
silafluofen
Pvrimidinamine Insecticides flufenerim
pyrimidifen
Pyrrole Insecticides
chlorfenapyr
Tetramic Acid Insecticides spirotetramat
Tetronic Acid Insecticides spiromesifen
Thiazole Insecticides clothianidin
thiamethoxam
Thiazolidine Insecticides tazimcarb
thiacloprid
Thiourea Insecticides diafenthiuron
Urea Insecticides
flucofuron
sulcofuron
Other Insecticides
closantel
copper naphthenate crotamiton
EXD
fenazaflor
fenoxacrim
hydramethylnon
isoprothiolane
malonoben
metaflumizone
nifluridide
plifenate
pyridaben
pyridalyl
pyrifluquinazon
rafoxanide
sulfoxaflor
triarathene
triazamate
Mammal Repellents copper naphthenate
trimethacarb
zinc naphthenate
ziram
Mating Disrupters disparlure
gossyplure
grandlure
Molluscicides bromoacetamide
calcium arsenate
cloethocarb
copper acetoarsenite
copper sulfate
fentin
metaldehyde
methiocarb
niclosamide
pentachlorophenol
sodium pentachlorophenoxide
tazimcarb
thiacloprid
thiodicarb
tralopyril
tributyltin oxide
trifenmorph
trimethacarb
Nematicides Antibiotic Nematicides
abamectin
Carbamate Nematicides
benomyl
carbofuran
carbosulfan
cloethocarb
Oxime Carbamate Nematicides alanycarb
aldicarb
aldoxycarb
oxamyl
Organophosphorus Nematicides
Organophosphate Nematicides diamidafos
fenamiphos
fosthietan
phosphamidon
Organothiophosphate Nematicides cadusafos
chlorpyrifos
dichlofenthion
dimethoate
ethoprophos
fensulfothion
fosthiazate
heterophos
isamidofos
isazofos
phorate
phosphocarb
terbufos
thionazin
triazophos
Phosphonothioate Nematicides imicyafos
mecarphon
Other Nematicides
acetoprole
benclothiaz
chloropicrin
dazomet
DBCP
DCIP
1 ,2-dichloropropane
1 ,3-dichloropropene
fluensulfone
furfural
iodomethane
metam
methyl bromide
methyl isothiocyanate
xylenols
Plant Activators acibenzolar
probenazole
Plant Growth Antiauxins
Regulators clofibric acid
2,3,5-tri-iodobenzoic acid
Auxins
4-CPA
2,4-D
2,4-DB
2,4-DEP
dichlorprop
fenoprop
IAA
IBA
naphthaleneacetamide
a-naphthaleneacetic acid
1-naphthol
naphthoxyacetic acids
potassium naphthenate
sodium naphthenate
2,4,5-T
Cvtokinins
2iP
benzyladenine
kinetin
zeatin
Defoliants
calcium cyanamide
dimethipin
endothal
ethephon
merphos
metoxuron
pentachlorophenol thidiazuron
tribufos
Ethylene Inhibitors aviglycine
1 -methylcyclopropene
Ethylene Releasers
ACC
etacelasil
ethephon
glyoxime
Gibberellins
gibberellins
gibberellic acid
Growth Inhibitors abscisic acid
ancymidol
butralin
carbaryl
chlorphonium
chlorpropham
dikegulac
flumetralin
fluoridamid
fosamine
glyphosine
isopyrimol
jasmonic acid
maleic hydrazide mepiquat
piproctanyl
prohydroj asmon propham
2,3,5-tri-iodobenzoic acid
Morphactins chlorfluren
chlorflurenol
dichlorflurenol flurenol
Growth Retardants chlormequat
daminozide
flurprimidol
mefluidide
paclobutrazol tetcyclacis
uniconazole
Growth Stimulators
brassinolide
forchlorfenuron
hymexazol
Other plant growth regulators benzofluor
buminafos
carvone
ciobutide
clofencet
cloxyfonac
cyanamide
cyclanilide
cycloheximide
cyprosulfamide
epocholeone
ethychlozate
ethylene
fenridazon
heptopargil
holosulf
inabenfide
karetazan
lead arsenate
methasulfocarb
prohexadione
pydanon
sintofen
triapenthenol
trinexapac
Rodenticides Botanical Rodenticides
scilliroside
strychnine
Coumarin Rodenticides brodifacoum
bromadiolone
coumachlor
coumafuryl
coumatetralyl
difenacoum
difethialone
flocoumafen
warfarin
Indandione Rodenticides chlorophacinone
diphacinone
pindone
Inorganic Rodenticides arsenous oxide
phosphorus
potassium arsenite
sodium arsenite
thallium sulfate
zinc phosphide
Organochlorine Rodenticides
gamma-HCH
HCH
lindane
Orsanophosphorus Rodenticides
phosacetim
Pvrimidinamine Rodenticides
crimidine
Thiourea Rodenticides
antu
Urea Rodenticides
pyrinuron
Other Rodenticides
bromethalin
chloralose
a-chlorohydrin
ergocalciferol
fluoroacetamide
flupropadine
hydrogen cyanide
norbormide
sodium fluoroacetate
Seed Treatments carbodan
carbofuran (2,3 dihydro-2,2-dimethylbenzofuran-7- yl methylcarbamate) diazol
diazinon (0,0-diethyl 0 -2-isopropyl-6-methylpyrimidin-4-yl
phosphorothioate)
magnate
imazalil ((±)-l-(b -allyloxy-2,4-dichlorophenylethyl) imidazole) merpan
captan (N-(trichloromethylthio)cyclohex-4-ene- 1 ,2-dicarboximide) mirage
prochloraz (N-propyl-N-[2-(2,4,6 trichlorophenoxy)ethyl]imidazole) orius
tebuconazole ((RS)-l-p-chlorophenyl-4,4-dimethyl-3-(l H -1,2,4-triazol- ylmethyl) pentan-3-ol)
panoctine
guazatine (mixture of the reaction products from polyamines, including mainly octamethylenediamine, iminodi-(octamethylene)diamine and octamethylenebis (imino-octamethylene)diamine, and carbamonitrile) pyristar
chlorpyrifos (0,0-diethyl 0-3,5,6-trichloro-2-pyridyl phosphorothioate) seedoprid
imidacloprid
shavit
triadimenol ((IRS, 2RS ;1RS , 2SR )-l-(4-chlorophenoxy)-3, 3 -dimethyl-
( 1 H- 1 ,2,4-triazol- 1 -yl) butan-2-ol)
Synergists piperonyl butoxide
piprotal
propyl isome
sesamex
sesamolin
sulfoxide
tribufos
Virucides ribavirin
Other Active Agents calcium cyanide
dinitrophenols
naphthylindane- 1 ,3-diones
nicotine sulfate
nonanol
piperazine
polybutenes
potassium ethylxanthate
sodium cyanide
thiocyanatodinitrobenzenes
trichlorotrinitrobenzenes
zinc trichlorophenoxide
[0117] In certain embodiments, the formulations as described herein include an active agent that is a herbicide and the herbicide may be one or more of
AFALON/LINUREX(Linuron); AGIL/SHOGUN/FALCON(Propaquizafop);
ALANEX(Alachlor); ALANEX PRO(Alachlor + Prometryn); ALANEX TBA(Alachlor + Terbuthylazine); ALAZINE(Alachlor + Atrazine); AMETREX(Ametryn); AMETREX EXTRA(Ametryn + Simazine); AMETRON(Ametryn + Diuron); AMIGAN(Ametryn + Terbutryn); ARIMO(Glyphosate + MCPA); ARROW(Clethodim); ATERBUTEX/
ATERBUTOX(Atrazine + Terbutryn); ATHLET(Bifenox + Chlortoluron); ATRAMET COMBI(Ametryn + Atrazine); ATRANEX( Atrazine) ; ATRASIM / FOGART /
ATRASIMEX(Atrazine + Simazine); AZOLAN(Aminotriazole); BENEFEX(Benfiuralin, benefm); BIFENAL / VERIGAL D(Bifenox + MCPP); BIFENIX N(Bifenox + Isoproturon); BLOIS / LINNET / ARIZONA / URANUS (Linuron + Trifluralin); BRIOTRIL(Bromoxynil + Ioxynil); BRIOTRIL MS(Bromoxynil + Ioxynil + MCPP); BROMOTRIL(Bromoxynil); BROMOTRIL T / TEMPLAR(Bromoxynil + Terbuthylazine); CARBETAMEX /
CRAWLER / LEGURAM(Carbetamide); COTTONEX / COTORAN(Fluometuron);
COTTONEX COM(Fluometuron + Trifluralin); COTTONEX D(Diuron + Fluometuron); COTTONEX P / DOUBLE TEAM(Fluometuron + Prometryn); COTTONEX
PG(Fluometuron + Glyphosate + Prometryn); DIUREX(Diuron); ETHOSAT (Ethofumesate);
FOX / MODOWN 4F(Bifenox); FOXPRO D(Bifenox + loxynil + MCPP-P); FOXTAR D+(Bifenox + Isoproturon + MCPP-P); FOXTRIL SUPER / CHARADE(Bifenox + loxynil + MCPP-P); GALIGAN(Oxyfluorfen); GALINEX(Oxyfiuorfen + Simazine);
GALIROM(Alachlor + Oxyfluorfen); GLIDUS / SAMBA(Diuron + Glyphosate);
GLIFAZIN / BUTAZIN(Glyphosate + Terbuthylazine); GLYPHOGAN(Glyphosate);
GOLTIX / TORONADO / MARQUISE / DANAGAN / GOLDBEET(Metamitron);
HEXARON(Diuron + Hexazinone); IOTRIL(Ioxynil); KALIF(Clomazone); KONTAKT (Phenmedipham); LEGATO PLUS(Diflufenican + Isoproturon); LEOPARD(Quizalofop-P- ethyl); LINPRO(Linuron + Prometryn); NAJA(Lactofen); NICANOR /
VALURON(Metsulfuron-methyl); OLAGAN / BATALLION(Terbuthylazine + Terbutryn); PENDIGAN / ACTIVUS / BEMA (Pendimethalin); PRAMITOL / SONORA(Prometon); PROLEX(Propachlor); PROMETREX(Prometryn); PROP ANIL PROFICOL /
PROPATOX(Propanil); PROTUGAN(Isoproturon); PROTUGAN PLUS /
HARLEQUIN(Isoproturon + Simazine); PROZINEX(Propazine); PYTHON / MISTRAL / FEINZIN(Metribuzin); RACER(Flurochloridone); SIMANEX(Simazine); SIMAZOL PLUS(Aminotriazole + Diuron + Simazine); SULTAN(Metazachlor); SUPRAZINE(Atrazine + Terbuthylazine); TERBALIN (Terbutryn + Trifluralin); TERBUTREX(Terbutryn);
TERBUTREX COMBI(Simazine + Terbutryn); TOLUGAN EXTRA(Chlortoluron + Isoproturon); TOLUREX(Chlortoluron); TOMAHAWK / TOMIGAN(Fluroxypyr);
TOPGAN(Imazaquin); TORERO / GOLTIX MIX(Ethofumesate + Metamitron);
TRIFLUREX(Trifluralin); TRILIN(Bromoxynil + Fluroxypyr + loxynil); TWIN /
POWERTWIN(Ethofumesate + Phenmedipham); TYLLANEX(Terbuthylazine);
VEZIR(Imazethapyr); or ZOOMER(Glyphosate + Oxyfluorfen).
[0118] In certain embodiments, the formulations as described herein include an active agent that is a fungicide and the fungicide may be one or more of ARDENT(Kresoxim- methyl); BUMPER(Propiconazole); BUMPER F(Folpet + Propiconazole); BUMPER P(Prochloraz + Propiconazole); FOLPAN(Folpet); M AGN ATE(Imazalil) ;
MERPAN(Captan); MIRAGE(Prochloraz); NIMROD(Bupirimate); ODEON(Chlorthalonil); ORIUS(Tebuconazole); ORIUS 5 FS(Tebuconazole Imazalil); ORIUS 6 FS(Tebuconazole Imazalil); PANOCTINE/RAVINE(Guazatine); SHAVIT(Triadimenol); SHAVIT F(Folpet + Triadimenol); SOPRANO(Epoxiconazole); SOPRANO-C(Carbendazim + Epoxiconazole); or ZAMIR(Prochloraz + Tebuconazole).
[0119] In certain embodiments, the formulations as described herein include an active agent that is a insecticide and the insecticide may be one or more of
BAYTHROID(Cyfluthrin); BULLDOCK(Beta Cyfhithrin); CARBODAN(Carbofuran); COTNION-METHYL(Azinphos-methyl); DIAZOL(Diazinon); ENDURO(Beta Cyfiuthrin + Oxydemeton-Methyl); FLURAMIM(Sulfuramid); KESHET(Deltamethrin);
KOHINOR(Imidacloprid); KOHINOR PLUS(Cyfluthrin + Imidacloprid);
LAMDEX(Lambda Cyhalothrin); MAVRIK/KLARTAN(Tau-Fluvalinate);
METASYSTOX(Oxydemeton-Methyl); METHOFAN(Endosulfan + Methomyl);
METHOMEX(Methomyl); NEMACUR(Fenamiphos); PILIER(Beta Cyfiuthrin +
Fenitrothion); PYRINEX(Chlorpyrifos); PYRINEX QUICK(Clorpyrifos + Delthamethrin); RIMON(Novaluron); SEIZER(Bifenthrin); SUPRATHION(Methidathion); or
THIONEX(Endosulfan).
[0120] In certain embodiments, the formulations as described herein include an active agent that is an acaricide and the acaricide may be one or more of APOLLO(Clofentezine); APOLLO /ACARISTOP(Clofentezine); MITIGAN COMBI / ACARINT(Dicofol +
Tetradifon); MITIGAN/ AC ARIN(Dicofol) ; or PARSEC/TAC PLUS(Amitraz).
[0121] In certain embodiments, the formulations as described herein include an active agent that is a growth regulator and the growth regulator may be CYCOGAN(Chlormequart).
[0122] In certain embodiments, the formulations as described herein include an active agent that may be one or more of DIAZOL 60(Control of a Wide Range of Insect Pests under Extreme Environmental Conditions); PYRINEX 25(Control of Insects in Sensitive Areas); PYRINEX 40(Control of a Wide Range of Insect Pests); PYRINEX 40 maybe(Control of Fleas&Ticks on Dogs and in their Environment); or PYRINEX 48(Control of a Wide Range of Insect Pests within and around the House).
[0123] In certain embodiments, the formulations as described herein include an active agent that is a seed treatment and the seed treatment may be one or more of CARBODAN ST(Carbofuran.); DIAZOL ST(Diazinon.); MAGNATE ST(ImazaliL); MERPAN
ST(Captan.); MIRAGE ST(Prochloraz.); ORIUS ST(Tebuconazole.); PANOCTINE
ST(Guazatine.); PYRISTAR ST(Chlorpyrifos.); SEEDOPRID(Imidacloprid.); or SHAVIT ST(TriadimenoL).
[0124] Lists of active agents such as pesticides that may also be used in the formulations and methods disclosed herein can be found in the Crop Protection Dictionary (contained in
the Meisterpro Crop Protection Handbook) and the British Crop Protection Council: The Pesticide Manual.
[0125] In certain embodiments an active agent such as disclosed herein is present in a formulation as described herein, for example the active ingredient may be present in the formulation in an amount that is at least 0.001% by weight; at least 0.01% by weight; at least 0.1%) by weight; at least 1% by weight; at least 2% by weight; at least 3% by weight; at least 5%) by weight; at least 10%> by weight; at least 15% by weight; at least 20% by weight; at least 25%o by weight; at least 30% by weight; at least 40% by weight; at least 50% by weight; at least 75% by weight or more. In some embodiments the active ingredient may be present in the formulation in an amount that is between about 0.001% to 0.01%; 0.01%to 0.1% by weight; 0.1 %to 1% by weight; l%to 2% by weight; 2-5% by weight; 5-10% by weight; 10- 15% by weight; 15-20% by weight; 20-25% by weight; 25-30% by weight; 35-40% by weight; or 40-50%) by weight.
[0126] Without intending to be limited by mechanism in any way, in certain embodiment, when the formulation is applied directly to a leaf, the vesicles may penetrate the leaf stomata, resulting in the desired activity, e.g., antifungal activity. In certain embodiments, the method is particularly advantageous for treating fungal infection of leaf where the fungi resides on the underside of the leaf (e.g., tobacco).
Insecticidal Methods and Compositions.
[0127] The compositions, formulations and methods herein may in certain embodiments be used for the purpose of providing insecticidal compositions, for example insecticidal compositions that can be applied to plants. For example, a formulation as described herein may include an active ingredient that is an insecticide such as described herein. In certain embodiments the formulations and methods as described herein provide effective immediate and long term action against insects. A further purpose of the present methods and disclosures is to provide a method for pest control, particularly insect control, which provides effective immediate action and effective long term activity.
[0128] In certain embodiments, the formulations may facilitate the transport of different agents (such as insecticides) into insects, thus increasing the effectiveness of the agent.
[0129] In certain embodiments, provided are formulations that include an insecticide (active agent) having immediate action on the pests (known in the art as "knock-down action") and/or an insecticide having long term action (known also as "residual action") (see
for example US Patent Application Publication No. 2008/0009542). Effective knock-down insecticides include pyrethroids, organic phosphoric acid esters, neonicotinoids, imidacloprid, acetamiprid and phenyl pyrazoles (fipronil). Effective long term insecticides include insect growth regulators (IGR) of various types, e.g. chitin synthesis inhibitors.
[0130] In particular, provided are compositions and methods that formulations that include at least one insecticidal compound with effective knock-down action selected from among group (A) consisting of imidacloprid, acetamiprid, thiamethoxam, thiacloprid, nitenpyram, dinotefuran, clothianidin, abamectin, emamectin, emamectin benzoate and fipronil, and at least one insecticidal compound with effective long-term action selected from among group (B) of insect growth regulators including benzoylphenyl urea (BPU)
compounds selected from among novaluron, lufenuron, hexaflumuron, triflumuron, diflubenzuron, chlorfluazuron, flufenoxuron, noviflumuron and teflubenzuron. Further provided is a method for insect control, including applying a formulation having at least one insecticidal compound with effective knock-down action selected from among group (A) including imidacloprid, acetamiprid, thiamethoxam, thiacloprid, nitenpyram, dinotefuran, clothianidin, abamectin, emamectin, emamectin benzoate and fipronil, and at least one insecticidal compound with effective long-term action selected from among group (B) of insect growth regulators (IGR) including benzoylphenyl urea (BPU) compounds; to a crop, agricultural product, plant matter, animal or locale.
[0131] According to a preferred embodiment of the method, the application of the insecticides is simultaneous, separate or sequential application.
[0132] According to some specific embodiments of the methods insecticides are administered at a dosage of 0.1 to 50 mg/Kg body weight; or at a dosage of 0.1 to 100 mg/Kg body weight; or at 1 to 10 mg/Kg body weight; or at 10 to 40 mg/Kg body weight.
[0133] In certain embodiments, the methods and formualtions disclosed herein are effective for controlling insects of, inter alia, the orders Lepidoptera, Coleoptera, Homoptera, Heteroptera, Diptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, Isoptera, Psocoptera and Hymenoptera, as well as representatives of the order Acarina of the families Ixodidae, Argasidae, Tetranychidae and Dermanyssidae.
[0134] In addition, the method and formulations may be effective in controlling flies, e.g. Musca domestica, termites, cockroaches and mosquito larvae. The presently claimed method and composition is also suitable for controlling plant-destructive feeding insects in
ornamentals and crops of useful plants, especially in cotton (e.g. against Spodoptera littoralis and Heliothis virescens) and in fruit and vegetables (e.g. against Laspeyresia pomonella, Cydia pomonella, Lithocolletis blancardella, Stigmella malella, Adoxophyes orana, Psylla piri, Cryptophlebia leucotreta, phyllocnistis citrella, Cydia molesta, Anarsia lineatella, Leptinotarsa decemlineata and Epilachna varivestis), as well as for controlling several species of mites, e.g., oleivora.
[0135] The method and formulations may be effective for controlling ectoparasites such as Lucilia sericata, in domestic animals and productive livestock, e.g. by treating animals, cowsheds, barns, stables, pastures and the like.
[0136] Without intending to be limited in any way by mechanism, insecticide activity may result because of absorption of the vesicles through the insect's spiracles.
Herbicide and/or Weed Control Methods and Formulations.
[0137] The compositions, formulations and methods herein may in certain embodiments be used for the purpose of providing herbicidal compositions, for example herbicidal compositions that can be applied to plants. For example, a formulation as described herein may include an active ingredient that is an herbicide such as described herein. A further purpose of certain embodiments is to provide a method for weed control control. Also provided are methods of selectively controlling weeds in a field, wherein the field may includes plants tolerant to the herbicide applied to the field.
[0138] Incertain embodiments the methods and formulations include one or more herbicides, for example as disclosed herein.
[0139] In certain embodiments the herbicide is a contact herbicides that destroy only the plant tissue in contact with the chemical. Often contact herbicides are the fastest acting herbicides. Contact herbicides may be less effective on perennial plants, which are able to regrow from rhizhomes, roots or tubers.
[0140] In some embodiments the herbicide is a systemic herbicides that are translocated through the plant, either from foliar application down to the roots, or from soil application up to the leaves. Systemic herbicides are capable of controlling perennial plants and may be slower acting but ultimately may be more effective than contact herbicides.
[0141] The methods and formulations may also include soil-applied herbicides that are applied to the soil and are taken up by the roots and/or hypocotyl of the target plant. There are three main types of soil-applied herbicides: (1) pre-plant incorporated herbicides applied
prior to planting and mechanically incorporated into the soil; (2) preemergent herbicides applied to the soil before the crop emerges to prevent germination or early growth of weed seeds and (3) post-emergent herbicides are applied after the crop has emerged.
[0142] In certain embodiments the herbicide is an ACCase inhibitor, i.e., compounds that kill grasses. Acetyl coenzyme A carboxylase (ACCase) is part of the first step of lipid synthesis. Thus, ACCase inhibitors affect cell membrane production in the meristems of the grass plant. The ACCases of grasses are sensitive to these herbicides, whereas the ACCases of dicot plants are not.
[0143] Incertain embodiments an herbicide of the formulations and methods may be an ALS inhibitor: the acetolactate synthase (ALS) enzyme (also known as acetohydroxyacid synthase, or AHAS) is the first step in the synthesis of the branched-chain amino acids (valine, leucine, and isoleucine). These herbicides slowly starve affected plants of these amino acids which eventually leads to inhibition of DNA synthesis. They affect grasses and dicots alike. The ALS inhibitor family includes sulfonylureas (SUs), imidazolinones (IMIs), triazolopyrimidines (TPs), pyrimidinyl oxybenzoates (POBs), and sulfonylamino carbonyl triazolinones (SCTs). ALS is a biological pathway that exists only in plants and not in animals thus making the ALS-inhibitors among the safest herbicides.
[0144] A herbicide may also be an EPSPS inhibitors. The enolpyruvylshikimate 3- phosphate synthase enzyme EPSPS is used in the synthesis of the amino acids tryptophan, phenylalanine and tyrosine. They affect grasses and dicots alike. Glyphosate (Roundup) is a systemic EPSPS inhibitor but inactivated by soil contact. Glyphosate, a systemic nonselective (it kills any type of plant) herbicide used in no-till burndown and for weed control in crops that are genetically modified to resist its effects is an example of an EPSPs inhibitor.
[0145] Without intending to be limited in any way by mechanism, herbicide activity may result from application of the vesicular formulations to the ground surrounding plants or weeds because of because of absorption of the vesicles by the near-surface roots of small weeds directly through the root tips (analogous to absorption by fungi).
[0146] The methods and compositions provided herein will now be described in greater detail by reference to the following non-limiting examples.
5. EXAMPLES
5.1 Example 1: Example Formulations
[0147] The following exemplary formulations for topical application may be prepared by the following procedure:
1. Organic phase production, which contains all lipophilic excipients
The organic phase is produced by weighing the lipid, the surfactant, any additional lipophilic excipients into suitable containers followed by mixing these components into anoptically isotropic phase which appears as a clear solution. During mixing, the organic phase will be heated up, but temperature must not rise above 45 °C.
2. Aqueous phase production
The aqueous phase is prepared by weighing the non-lipophilic components and water, which serves as solvent, into suitable containers and then mixing these components into a clear solution. During mixing, the temperature will be elevated to 40 °C.
3. Production of a concentrated intermediate by combination of both phases
The isotropic organic phase and the clear aqueous phase are combined under stirring in a suitable vessel. Before and during the combination the temperature of both phases must be kept between 35 °C and 45 °C. The resulting intermediate is homogenised mechanically at 40 °C. Before starting homogenisation, the pressure in the production vessel is lowered to - 0.08 MPa. The desired average carrier size is typically reached after 10 minutes of homogenisation.
Three process parameters must be controlled carefully during the production of the concentrated intermediate: temperature, homogeniser circulation velocity, and
overall processing time.
4. Production of the final bulk product by mixing the concentrated intermediate
with dilution buffer.
The concentrated intermediate is diluted with the dilution buffer to the intended final concentration. The mixture is carefully stirred in the mixing vessel at 20 °C to homogeneity.
[0148] Table 8 describes the amounts of surfactant and lipids, and other excipients in the tranfersome formulations, described in terms of the percent of the total amount of formulation.
TABLE 8: Preferred Formulations
Table 8A: This table lists the relative amounts of each of the components of Preferred Formulations
Surfactant
mg/g
Lipid mg/g (1 to 10% by Buffer Antimicrobials Antioxidants (0- Emollient Chelator (0- wt.) (pH 4-7.5) (0-10 mg/g) lOmg/g) (0-50 mg/g) Other (0-50mg/g) 25mg/g)
1 47.944 42.056 4 5.000 0.700 30.000 30.000 3.000
2 53.750 31.250 4 5.000 0.700 30.000 15.000 3.000
3 90.561 79.439 4 5.000 0.700 30.000 30.000 3.000
4 47.944 42.056 5 5.000 0.700 30.000 30.000 3.000
5 50.607 44.393 5 5.000 0.700 0.000 10.000 3.000
6 90.561 79.439 5 5.000 0.700 30.000 30.000 3.000
7 49.276 43.224 6.5 5.000 0.700 30.000 30.000 3.000
8 53.750 31.250 6.5 5.000 0.200 30.000 0.000 3.000
9 90.561 79.439 6.5 5.000 0.200 30.000 20.000 3.000
10 41.351 48.649 4 5.000 0.200 30.000 30.000 3.000
11 47.882 37.118 4 5.000 0.200 0.000 30.000 3.000
12 95.764 74.236 4 5.000 0.200 30.000 30.000 3.000
13 65.676 24.324 5 5.000 0.200 0.000 25.000 3.000
14 62.027 22.973 5 5.000 0.200 0.000 30.000 3.000
15 124.054 45.946 5 5.000 0.200 15.000 36.510 3.000
16 62.687 32.313 6.5 5.000 0.200 15.000 0.000 3.000
17 41.853 43.147 6.5 5.000 0.200 30.000 30.000 3.000
18 95.764 74.236 6.5 5.000 0.200 0.000 30.000 3.000
19 47.882 37.118 6.5 5.000 0.200 0.000 0.000 3.000
20 45.000 45.000 6.5 5.000 0.200 0.000 0.000 1.000
21 31.935 58.065 5 5.000 0.200 30.000 15.000 3.000
22 42.500 42.500 6.5 5.000 0.200 30.000 0.000 3.000
23 38.276 51.724 4 5.000 0.200 0.000 36.510 3.000
24 42.500 42.500 4 5.000 0.200 0.000 15.000 3.000
25 85.000 85.000 4 5.000 0.200 30.000 30.000 3.000
26 38.276 51.724 5 5.000 0.200 30.000 0.000 1.000
27 36.429 48.571 5 5.000 0.200 30.000 30.000 3.000
28 72.299 97.701 5 5.000 0.200 30.000 15.000 3.000
29 46.250 46.250 6.5 5.000 0.700 0.000 20.000 3.000
30 38.804 46.196 6.5 5.000 0.700 15.000 30.000 3.000
31 36.667 33.333 6.5 5.000 0.700 30.000 10.000 3.000
32 66.667 23.333 4 5.000 0.200 0.000 0.000 3.000
33 45.833 41.667 4 5.000 0.200 30.000 0.000 3.000
34 31.957 38.043 4 5.000 0.200 0.000 30.000 3.000
35 47.143 42.857 5 5.000 0.200 30.000 25.000 1.000
36 96.905 88.095 5 5.000 0.200 30.000 20.000 3.000
37 31.957 38.043 5 5.000 0.200 0.000 30.000 3.000
38 35.455 54.545 6.5 5.000 0.700 30.000 0.000 3.000
39 84.457 100.543 6.5 5.000 0.700 30.000 30.000 3.000
40 89.048 80.952 6.5 5.000 0.700 30.000 30.000 3.000
41 41.087 48.913 4 5.000 0.700 30.000 36.510 3.000
42 45.280 39.720 4 5.000 0.700 0.000 0.000 3.000
43 107.500 62.500 4 5.000 0.700 30.000 30.000 3.000
44 77.243 67.757 4 5.000 0.700 0.000 15.000 3.000
45 45.280 39.720 5 5.000 0.700 0.000 20.000 3.000
46 90.561 79.439 5 5.000 0.700 0.000 30.000 3.000
47 47.944 42.056 5 5.000 0.700 0.000 10.000 3.000
48 50.607 44.393 5.5 5.000 0.700 30.000 0.000 1.000
49 107.500 62.500 5.5 5.000 0.700 30.000 0.000 3.000
50 47.944 42.056 5.5 5.000 0.700 30.000 30.000 3.000
51 46.364 38.636 4 5.000 0.200 30.000 25.000 3.000
52 46.364 38.636 4 5.000 0.200 0.000 20.000 3.000
53 46.098 43.902 5 5.000 0.200 15.000 30.000 3.000
54 43.537 41.463 5 5.000 0.200 30.000 0.000 3.000
55 45.000 45.000 5 5.000 0.200 0.000 30.000 3.000
56 59.492 30.508 6.5 5.000 0.200 30.000 30.000 3.000
57 39.054 45.946 6.5 5.000 0.200 0.000 0.000 3.000
58 35.854 34.146 6.5 5.000 0.200 30.000 0.000 3.000
59 50.000 40.000 6.5 5.000 0.700 30.000 30.000 3.000
60 38.571 51.429 6.5 5.000 0.700 30.000 30.000 3.000
61 41.954 50.546 6.5 5.000 0.700 30.000 30.000 3.000
62 42.632 47.368 6.5 5.000 0.700 30.000 30.000 3.000
63 46.098 43.902 6.5 5.000 0.700 30.000 30.000 3.000
64 39.721 50.279 6.5 5.000 0.700 30.000 30.000 3.000
65 44.198 50.802 6.5 5.000 0.700 30.000 30.000 3.000
66 46.453 51.047 6.5 5.000 0.700 30.000 30.000 3.000
67 51.221 43.779 6.5 5.000 0.700 30.000 30.000 3.000
68 54.167 43.333 6.5 5.000 0.700 30.000 30.000 3.000
69 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
70 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
71 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
72 40.000 50.000 6.5 5.000 0.700 30.000 30.000 3.000
73 40.000 50.000 6.5 5.000 0.700 30.000 30.000 3.000
74 40.000 50.000 5.5 0.000 0.700 30.000 30.000 3.000
75 40.000 50.000 6.5 5.000 0.700 30.000 30.000 3.000
76 40.000 50.000 6.5 5.000 0.700 30.000 30.000 3.000
77 40.000 50.000 6.5 5.000 0.700 30.000 30.000 3.000
78 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
79 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
80 40.000 50.000 5.5 0.000 0.700 30.000 30.000 3.000
81 40.000 50.000 5.5 5.000 0.700 30.000 30.000 3.000
82 44.444 55.556 5.5 5.000 0.700 30.000 30.000 3.000
83 66.440 23.560 5.5 5.000 0.700 30.000 30.000 3.000
84 54.000 36.000 4 5.000 0.700 30.000 30.000 3.000
85 50.000 40.000 4 5.000 0.700 30.000 30.000 3.000
86 48.611 38.889 4 5.000 0.700 30.000 30.000 3.000
87 46.575 38.425 4 5.000 0.700 30.000 30.000 3.000
88 46.575 38.425 4 5.000 0.700 30.000 30.000 3.000
89 46.575 38.425 4 5.000 0.700 30.000 30.000 3.000
90 50.000 40.000 4.5 5.000 0.700 30.000 30.000 3.000
91 94.444 75.556 4 5.000 0.700 30.000 30.000 3.000
92 46.712 38.288 4 5.000 0.700 30.000 30.000 3.000
93 48.889 39.111 4 5.000 0.700 30.000 30.000 3.000
94 39.721 50.279 6.5 5.000 0.700 30.000 30.000 3.000
95 90.000 0.000 6.5 5.000 0.700 30.000 30.000 3.000
96 68.700 8.500 7.5 5.000 0.700 30.000 36.510 1.000
97 71.460 4.720 7.8 5.000 0.700 50.000 35.000 3.000
99 71.460 4.720 7.8 5.000 0.700 50.000 15.000 3.000
98 71.460 4.720 7.8 0.000 0.700 50.000 15.000 3.000
100 71.460 4.720 7.8 0.000 0.700 50.000 35.000 3.000
101 46.575 38.425 4 0.000 0.700 0.000 0.000 3.000
102 46.575 38.425 4 0.000 0.700 0.000 0.000 3.000
103 54.643 30.357 4 5.000 0.700 0.000 0.000 3.000
104 39.72 50.279 6.5 5.000 0.700 30.000 30.000 3.000
105 90.00 6.5 5.000 0.700 30.000 30.000 3.000
106 46.57 38.425 4 0.700 3.000
107 46.75 38.425 4 0.700 3.000
108 54.64 30.357 4 0.700 3.000
109 46.364 38.636 4 5.000 0.200 30.000 25.000 3.000
110 46.364 38.636 4 5.000 0.200 0.000 20.000 3.000
111 46.098 43.902 5 5.000 0.200 15.000 30.000 3.000
112 43.537 41.463 5 5.000 0.200 30.000 0.000 3.000
113 45.000 45.000 5 5.000 0.200 0.000 30.000 3.000
114 59.492 30.508 6.5 5.000 0.200 30.000 30.000 3.000
115 39.054 45.946 6.5 5.000 0.200 0.000 0.000 3.000
116 35.854 34.146 6.5 5.000 0.200 30.000 0.000 3.000
117 50.000 40.000 6.5 5.000 0.700 30.000 30.000 3.000
118 38.571 51.429 6.5 5.000 0.700 30.000 30.000 3.000
119 41.954 50.546 6.5 5.000 0.700 30.000 30.000 3.000
120 42.632 47.368 6.5 5.000 0.700 30.000 30.000 3.000
121 46.098 43.902 6.5 5.000 0.700 30.000 30.000 3.000
122 39.721 50.279 6.5 5.000 0.700 30.000 30.000 3.000
©
O 123 44.198 50.802 6.5 5.000 0.700 30.000 30.000 3.000
124 46.453 51.047 6.5 5.000 0.700 30.000 30.000 3.000
125 51.221 43.779 6.5 5.000 0.700 30.000 30.000 3.000
126 54.167 43.333 6.5 5.000 0.700 30.000 30.000 3.000
127 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
128 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
129 66.440 23.560 6.5 5.000 0.700 30.000 30.000 3.000
Table 8B: The table lists the specific components of the formulas listed above.
Formula Lipid Surfactant Buffer Antimicrobial Antioxidants Emollient Chelator Other
1-4 Sphingomyelin, e.g., Tween 80 Lactate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol
brain or paraben sodium
metabisulfite
(0.500)
5-7 Sphingomyelin, Brij 98 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol
sodium
lauroyl or paraben metabisulfite
(0.500)
8-12 Phosphatidyl choline Brij 98 Phosphate Benzyl alcohol HTHQ Glycerol EDTA Ethanol
+ or paraben
Phosphatidylglycerol
13-16 Phosphatidyl Span 20 Acetate Benzyl alcohol HTHQ Glycerol EDTA Ethanol choline + or paraben
phosphatidylinositol
17-18 Phosphatidyl Tween 80 Phosphate Benzyl alcohol BHT Glycerol EDTA Ethanol choline + or paraben
phosphatidic acid
19 Phosphatidyl Brij 98 + Phosphate Benzyl alcohol BHT Glycerol EDTA Ethanol choline + Tween 80 or paraben
phosphatidic acid
20 Phosphatidyl Span 20 + Phosphate Benzyl alcohol BHT Glycerol EDTA Ethanol choline + Tween 80 or paraben
phosphatidic acid
21 Phosphatidyl Cremophor Lactate Thimerosal BHA Glycerol EDTA Ethanol choline + Span 20
22 Phosphatidyl Cremophor Lactate Thimerosal BHA Glycerol EDTA Ethanol choline + Tween 80
23-28 Phosphatidyl Cremophor Lactate Thimerosal BHA Glycerol EDTA Ethanol choline
29-30 Phosphatidyl Tween 80 Phosphate Thimerosal BHT (0.200) Glycerol EDTA Ethanol ethanolamine sodium
metabisulfite
(0.500)
31 Phosphatidyl Brij 98 + Phosphate Thimerosal BHT (0.200) Glycerol EDTA Ethanol ethanolamine Tween 80 sodium
metabisulfite
(0.500)
74 Phosphatidyl choline Tween 80 Acetate BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite
(0.500)
75 Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
76 Phosphatidyl choline Brij 98 Phosphate Benzalkonium BHT (0.200) Glycerol EDTA Ethanol chloride sodium
metabisulfite
(0.500)
77 Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
78 Phosphatidyl choline Brij 98 Phosphate Benzalkonium BHT (0.200) Glycerol EDTA Ethanol chloride sodium
metabisulfite
(0.500)
79 Phosphatidyl choline Brij 98 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
80 Phosphatidyl choline Tween 80 Acetate BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite
(0.500)
81 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
82-83 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
84-88 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHA (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
89 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
90-93 Phosphatidyl choline Tween 80 Acetate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
94-96 Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
97-98 Phosphatidyl choline Tween 80 Phosphate Benzyl alcohol BHT (0.200) Glycerol EDTA Ethanol or paraben sodium
metabisulfite
(0.500)
99-100 Phosphatidyl choline Tween 80 Phosphate BHT (0.200) Glycerol EDTA Ethanol sodium
metabisulfite
(0.500)
101-103 Phosphatidyl choline Tween 80 Acetate BHT (0.200) EDTA
sodium
metabisulfite
Example Formulation 1
[0149] Formulation 1 includes sphingomyelin (brain) (47.944 mg/g) as a lipid, Tween 80 (42.056mg/g) as a surfactant, lactate buffer (pH 4), benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (.0500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 2
[0150] Formulation 2 includes sphingomyelin (brain) (53.750 mg/g) as a lipid, Tween 80 (31.250 mg/g) as a surfactant, lactate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 3
[0151] Formulation 3 includes sphingomyelin (brain) (90.561 mg/g) as a lipid, Tween 80 (79.439 mg/g) as a surfactant, lactate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 4
[0152] Formulation 4 includes sphingomyelin (brain) (47.944 mg/g) as a lipid, Tween
80 (42.056 mg/g) as a surfactant, lactate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 5
[0153] Formulation 5 includes sphingomyelin lauroyl (50.607 mg/g) as a lipid, Brij 98 (44.393 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (10.000 mg/g).
Example Formulation 6
[0154] Formulation 6 includes sphingomyelin lauroyl (90.561 mg/g) as a lipid, Brij 98 (79.439 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g)
as as antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 7
[0155] Formulation 7 includes sphingomyelin lauroyl (49.276 mg/g) as a lipid, Brij 98 (79.439 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 8
[0156] Formulation 8 includes phosphatidyl choline and phosphatidyl glycerol (53.750 mg/g) as a lipid, Brij 98 (31.250 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 9
[0157] Formulation 9 includes phosphatidyl choline and phosphatidyl glycerol (90.561 mg/g) as a lipid, Brij 98 (79.439 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as as antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 10
[0158] Formulation 10 includes phosphatidyl choline and phosphatidyl glycerol
(41.351mg/g) as a lipid, Brij 98 (48.649 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 11
[0159] Formulation 11 includes phosphatidyl choline and phosphatidyl glycerol (47.882 mg/g) as a lipid, Brij 98 (37.118 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 12
[0160] Formulation 12 includes phosphatidyl choline and phosphatidyl glycerol (95.764 mg/g) as a lipid, Brij 98 (74.236 mg/g) as a surfactant, phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 13
[0161] Formulation 13 includes phosphatidyl choline and phosphatidylmositol (66.676 mg/g) as a lipid, Span 20 (24.324 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (25.000 mg/g).
Example Formulation 14
[0162] Formulation 14 includes phosphatidyl choline and phosphatidylmositol (62.027 mg/g) as a lipid, Span 20 (22.973 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 15
[0163] Formulation 15 includes phosphatidyl choline and phosphatidylmositol (124.054 mg/g) as a lipid, Span 20 (45.946 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent, and ethanol (36.510 mg/g).
Example Formulation 16
[0164] Formulation 16 includes phosphatidyl choline and phosphatidylmositol (62.687 mg/g) as a lipid, Span 20 (32.313 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, HTHQ (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 17
[0165] Formulation 17 includes phosphatidyl choline and phosphatidic acid (41.853 mg/g) as a lipid, Tween 80 (43.147 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl
alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 18
[0166] Formulation 18 includes phosphatidyl choline and phosphatidic acid (95.764 mg/g) as a lipid, Tween 80 (74.236 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 19
[0167] Formulation 19 includes phosphatidyl choline and phosphatidic acid (47.882 mg/g) as a lipid, Brij 98 and Tween 80 (37.118 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, and EDTA (3.000 mg/g).
Example Formulation 20
[0168] Formulation 20 includes phosphatidyl choline and phosphatidic acid (45.000 mg/g) as a lipid, Span 20 and Tween 80 (45.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as as antioxidant, and EDTA (1.000 mg/g).
Example Formulation 21
[0169] Formulation 21 includes phosphatidyl choline (31.935 mg/g) as a lipid, cremophor and Span 20 (58.065 mg/g) as a surfactant, lactate (pH 5) buffer, thimerosal (5.000 mg/g) as an antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 22
[0170] Formulation 22 includes phosphatidyl choline (42.500 mg/g ) as a lipid, cremophor and Tween 80 (42.500 mg/g ) as a surfactant, lactate (pH 6.5) buffer, thimerosal (5.000 mg/g) as an antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 23
[0171] Formulation 23 includes phosphatidyl choline (38.276 mg/g) as a lipid, cremophor (51.724 mg/g) as a surfactant, lactate (pH 4) buffer, thimerosal (5.000 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (36.510 mg/g).
Example Formulation 24
[0172] Formulation 24 includes phosphatidyl choline (42.500 mg/g ) as a lipid, cremophor (42.500 mg/g) as a surfactant, lactate (pH 4) buffer, thimerosal (5.000 mg/g) as an antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 25
[0173] Formulation 25 includes phosphatidyl choline (85.000 mg/g) as a lipid, cremophor (85.000 mg/g) as a surfactant, lactate (pH 4) buffer, thimerosal (5.000 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 26
[0174] Formulation 26 includes phosphatidyl choline (38.276 mg/g) as a lipid, cremophor (51.276 mg/g) as a surfactant, lactate (pH 5) buffer, thimerosal (5.000 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, and EDTA (1.000 mg/g) as a chelating agent.
Example Formulation 27
[0175] Formulation 27 includes phosphatidyl choline (36.429 mg/g) as a lipid, cremophor (48.571 mg/g) as a surfactant, lactate (pH 5) buffer, thimerosal (5.000 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 28
[0176] Formulation 28 includes phosphatidyl choline (72.299 mg/g) as a lipid, cremophor (97.701 mg/g) as a surfactant, lactate (pH 5) buffer, thimerosal (5.000 mg/g) as an
antimicrobial agent, BHA (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 29
[0177] Formulation 29 includes phosphatidyl ethanolamine (46.250 mg/g) as a lipid, Tween 80 (46.250 mg/g) as a surfactant, phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g)
as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (20.000 mg/g).
Example Formulation 30
[0178] Formulation 30 includes phosphatidyl ethanolamine (38.804 mg/g) as a lipid, Tween 80 (46.196 mg/g) as a surfactant, phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as an antioxidant, glycerol (15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 31
[0179] Formulation 31 includes phosphatidyl ethanolamine (36.667 mg/g) as a lipid, Brij 98 and Tween 80 (33.333 mg/g) as a surfactant, phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 32
[0180] Formulation 32 includes phosphatidyl glycerol (23.333 mg/g) as a lipid, cremophor and Brij 98 (66.667 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 33
[0181] Formulation 33 includes phosphatidyl glycerol (45.833 mg/g) as a lipid, Brij 98 (41.667 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 34
[0182] Formulation 34 includes phosphatidyl glycerol (31.957 mg/g) as a lipid, Brij 98 (38.043 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as as antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 35
[0183] Formulation 35 includes phosphatidyl glycerol (47.143 mg/g) as a lipid, Brij 98 (42.857 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, and ethanol (25.000 mg/g).
Example Formulation 36
[0184] Formulation 36 includes phosphatidyl glycerol (96.905 mg/g) as a lipid, Brij 98 (88.095 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (20.000 mg/g).
Example Formulation 37
[0185] Formulation 37 includes phosphatidyl glycerol (31.957 mg/g) as a lipid, Brij 98 (38.043) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 38
[0186] Formulation 38 includes phosphatidyl ethanolamine (35.455 mg/g) as a lipid, cremophor (54.545 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 39
[0187] Formulation 39 includes phosphatidyl ethanolamine (84.457 mg/g) as a lipid, cremophor (100.543 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 40
[0188] Formulation 40 includes phosphatidyl ethanolamine (89.048 mg/g) as a lipid, cremophor (80.952 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as
antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 41
[0189] Formulation 41 includes phosphatidyl glycerol (41.087 mg/g) as a lipid, Tween 80 (48.913 mg/g) as a surfactant, propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (36.510 mg/g).
Example Formulation 42
[0190] Formulation 42 includes phosphatidyl glycerol (45.280 mg/g) as a lipid, Tween 80 (39.720 mg/g) as a surfactant, propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 43
[0191] Formulation 43 includes phosphatidyl glycerol (107.500 mg/g) as a lipid, Tween 80 (62.500 mg/g) as a surfactant, propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 44
[0192] Formulation 44 includes phosphatidyl glycerol (77.243 mg/g) as a lipid, Tween 80 (67.757 mg/g) as a surfactant, propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 45
[0193] Formulation 45 includes phosphatidyl glycerol (45.280 mg/g) as a lipid, Tween 80 (39.720 mg/g) as a surfactant, propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 46
[0194] Formulation 46 includes phosphatidyl glycerol (90.561 mg/g) as a lipid, Tween 80 (79.439 mg/g) as a surfactant, propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 47
[0195] Formulation 47 includes phosphatidyl glycerol (47.944 mg/g) as a lipid, Tween 80 (42.056 mg/g) as a surfactant, propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, EDTA (3.000 mg/g) as a chelating agent, and ethanol (10.000 mg/g).
Example Formulation 48
[0196] Formulation 48 includes phosphatidyl serine (50.607 mg/g) as a lipid, Brij 98 (44.393 mg/g) as a surfactant, phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), and EDTA (1.000 mg/g) as a chelating agent.
Example Formulation 49
[0197] Formulation 49 includes phosphatidyl serine (107.500 mg/g) as a lipid, Brij 98 (62.500 mg/g) as a surfactant, phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as
antioxidants, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 50
[0198] Formulation 50 includes phosphatidyl serine (47.944 mg/g) as a lipid, Brij 98 (42.056 mg/g) as a surfactant, phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g) as an antimicrobial agent, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as
antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 51
[0199] Formulation 51 includes phosphatidyl glycerol (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (25.000 mg/g).
Example Formulation 52
[0200] Formulation 52 includes phosphatidyl glycerol (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (20.000 mg/g).
Example Formulation 53
[0201] Formulation 53 includes phosphatidyl glycerol (46.098 mg/g) as a lipid, Brij 98 (43.902 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 54
[0202] Formulation 54 includes phosphatidyl glycerol (43.537 mg/g) as a lipid, Brij 98 (41.463 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 55
[0203] Formulation 55 includes phosphatidyl glycerol (45.000 mg/g) as a lipid, Brij 98 (45.000 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 56
[0204] Formulation 56 includes phosphatidyl glycerol (59.492 mg/g) as a lipid, Brij 98 (30.508 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 57
[0205] Formulation 57 includes phosphatidyl glycerol (39.054 mg/g) as a lipid, Brij 98 (45.946 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 58
[0206] Formulation 58 includes phosphatidyl glycerol (35.854 mg/g) as a lipid, Brij 98 (34.146 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 59
[0207] Formulation 59 includes phosphatidyl choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 60
[0208] Formulation 60 includes phosphatidyl choline (38.571 mg/g) as a lipid, Tween 80 (51.429 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 61
[0209] Formulation 61 includes phosphatidyl choline (41.954 mg/g) as phospholipid, Tween 80 (50.546 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 62
[0210] Formulation 62 includes phosphatidyl choline (42.632 mg/g) as a lipid, Tween 80 (47.368 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 63
[0211] Formulation 63 includes phosphatidyl choline (46.098 mg/g) as a lipid, Tween 80 (43.902 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as
antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 64
[0212] Formulation 64 includes phosphatidyl choline (39.721 mg/g) as a lipid, Tween 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 65
[0213] Formulation 65 includes phosphatidyl choline (44.198 mg/g) as a lipid, Tween 80 (50.802 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 66
[0214] Formulation 66 includes phosphatidyl choline (46.453 mg/g) as a lipid, Tween 80 (51.047 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 67
[0215] Formulation 67 includes phosphatidyl choline (51.221 mg/g) as a lipid, Tween 80 (43.779 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 68
[0216] Formulation 68 includes phosphatidyl choline (54.167 mg/g) as a lipid, Tween 80 (43.333 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 69
[0217] Formulation 69 includes phosphatidyl choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 69 is an emulsion.
Example Formulation 70
[0218] Formulation 70 includes phosphatidyl choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 70 is a suspension.
Example Formulation 71
[0219] Formulation 71 includes phosphatidyl choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 72
[0220] Formulation 72 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 72 is an emulsion.
Example Formulation 73
[0221] Formulation 73 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 73 is a suspension.
Example Formulation 74
[0222] Formulation 74 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 75
[0223] Formulation 75 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 76
[0224] Formulation 76 includes phosphatidyl choline (40.000 mg/g) as a lipid, Brij 98 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 77
[0225] Formulation 77 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 78
[0226] Formulation 78 includes phosphatidyl choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzalkonium chloride (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 79
[0227] Formulation 79 includes phosphatidyl choline (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000
mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 80
[0228] Formulation 80 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 81
[0229] Formulation 81 includes phosphatidyl choline (40.000 mg/g) as a lipid, Tween 80 (50.000 mg/g) as a surfactant, acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 82
[0230] Formulation 82 includes phosphatidyl choline (44.444 mg/g) as a lipid, Tween 80 (55.556 mg/g) as a surfactant, acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 83
[0231] Formulation 83 includes phosphatidyl choline (66.440 mg/g) as a lipid, Tween 80 (23.560 mg/g) as a surfactant, acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 84
[0232] Formulation 84 includes phosphatidyl choline (54.000 mg/g) as a lipid, Tween 80 (36.000 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 85
[0233] Formulation 85 includes phosphatidyl choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 86
[0234] Formulation 86 includes phosphatidyl choline (48.611 mg/g) as a lipid, Tween 80 (38.889 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 87
[0235] Formulation 87 includes phosphatidyl choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 87 is an emulsion.
Example Formulation 88
[0236] Formulation 88 includes phosphatidyl choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 88 is suspension.
Example Formulation 89
[0237] Formulation 89 includes phosphatidyl choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 90
[0238] Formulation 90 includes phosphatidyl choline (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a surfactant, acetate (pH 4.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 91
[0239] Formulation 91 includes phosphatidyl choline (94.444 mg/g) as a lipid, Tween 80 (75.556 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 92
[0240] Formulation 92 includes phosphatidyl choline (46.712 mg/g) as a lipid, Tween 80 (38.288 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 93
[0241] Formulation 93 includes phosphatidyl choline (48.889 mg/g) as a lipid, Tween 80 (39.111 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 94
[0242] Formulation 94 includes phosphatidyl choline (39.721 mg/g) as a lipid, Tween 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.25 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 95
[0243] Formulation 95 includes phosphatidyl choline (90.000 mg/g) as a lipid, phosphate buffer (pH 6.5), benzyl alcohol or paraben as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 96
[0244] Formulation 96 includes phosphatidyl choline (68.700 mg/g) as a lipid, Tween 80 (8.500 mg/g) as a surfactant, phosphate (pH 7.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (30.000 mg/g), EDTA (1.000 mg/g) as a chelating agent, and ethanol (36.51 mg/g).
Example Formulation 97
[0245] Formulation 97 includes phosphatidyl choline (71.460 mg/g) as a lipid, Tween 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (35.000 mg/g).
Example Formulation 98
[0246] Formulation 98 includes phosphatidyl choline (71.460 mg/g) as a lipid, Tween 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, glycerol (15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (35.000 mg/g).
Example Formulation 99
[0247] Formulation 99 includes phosphatidyl choline (71.460 mg/g) as a lipid, Tween 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (15.000 mg/g).
Example Formulation 100
[0248] Formulation 100 includes phosphatidyl choline (71.460 mg/g) as a lipid, Tween 80 (4.720 mg/g) as a surfactant, phosphate (pH 7.8) buffer, BHA (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (50.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (35.000 mg/g).
Example Formulation 101
[0249] Formulation 101 includes phosphatidyl choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200mg/g) as antioxidants, and EDTA (3.000 mg/g) as a chelating agent. Example formulation 101 is an emulsion.
Example Formulation 102
[0250] Formulation 102 includes phosphatidyl choline (46.575 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200mg/g) as antioxidants, and EDTA (3.000 mg/g). Example formulation 102 is a suspension.
Example Formulation 103
[0251] Formulation 103 includes phosphatidyl choline (54.643 mg/g) as a lipid, Tween 80 (30.357 mg/g) as a surfactant, phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium metabisulfite (0.200mg/g) as antioxidants, and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 104
[0252] Formulation 104 includes phosphatidyl choline (39.72 mg/g)as a lipid, Tween 80 (50.279 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.00 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g) as emollient, EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000 mg/g).
Example Formulation 105
[0253] Formulation 105 includes phosphatidyl choline (90.00 mg/g) as a lipid, phosphate (pH 6.5) buffer, benzyl alcohol or paraben as antimicrobial (5.000 mg/s), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g) as emollient, EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000 mg/g).
Example Formulation 106
[0254] Formulation 106 includes phosphatidyl choline (46.57 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium
metabisulfite (0.200mg/g) as antioxidants, and EDTA (3.000 mg/g) as the chelating agent. Formulation 106 is formulated as an emulsion.
Example Formulation 107
[0255] Formulation 107 includes phosphatidyl choline (46.57 mg/g) as a lipid, Tween 80 (38.425 mg/g) as a surfactant, phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200mg/g) as antioxidants, and EDTA (3.000 mg/g) as the chelating agent. Formulation 107 as a suspension.
Example Formulation 108
[0256] Formulation 108 includes phosphatidyl choline (54.64 mg/g)as a lipid, Tween 80 (30.357 mg/g) as a surfactant, phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium metabisulfite (0.200mg/g) as antioxidants, EDTA (3.000 mg/g) as the chelating agent.
Example Formulation 109
[0257] Formulation 109 includes phosphatidyl glycerol and lysophospholipid (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (25.000 mg/g).
Example Formulation 110
[0258] Formulation 110 includes phosphatidyl glycerol and lysophospholipid (46.364 mg/g) as a lipid, Brij 98 (38.636 mg/g) as a surfactant, acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (20.000 mg/g).
Example Formulation 111
[0259] Formulation 111 includes phosphatidyl glycerol and lysophospholipid (46.098 mg/g) as a lipid, Brij 98 (43.902 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (15.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 112
[0260] Formulation 112 includes phosphatidyl glycerol and lysophospholipid (43.537 mg/g) as a lipid, Brij 98 (41.463 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 113
[0261] Formulation 113 includes phosphatidyl glycerol and lysophospholipid (45.000 mg/g) as a lipid, Brij 98 (45.000 mg/g) as a surfactant, acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 114
[0262] Formulation 114 includes phosphatidyl glycerol and lysophospholipid (59.492 mg/g) as a lipid, Brij 98 (30.508 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 115
[0263] Formulation 115 includes phosphatidyl glycerol and lysophospholipid (39.054 mg/g) as a lipid, Brij 98 (45.946 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 116
[0264] Formulation 116 includes phosphatidyl glycerol and lysophospholipid (35.854 mg/g) as a lipid, Brij 98 (34.146 mg/g) as a surfactant, acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) as an antioxidant, glycerol (30.000 mg/g), and EDTA (3.000 mg/g) as a chelating agent.
Example Formulation 117
[0265] Formulation 117 includes phosphatidyl choline and lysophospholipid (50.000 mg/g) as a lipid, Tween 80 (40.000 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 118
[0266] Formulation 118 includes phosphatidyl choline and lysophospholipid (38.571 mg/g) as a lipid, Tween 80 (51.429 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 119
[0267] Formulation 119 includes phosphatidyl choline and lysophospholipid (41.954 mg/g) as phospholipid, Tween 80 (50.546 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
Example Formulation 120
[0268] Formulation 120 includes phosphatidyl choline and lysophospholipid (42.632 mg/g) as a lipid, Tween 80 (47.368 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 121
[0269] Formulation 121 includes phosphatidyl choline and lysophospholipid (46.098 mg/g) as a lipid, Tween 80 (43.902 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 122
[0270] Formulation 122 includes phosphatidyl choline and lysophospholipid (39.721 mg/g) as a lipid, Tween 80 (50.279 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 123
[0271] Formulation 123 includes phosphatidyl choline and lysophospholipid (44.198 mg/g) as a lipid, Tween 80 (50.802 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 124
[0272] Formulation 124 includes phosphatidyl choline and lysophospholipid (46.453 mg/g) as a lipid, Tween 80 (51.047 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 125
[0273] Formulation 125 includes phosphatidyl choline and lysophospholipid (51.221 mg/g) as a lipid, Tween 80 (43.779 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 126
[0274] Formulation 126 includes phosphatidyl choline (54.167 mg/g) as a lipid, Tween 80 (43.333 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
Example Formulation 127
[0275] Formulation 127 includes phosphatidyl choline and lysophospholipid (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 69 is an emulsion.
Example Formulation 128
[0276] Formulation 128 includes phosphatidyl choline and lysophospholipid (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium
metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g). Example formulation 70 is a suspension.
Example Formulation 129
[0277] Formulation 129 includes phosphatidyl choline and lysophospho lipid (66.440 mg/g) as a lipid, Brij 98 (23.560 mg/g) as a surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) as antioxidants, glycerol (30.000 mg/g), EDTA (3.000 mg/g) as a chelating agent, and ethanol (30.000 mg/g).
[0278] It will be understood that the exact amounts of the components of the formula may be adjusted slightly without departing from the scope of the methods and compositions disclosed herein. For example, in each of the above formulations, the amount antimicrobial be 5.25 mg/g.
[0279] Example Formulations 1 through 129 may also optionally include thickeners such as pectin, xanthan gum, HPMC gel, methylcellulose or carbopol.
[0280] Example Formulations 1 through 129 may optionally be diluted into water by a factor of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, or about 10.
[0281] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
[0282] Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.
[0283] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising", "having," "including," containing", etc. shall be read expansively and without limitation (e.g., meaning "including, but not
limited to,"). Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.
[0284] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.
Claims
1. A method comprising administering to a plant, seed or soil a formulation comprising one or more phospholipids and one or more surfactants.
2. The method of claim 1, wherein said formulation is effective as one or more selected from the group consisting of an acaricide, avicide, herbicide, insecticide,
molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, synergist.
3. The method of claim 1 or 2, wherein the formulation is a cream, lotion, ointment, gel, solution, spray, lacquer or film forming solution.
4. The method of claim 1 or 2, wherein the formulation is administered for at least 12 weeks.
5. The method of claim 4, wherein the ratio of phospholipid to surfactant is 1/1 to 5/1 w/w.
6. The method of claim 4, wherein the formulation contains 2.0-10.0% by weight phospholipid.
7. The method of claim 6, wherein the formulation comprises two or more phospholipids.
8. The method of claim 1 or 2, wherein the formulation contains 1.0-5.0% by weight surfactant.
9. The method of claim 8, wherein the formulation comprises two or more surfactants.
10. The method of claim 4, wherein the phospholipid is phosphatidylcholine.
11. The method of claim 1 or 2, wherein the surfactant is a nonionic surfactant selected from the group consisting of: polyoxyethylene sorbitans, polyhydroxyethylene stearates or polyhydroxyethylene laurylethers.
12. The method of claim 11, wherein the surfactant is polysorbate 80 (Tween
13. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin (brain) (47.944 mg/g), Tween 80 (42.056 mg/g), lactate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
14. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin (brain) (53.750 mg/g), Tween 80 (31.250 mg/g), lactate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (15.000 mg/g).
15. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin (brain) (90.561 mg/g), Tween 80 (79.439 mg/g), lactate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
16. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin (brain) (47.944 mg/g), Tween 80 (42.056 mg/g), lactate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
17. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin lauroyl (50.607 mg/g), Brij 98 (44.393 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g). EDTA (3.000 mg/g), and ethanol (10.000 mg/g).
18. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin lauroyl (90.561 mg/g), Brij 98 (79.439 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
19. The method of claim 1 or 2 wherein the formulation comprises sphingomyelin lauroyl (49.276 mg/g), Brij 98 (79.439 mg/g), acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g)and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
20. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidyl glycerol (53.750 mg/g), Brij 98 (31.250 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
21. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidyl glycerol (90.561 mg/g), Brij 98 (79.439 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (.0200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
22. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidyl glycerol (41.351 mg/g), Brij 98 (48.649 mg/g), phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), pectin thickener, glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
23. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidyl glycerol (47.882 mg/g), Brij 98 (37.1 18 mg/g), phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), glycerol, EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
24. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidyl glycerol (95.764 mg/g), Brij 98 (74.236 mg/g), phosphate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
25. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidylinositol (66.676 mg/g), Span 20 (24.324 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (25.000 mg/g).
26. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidylinositol (62.027 mg/g), Span 20 (22.973 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g). EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
27. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidylinositol (124.054 mg/g), Span 20 (45.946 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (36.510 mg/g).
28. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidylinositol (62.687 mg/g), Span 20 (32.313 mg/g), acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), HTHQ (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
29. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidic acid (41.853 mg/g), Tween 80 (43.147 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
30. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidic acid 95.764 mg/g), Tween 80 (74.236 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
31. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidic acid (47.882 mg/g), Tween 80 (37.118 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), and EDTA (3.000 mg/g).
32. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline and phosphatidic acid (45.000 mg/g), Tween 80 (45.000 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), and EDTA (3.000 mg/g).
33. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (31.935 mg/g), cremophor (58.065 mg/g), lactate (pH 5) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (15.000 mg/g).
34. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (42.500 mg/g ), cremophor (42.500 mg/g ), lactate (pH 6.5) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
35. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (38.276 mg/g), cremophor (51.724 mg/g), lactate (pH 4) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (36.510 mg/g).
36. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (42.500 mg/g), cremophor (42.500 mg/g ), lactate (pH 4) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (15.000 mg/g).
37. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (85.000 mg/g), cremophor (85.000 mg/g), lactate (pH 4) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
38. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (38.276 mg/g), cremophor (51.276 mg/g), lactate (pH 5) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), and EDTA (3.000 mg/g).
39. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (36.429 mg/g), cremophor (48.571 mg/g), lactate (pH 5) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
40. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (72.299 mg/g), cremophor (97.701 mg/g), lactate (pH 5) buffer, thimerosal (5.000 mg/g), BHA (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (15.000 mg/g).
41. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (46.250 mg/g), Tween 80 (46.250 mg/g), phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (20.000 mg/g).
42. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (38.804 mg/g), Tween 80 (46.196 mg/g), phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (15.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
43. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (36.667 mg/g), Tween 80 (33.333 mg/g), phosphate (pH 6.5) buffer, thimerosal (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
44. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (23.333 mg/g), Brij 98 (66.667 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), and EDTA (3.000 mg/g).
45. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (45.833 mg/g), Brij 98 (41.667 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
46. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (31.957 mg/g), Brij 98 (38.043 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
47. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (47.143 mg/g), Brij 98 (42.857 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (25.000 mg/g).
48. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (96.905 mg/g), Brij 98 (88.095 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (20.000 mg/g).
49. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (31.957 mg/g), Brij 98 (38.043), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
50. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (35.455 mg/g), cremophor (54.545 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
51. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (84.457 mg/g), cremophor (100.543 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
52. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl ethanolamine (89.048 mg/g), cremophor (80.952 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
53. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (41.087 mg/g), Tween 80 (48.913 mg/g), propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (36.510 mg/g).
54. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (45.280 mg/g), Tween 80 (39.720 mg/g), propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), and EDTA (3.000 mg/g).
55. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (107.500 mg/g), Tween 80 (62.500 mg/g), propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
56. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (77.243 mg/g), Tween 80 (67.757 mg/g), propionate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
57. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (45.280 mg/g), Tween 80 (39.720 mg/g), propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
58. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (90.561 mg/g), Tween 80 (79.439 mg/g), propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
59. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (47.944 mg/g), Tween 80 (42.056 mg/g), propionate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), EDTA (3.000 mg/g), and ethanol (10.000 mg/g).
60. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl serine (50.607 mg/g) as a lipid, Brij 98 (44.393 mg/g), phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g) , glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
61. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl serine (107.500 mg/g) as a lipid, Brij 98 (62.500 mg/g) as a surfactant, phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
62. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl serine (47.944 mg/g) as a lipid, Brij 98 (42.056 mg/g), phosphate (pH 5.5) buffer, thimerasol (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
63. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (46.364 mg/g), Brij 98 (38.636 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (25.000 mg/g).
64. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (46.364 mg/g), Brij 98 (38.636 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (20.000 mg/g).
65. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (46.098 mg/g), Brij 98 (43.902 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (15.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
66. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (43.537 mg/g), Brij 98 (41.463 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
67. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (45.000 mg/g), Brij 98 (45.000 mg/g), acetate (pH 5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
68. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (59.492 mg/g), Brij 98 (30.508 mg/g), acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
69. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (39.054 mg/g), Brij 98 (45.946 mg/g), acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), and EDTA (3.000 mg/g).
70. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl glycerol (35.854 mg/g), Brij 98 (34.146 mg/g), acetate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g), glycerol (30.000 mg/g), and EDTA (3.000 mg/g).
71. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (50.000 mg/g), Tween 80 (40.000 mg/g), phosphate (pH 6.5), benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
72. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (38.571 mg/g), Tween 80 (51.429 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
73. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (41.954 mg/g), Tween 80 (50.546 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
74. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (42.632 mg/g), Tween 80 (47.368 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
75. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.098 mg/g), Tween 80 (43.902 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
76. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (39.721 mg/g), Tween 80 (50.279 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
77. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (44.198 mg/g), Tween 80 (50.802 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
78. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.453 mg/g), Tween 80 (51.047 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
79. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (51.221 mg/g) as phospholipid, Tween 80 (43.779 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
80. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (54.167 mg/g) as phospholipid, Tween 80 (43.333 mg/g) as surfactant, phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
81. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Brij 98 (23.560 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as an emulsion.
82. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Brij 98 (23.560 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as a suspension.
83. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Brij 98 (23.560 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
84. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as an emulsion.
85. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as a suspension.
86. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
87. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
88. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Brij 98 (50.000 mg/g), phosphate (pH 6.5) buffer, benzalkonium chloride (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
89. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
90. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Brij 98 (23.560 mg/g), phosphate (pH 6.5) buffer, benzalkonium chloride (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
91. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Brij 98 (23.560 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
92. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), acetate (pH 5.5) buffer, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
93. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (40.000 mg/g), Tween 80 (50.000 mg/g), acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g) as an antimicrobial, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
94. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (44.444 mg/g) as phospholipid, Tween 80 (55.556 mg/g), acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
95. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (66.440 mg/g), Tween 80 (23.560 mg/g), acetate (pH 5.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
96. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (54.000 mg/g), Tween 80 (36.000 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
97. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (50.000 mg/g), Tween 80 (40.000 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
98. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (48.611 mg/g), Tween 80 (38.889 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
99. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.575 mg/g), Tween 80 (38.425 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as an emulsion.
100. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.575 mg/g), Tween 80 (38.425 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHA (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g) and formulated as a suspension.
101. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.575 mg/g), Tween 80 (38.425 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
102. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (50.000 mg/g), Tween 80 (40.000 mg/g), acetate (pH 4.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
103. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (94.444 mg/g), Tween 80 (75.556 mg/g), acetate (pH 4) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
104. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.712 mg/g), Tween 80 (38.288 mg/g), acetate (pH 4), benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
105. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (48.889 mg/g), Tween 80 (39.111 mg/g), acetate (pH 4), benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
106. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (39.721 mg/g), Tween 80 (50.279 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.25 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
107. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (90.000 mg/g), phosphate buffer (pH 6.5), benzyl alcohol or paraben, BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
108. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.575 mg/g), Tween 80 (38.425 mg/g), phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200), and EDTA (3.000 mg/g) and formulated as an emulsion.
109. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.575 mg/g), Tween 80 (38.425 mg/g), phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200), and EDTA (3.000 mg/g) and formulated as a suspension.
110. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (54.643 mg/g), Tween 80 (30.357 mg/g), phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium metabisulfite (0.200), and EDTA (3.000 mg/g).
111. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (39.72 mg/g), Tween 80 (50.279 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g), and ethanol (30.000 mg/g).
112. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (90.00 mg/g), phosphate (pH 6.5) buffer, benzyl alcohol or paraben (5.000 mg/g), BHT (0.200 mg/g) and sodium metabisulfite (0.500 mg/g), glycerol (30.000 mg/g), EDTA (3.000 mg/g) as the chelating agent, and ethanol (30.000 mg/g).
113. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (68.700 mg/g), Tween 80 (8.500 mg/g), phosphate (pH 7.5) buffer, BHT (0.200 mg/g), sodium metabisulfite (0.500 mg/g), benzyl alcohol or paraben (5.000 mg/g), EDTA (1.000 mg/g), glycerol (30.000 mg/g), and ethanol (36.510 mg/g).
114. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.57 mg/g), Tween 80 (38.425 mg/g), phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200mg/g), and EDTA (3.000 mg/g); formulated as an emulsion.
115. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (46.57 mg/g), Tween 80 (38.425 mg/g), phosphate (pH 4) buffer, BHT (0.500 mg/g) and sodium metabisulfite (0.200mg/g), and EDTA (3.000 mg/g); formulated as a suspension.
116. The method of claim 1 or 2 wherein the formulation comprises phosphatidyl choline (54.64 mg/g), Tween 80 (30.357 mg/g), phosphate (pH 4) buffer, BHA (0.500 mg/g) and sodium metabisulfite (0.200) as antioxidants, and EDTA (3.000 mg/g).
117. The method of any of the preceeding claims, wherein the formulation further comprises an active agent selected from the group consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
118. The method of any of the preceeding claims, wherein the forumulation comprises one or more active agents selected from the agents listed on Table 9.
119. The method of any of the preceeding claims, wherein the forumulation does not include any of the active agents listed on Table 9.
120. A method for controlling weeds, pests, insects, diseases in or on a plant, a field of plants or a crop, said method comprising administering to said plant, field of plants or crop a formulation as in any of the preceeding claims.
121. A formulation having the compositions of any of Example Formulations 1-125 and further comprising one or more active agent selected from the agents on Table 9.
122. The method of any of the preceeding claims wherein said plant is selected from the group consisting of canola, sunflower, tobacco, sugar beet, cotton, maize, wheat, barley, rice, sorghum, tomato, mango, peach, apple, pear, strawberry, banana, melon, potato, carrot, lettuce, onion, soya spp, sugar cane, pea, field beans, poplar, grape, citrus, alfalfa, rye, oats, turf and forage grasses, flax, oilseed rape, cucumber, morning glory, balsam, pepper, eggplant, marigold, lotus, cabbage, daisy, carnation, tulip, iris, lily, and nut producing plants. A package, bag or kit, comprising a formulation such as in any of the preceeding claims, and instructions for indicating that the formulation is suitable for application to a plant, seed or soil.
123. The package, bag or kit, wherein said instructions further indicate that the formulation is suitable for use as one or more selected from the group consisting of consisting of an acaricide, avicide, herbicide, insecticide, molluscicide, virucide, algicide, antibiotic, bactericide, fungicide, nematicide, rodenticide, plant growth regulator, seed treatment, chemosterilant, insect attractant, mammal repellent, antifeedant, bird repellant, herbicide safener, insect repellant, mating disrupter, pesticide, plant activator, and synergist.
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US29853210P | 2010-01-26 | 2010-01-26 | |
US61/298,532 | 2010-01-26 | ||
US32196610P | 2010-04-08 | 2010-04-08 | |
US61/321,966 | 2010-04-08 |
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WO2011094219A1 true WO2011094219A1 (en) | 2011-08-04 |
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PCT/US2011/022439 WO2011094219A1 (en) | 2010-01-26 | 2011-01-25 | Vesicular formulations |
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RU2497363C1 (en) * | 2012-07-27 | 2013-11-10 | Ильшат Ахатович Гайсин | Composition for stimulation of growth and development of agricultural crops |
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