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WO2024127397A1 - Rehydratable ingestible plant-based formulation - Google Patents

Rehydratable ingestible plant-based formulation Download PDF

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Publication number
WO2024127397A1
WO2024127397A1 PCT/IL2023/051264 IL2023051264W WO2024127397A1 WO 2024127397 A1 WO2024127397 A1 WO 2024127397A1 IL 2023051264 W IL2023051264 W IL 2023051264W WO 2024127397 A1 WO2024127397 A1 WO 2024127397A1
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WO
WIPO (PCT)
Prior art keywords
colloid
dry powder
composition
mixture
water
Prior art date
Application number
PCT/IL2023/051264
Other languages
French (fr)
Inventor
Dan Lewitus
Almog UZIEL
Gavriel KLIN
Original Assignee
Ipt Edibles Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ipt Edibles Ltd. filed Critical Ipt Edibles Ltd.
Publication of WO2024127397A1 publication Critical patent/WO2024127397A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/20—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents
    • A23L29/206—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin
    • A23L29/256—Foods or foodstuffs containing additives; Preparation or treatment thereof containing gelling or thickening agents of vegetable origin from seaweeds, e.g. alginates, agar or carrageenan
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • the present invention in some embodiments thereof, relates to an edible formulations, and more particularly, but not exclusively, to dry formulations of water-insoluble lipophilic substances that can be rehydrated in an aqueous carrier to form an edible colloid.
  • bioactive agents e.g., drugs, vitamins, etc.
  • oral administration is limited by problems related to physico-chemical properties of the bioactive, including poor solubility, low permeability, instability, and rapid metabolism, all of which decrease oral bioavailability.
  • bioactive agents are characterized by poor aqueous solubility, which limits oral bioavailability. These bioactive agents have low solubility which leads to low dissolution and limits absorption. This poor solubility not only gives low oral bioavailability but also leads to high inter- and intra-subject variability and lack of dose proportionality. Also, some of these bioactive agents have enhanced bioavailability when co-administered along with food. In order to formulate such bioactive agents in a safe and efficacious form, a balance must be maintained between bioavailability, toxicity and disposition within the body. Various techniques like micronization, complexation with cyclodextrins, solid dispersions, permeation enhancers, lipids and surfactants have been reported to overcome some solubility and permeability issues.
  • Substances originating from plants are used in many applications, including food, food supplement, medicine, cosmetics and pleasure (taste, color, shape). Plants are a source of nutritional and medicinal products for millennia, with many useful drugs developed from plant sources. However, the quality and concentration of substances and functionality, e.g., color, taste or humidity of plants, varies depending on the origin of species, the geographic localization, seasonality, the nature of the soil, growing conditions, harvest date, etc. Further, natural plants can comprise undesired substances or be contaminated, e.g., with bacterial loads, pesticides, heavy metals, mycotoxins and toxic substances. Still further, the desired substances from a natural plant can in many cases not be easily extracted during digestion, e.g., the lycopene trapped in the skin of tomatoes.
  • processed plants can be consumed in different forms, e.g., fresh, dehydrated, cooked, fermented or concentrated (extracts), once of the more convenient and controllable forms of consumption is a form that can be quantified and delivered easily, without compromising the efficacy and bioavailability of the desired bioactive agents of the plant.
  • extracts e.g., fresh, dehydrated, cooked, fermented or concentrated
  • Oral administration of plant extracts is oftentimes characterized by lower bioavailability, long onset time, uncontrolled effect duration and instability of the extract.
  • Some of the disadvantages of oral consumption are low bioavailability due to poor solubility of the desired active substances in water, and decomposition of active substances.
  • WO 2021/084527 to some of the present inventors, the contents of which are incorporated herein by reference, provides solid self-emulsifying cannabis plant extract formulations, methods for their preparation and uses thereof.
  • the provisions of WO 2021/084527 are based on a plant extract formulation comprising whole cannabis plant extract, a solid carrier and a lipidic component wherein upon rehydrating the solid formulation in liquid, the cannabis plant extract is self-emulsified within the liquid.
  • U.S. Patent No. 11,013,715 provides compositions, having nanosized droplets, wherein the nanosized droplets may contain a cannabinoid oil, a dietically acceptable carrier oil, a surfactant, and water. Also disclosed herein are methods of making and using the same.
  • Apricity, Inc. claims to provide nano-sized hydrophilic (water-attractant) emulsifier to encapsulate active cannabinoids by enveloping the oil-based cannabinoids, thereby producing a water-soluble formulation that is safe, reliable, and extremely effective.
  • Apricity, Inc. technology is said to be applicable for any cannabinoid (CBD, CBG, THC, CBC, etc.) or terpene.
  • WO 2021026366 provides compositions comprising cannabinoids and active ingredients and/or excipients and methods of producing the compositions.
  • WO 2021/003091 provides beverage compositions comprising a mixture of: (a) an emulsion of about 2 wt % of a cannabinoid; about 2-10 wt % of a carrier oil; about 2-24 wt % of an amphipathic glycoside; and about 64-94 wt % of water; and (b) a polyphenol or tannin rich beverage base, wherein the beverage composition does not precipitate over an extended time. Also disclosed herein are methods of making and using the same.
  • WO 20201/50616 provides solid, micellar compositions, comprising micelles of one or more cannabinoid acids and a metal, wherein the cannabinoid acids are in a salt form, the salt form has a monovalent counter ion, and the micelles are free of added surfactants, are disclosed, as well as processes for obtaining the same, and methods of treating a number of disorders using the same.
  • WO 2021/138597 provides a water-soluble cannabinoid-containing solid dispersion and method of preparation thereof; the solid dispersion comprises one or more cannabinoids as active ingredients, a hydrophilic polymeric carrier, an antioxidant and optionally the palatability- improving agent.
  • the solid dispersion is suitable for oral delivery application in form of solid material or an aqueous colloidal dispersion or for transdermal delivery application.
  • WO 2022/066936 provides beverages including an active emulsion and a blank emulsion, wherein the blank emulsion is used as a sacrificial agent to retain the active emulsion's potency within an infused beverage.
  • WO 2020/035850 discloses a water-dispersible solid formulation of a cannabinoid or a cannabis extract, present in the form of a nanoemulsion, and upon dispersion in water said formulation produces droplets of a submicron size with an average size of up to about 500 nm, as well as methods of making thereof, and therapeutic applications in humans for treating disorders and broader application for a range of medical conditions.
  • WO 2022/024126 discloses compositions that increase oral bioavailability of beneficial edible lipophilic substances such as edible oils, oil-soluble vitamins, and nutraceuticals.
  • the present invention provides a highly effective rendering of non-soluble lipophilic substances into easy-to-use drinkable formulation that can be prepared by an end user utilizing everyday tools and methods.
  • the invention provides dry powder compositions prepared from lipophilic substances, such as oily plant extracts, that can be dissolved/suspended/emulsified into edible aqueous colloids (a drink), while improving the bioavailability and the efficiency of the active ingredients in the substance, compared to other modes of administration of the same.
  • a dry powder composition which includes: a room-temperature liquid (RTL) lipophilic substance;
  • RTL room-temperature liquid
  • X-carrageenan (lambda-carrageenan); a surfactant; and a room-temperature solid (RTS) lipid; wherein:
  • X-carrageenan constitutes 10-25 wt.% of the composition
  • the RTL lipophilic substance constitutes 3-80 wt.% of the composition
  • the surfactant constitutes 8-10 wt.% of the composition
  • the RTS lipid constitutes 3-60 wt.% of the composition
  • the dry powder composition is characterized by at least one of: an average particle size that ranges 1 - 5,000 pm; a water activity of less than 0.5; and a humidity of less than 10 %.
  • the dry powder composition provided herein is a dehydration residue of an original colloid, that forms a regenerated colloid upon mixing the dry powder composition with an aqueous medium.
  • the dry powder composition provided herein is essentially devoid of a gelling agent that is not naturally occurring in the lipophilic substance; for example, devoid of gelatin.
  • the dry powder composition provided herein is essentially devoid of a polyphenol that is not naturally occurring in the lipophilic substance.
  • the dry powder composition provided herein is essentially devoid of an animal-based ingredient that is not naturally occurring in the lipophilic substance.
  • the dry powder composition provided herein includes maltodextrin.
  • the dry powder composition provided herein includes glucomannan.
  • glucomannan constitutes 10-25 wt.% of the total weight of the composition.
  • glucomannan together with the X-carrageenan constitutes 10-25 wt.% of the total weight of the composition.
  • the RTS lipid is a triglyceride.
  • the triglyceride is stearin (glyceryl tristearate).
  • the surfactant is added to the original colloid as an extract of Quillaja saponaria and/or Quillaja brasiliensis containing natural triterpene glycosides (saponins).
  • the surfactant is a triterpene glycoside (a saponin).
  • the dry powder composition provided herein further includes an additive, such as, for a non-limiting example, a food preservative, an antioxidant, an anticaking agent, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food supplement, and a pharmaceutical agent.
  • an additive such as, for a non-limiting example, a food preservative, an antioxidant, an anticaking agent, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food supplement, and a pharmaceutical agent.
  • the lipophilic substance is an oily plant extract.
  • the oily plant extract is a cannabis plant extract.
  • the lipophilic substance is a wax, namely a solid that melts at 40-70 °C, which liquifies during the preparation of the dry powder composition, as presented herein.
  • the dry powder composition provided herein consists of generally recognized as safe (GRAS) ingredients, and the composition is an edible composition.
  • GRAS generally recognized as safe
  • a dry powder composition which includes: from 45 to 55 wt.% of an oily cannabis extract as an RTL lipophilic substance; from 20 to 25 wt.% of /.-carrageenan as a non-gelling thickening agent; from 8 to 10 wt.% saponin as a surfactant; from 4 to 5 wt.% glyceryl tristearate as a RTS lipid; and from 8 to 10 wt.% maltodextrin.
  • a regenerated colloid that includes the dry powder composition as provided herein, and an aqueous medium.
  • the aqueous medium is water, or an edible/drinkable aqueous solution.
  • additional ingredients in the aqueous solution may be, for a nonlimiting example, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food additive/supplement, and a pharmaceutical agent.
  • the regenerated colloid provided herein is afforded by mixing the dry powder composition as provided herein, with the aqueous medium, for example at roomtemperature, or with the aqueous medium heated, for example, to about 30-90 °C, thereby obtaining the regenerated colloid (or generating the colloid from the dry powder).
  • mixing the dry powder is effected by manual stirring using a household container and a household utensil.
  • the regenerated colloid as provided herein is characterized by at least one of: a particle size of less than 1000 nm; and a loading efficiency of at least 90 % of the active ingredients compared to the original colloid.
  • the regenerated colloid is for use in the treatment of a medical condition in a subject in need thereof, which is treatable by at least one bioactive agent in the RTL lipophilic substance.
  • a process of preparing the dry powder composition as provided herein which is effected by: mixing the lipophilic substance with the room-temperature solid lipid at a temperature equal or higher than a melting point of the lipid to thereby obtain a lipophilic mixture; mixing under heat the non-gelling thickening agent and the surfactant in water to thereby obtain an aqueous mixture; combining (stirring) the lipophilic mixture and the aqueous mixture to thereby obtain a biphasic mixture; adding hot water to the bi-phasic mixture and homogenizing the hot water and the bi-phasic mixture to thereby obtain the original colloid; and freeze-dry the original colloid to thereby afford the dry powder composition.
  • the process further includes adding optional lipophilic ingredients to the lipophilic mixture, and/or adding optional water-soluble ingredients to the aqueous mixture.
  • a method of treating a medical condition in a subject in need thereof that includes orally administering the regenerated colloid as provided herein, prepared from the dry powder composition provided herein.
  • the lipophilic substance is a cannabis extract
  • the medical condition is selected from the group consisting of pain, insomnia, depression, anxiety, PTSD, multiple sclerosis, migraines, fibromyalgia, seizures, Alzheimer’s disease, dementia, Parkinson’s disease, Crohn’s disease, and glaucoma.
  • FIG. 1 presents a flowchart of the basic steps in the process of preparing the dry powder provided herein;
  • the present invention in some embodiments thereof, relates to an edible formulations, and more particularly, but not exclusively, to dry formulations of water-insoluble lipophilic substances that can be rehydrated in an aqueous carrier to form an edible colloid.
  • the present inventors While seeking to improve the stability and regeneration of colloids of/from dry rehydratable lipophilic plant liquid extract formulation, the present inventors have surprisingly found that forming a colloid of a room-temperature liquid (RTL) lipophilic (oily) plant extract with a non-gelling carbohydrate of an edible algae source, and subsequently drying the colloid affords a powder that can be mixed with water to regenerate the colloid while preserving the amount and activity of the bioactive agents in the lipophilic substances originating from the plant extract.
  • RTL room-temperature liquid
  • RTL lipophilic substances can be rendered as a dry powder composition from an original colloid, which can be rehydrated to form a regenerated colloid of the RTL lipophilic substances.
  • These regenerated colloids can be ingested as a form of oral delivery vehicle, which have been shown to exhibit high oral bioavailability, especially compared to other modes of administration of the same lipophilic substances.
  • a dry powder of a rehydratable colloid A dry powder of a rehydratable colloid:
  • dry powder composition being the dehydration residue of an original colloid, which includes: a room-temperature liquid (RTL) lipophilic substance, a non-gelling thickening agent, a surfactant, and a room-temperature solid (RTS) lipid.
  • RTL room-temperature liquid
  • RTS room-temperature solid
  • the present invention is drawn to a dry powder that is obtained from drying (dehydrating) a colloid or an emulsion - a powder that can be rehydrated to form (regenerate) the colloid it originated from when mixing the powder with the same amount of water that was evaporated, or any colloid that comprises the components of the original colloid when the powder is rehydrated with any aqueous medium.
  • the dry and rehydratable powder is referred to herein as a “rehydratable dry powdered colloid”, a “rehydratable colloid”, a “rehydratable dry powder composition”, or simply a “dry powder composition”.
  • the dry powder composition of the present invention is characterized primarily by the capacity to rehydrate to generate a colloid upon mixing the dry powder in an aqueous media, such as water.
  • the dry powder composition is obtained by dehydrating an aqueous mixture that is referred to herein as the original aqueous mixture, or the original colloid.
  • the original aqueous mixture is characterized by being a colloid of a lipophilic substance, and more specifically, a room-temperature liquid lipophilic substance.
  • colloid refers to a mixture of a compound or a plurality of compounds that can be in solid, liquid or gas state, and a liquid.
  • a colloid is generally a homogeneous noncrystalline substance consisting of large molecules or complexes, or ultramicroscopic particles of a substance (the substance may comprise a plurality of different types of compounds) dispersed through a second substance that is a liquid, whereas the dispersed particles do not settle down spontaneously (stable).
  • colloids include: Sol - a colloidal suspension which has solid particles distributed in a liquid; Emulsion - a colloidal suspension containing a combination of two liquids; Foam - this forms when gas particles get trapped in a liquid or a solid; and Aerosol - forms when solid or liquid particles distribute throughout the air.
  • colloid and emulsion are often used synonymously but it should be kept in mind that emulsions result when immiscible liquids are mixed whereas in a colloid solution it can be a liquid or solid dispersion in another liquid.
  • an emulsion can be termed as a colloid but not all colloids are emulsions.
  • colloids there are three forms of colloids; multimolecular colloids, macromolecular colloids, and micelles. This classification categorizes colloids according to the particle size and behavior of those particles in a colloid.
  • a multimolecular colloid forms if the molecules of a compound aggregate when the compound is dissolve in a suitable solvent.
  • macromolecular colloid the individual particles are large enough for the mixture to be called a colloid.
  • micelles it contains an aggregate of molecules in a colloidal solution, such as those formed by detergents/surfactants in a spherical manner.
  • the rehydratable dry powder composition is a result of dehydrating an original aqueous mixture, which falls under the definition of a colloid, as defined hereinabove.
  • the rehydratable dry powder composition is a result of dehydrating a sol-type or an emulsion-type colloid, and is further characterized by the capacity to rehydrate to form a sol-type or an emulsion-type colloid.
  • the colloid that is afforded by rehydrating the dry powder composition provided herein is referred to herein interchangeably as an “edible colloid” or a “regenerated colloid”.
  • the rehydratable dry powder composition provided herein forms a sol-type or an emulsion-type colloid upon rehydration thereof in an aqueous medium, which can be water or any aqueous solution or carrier.
  • an aqueous medium which can be water or any aqueous solution or carrier.
  • the dry powder composition provided herein can rehydrate to afford a regenerated colloid that is essentially identical in composition (and possibly concentration) to the original colloid when rehydrated with water, or a different colloid when rehydrated with any aqueous solution, adding ingredients that were not part of the original colloid.
  • dehydration residue refers to the product obtained from a solution, a suspension or a colloid, which has been subjected to a drying process, wherein most of or essentially all the liquid carrier has been removed.
  • the drying process may include room-temperature drying, drying under heating, and freeze drying.
  • the dehydration residue is obtained by subjecting the original colloid to freeze-drying.
  • the rehydratable dry powder composition is characterized by chemical, physical and mechanical stability, low hygroscopic nature, and long-term rehydratablilty.
  • Moisture contents of the powder provided herein can be determined by drying the powder in an oven at a temperature of at least about 50, 60, 70, 80 or 90 °C until consecutive constant weights are obtained, and optionally followed by 1- or 2-hours interval weighting, which gave variation less than 0.3 %. Moisture content expressed as % of moisture in wet basis.
  • Bulk (dry) density of the powder provided herein can be measured by gently adding a few (e.g., 2) grams of powder to an empty graduated cylinder (e.g., 10 mL) and holding the cylinder in a vibrator for a few moments (e.g., 1 min). The volume is then recorded and used to calculate the bulk density in g/mL.
  • Rehydration rate of the powder provided herein can be determined by adding a few grams (e.g., 2 g) of powder into distilled water (e.g., a 50 mL) at room-temperature (e.g., 25 °C) in a low form glass beaker (e.g., 100 mL). The mixture is agitated on a hot plate/stirrer at a given speed (e.g., 900 rpm) using a magnetic stirrer bar with a given size (e.g., 2-7 mm), and the time in seconds required for the powder to be completely rehydrated is recorded.
  • a given speed e.g., 900 rpm
  • Hygroscopicity is the ability of a substance (e.i., the powder) to absorb moisture from high relative humidity environment.
  • a substance e.i., the powder
  • carbohydrates and sugars may be responsible for significant interaction with the water molecules due to the polar terminals present in these molecules.
  • Hygroscopicity of the powder provided herein can be determined by placing a few grams (e.g., 2 g) of the powder in the flow-path of air having a known and steady humidity level (air bubbled through a saturate solution of a salt having about 75-85 % relative humidity), and thereafter calculating the increase in weight of the sample after a given time interval(s) to express hygroscopicity in percent of the weight of the hygroscopic moisture per gram of dry solid sample.
  • parameters which can be used to characterize the dry powder provided herein include degree of caking, dispersibility, flowability and other parameters used to define a powder, particularly when intended for storage and rehydration. These parameters can be measured and determined by any method known in the art, such as, for example, the methodologies presented by Jaya, S. et al. [Journal of Food Engineering, 2004, 63, pp. 125-134].
  • the dry powder composition is a dehydration residue of an original colloid, which characterized by at least one of: an average particle size that ranges 1 - 5,000 pm, a moisture content (humidity) of less than 1 %, less than 2 %, less than 3 %, less than 4 %, less than 5 %, less than 6 %, less than 7 %, less than 8 %, less than 9 %, or less than 10 % humidity (water) in the dry composition; and a water activity of less than 0.2, less than 0.3, less than 0.4, less than 0.5, less than 0.6, less than 0.8, less than 0.9, or less than 1.
  • the dry powder composition is further characterized by a degree of caking of less than 50 %, less than 60 %, less than 70 %, less than 80 % or less than 90 %. According to some preferred embodiments, the degree of caking is less than 50 %.
  • Caking of powders used in the food and pharmaceutical industries can be assessed and quantitated using any method known in the art; for example, see Freeman, T. et al., “Measurement and Quantification of Caking in Powders”, Procedia Engineering, 2015, 102, pp. 35-44, D01:10.1016/j.proeng.2015.01.104.
  • the original colloid, the dry composition derived therefrom, and the regenerated colloid, as discussed hereinbelow contain GRAS and edible ingredients, and are therefore also edible (fit, suitable and approved for human consumption by eating or drinking).
  • the amount of each of the ingredients of the composition is given below as a percent by weight of the ingredient out of the total weight of the non- water (dry) ingredients on the composition.
  • the composition provided herein is essentially a delivery vehicle for edible substances that, given in a particular formulation, can be absorbed into the body by oral administration and ingestion, and preferably a vehicle for edible lipophilic substances that do not or hardly dissolve in water.
  • the dry composition provided herein constitutes a formulation of a lipophilic substance which can easily turned into an ingestible colloid that can be prepared by the user in as much effort as required to prepare a cup of instant coffee.
  • Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents, and is oftentimes estimated in values of the partition coefficient of a given substance.
  • a partition coefficient can be determined empirically, such as the n-octanol-water partition coefficient, or K ow , which is a partition coefficient for the two-phase system consisting of n-octanol and water. K ow is also frequently referred to by the symbol P, and it is called n- octanol-water partition ratio and reported in log units as LogPow.
  • the partition coefficient LogP can also be calculated based on molecular descriptors and observational data (CLogP).
  • the lipophilicity of a substance can be determined empirically or estimated computationally, and stated in terms of LogP.
  • LogP encompasses experimental (LogP ow ) and/or calculated (CLogP), as well a distribution coefficient (D; LogD), and other representation of lipophilicity expresses in log units and that is commonly used to denote lipophilicity in quantitative terms.
  • lipophilic substance is a molecular entity, a complex of molecules, a macromolecule, a nanoparticle, an oily extract or a mixture of substances that is essentially lipophilic as a mixture even if it contains some water-soluble components.
  • the present invention is particularly useful for turning a room-temperature liquid lipophilic substance into a dry and rehydratable powder, which can be ingested as an aqueous colloid by simply mixing the powder in water using any household kitchen utensils and dishes.
  • the lipophilic substance is a roomtemperature liquid lipophilic substance, or for short, “RTL lipophilic substance”, which is a lipophilic substance that liquifies above 14 °C, or above 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, or above 30 °C.
  • RTL lipophilic substance is a lipophilic substance that liquifies above 14 °C, or above 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, or above 30 °C.
  • the lipophilic substance used to form the dry powder provided herein is a liquid above a 14-30 °C in its isolated form (not as part of the colloid or the powder presented herein) - such lipophilic substance is also referred to herein as an RTL lipophilic substance.
  • the lipophilic substance is a wax at room-temperature, which melts at relatively low temperatures (40-70 °C), such as used in the process of preparing the dry powder composition provided herein.
  • a waxy lipophilic substance can also be rendered liquid by adding thereto a small amount of oil, or a small amount of an organic solvent, thereby liquidating the wax without heating.
  • the organic solvent can be an edible (GRAS) substance, and/or a substance that can easily be evaporated off the composition during the preparation process.
  • the lipophilic substance is characterized by a partition coefficient (LogP) of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 log units.
  • the partition coefficient of the lipophilic substance is greater than 5, and more preferably, the partition coefficient of the lipophilic substance is greater than 6.
  • the partition coefficient of the lipophilic substance is greater than 7 log units.
  • the RTL lipophilic substance is, or contains tetrahydrocannabinol (THC) having a LogP ow of 7.2 log units, astaxanthin (a keto-carotenoid; LogP 6.8) and D-alpha-tocopherol (Vitamin E; LogP 10.7).
  • THC tetrahydrocannabinol
  • the amount of the RTL lipophilic substance in the dry composition correlates to the amount of the RTL lipophilic substance used to form the original colloid.
  • the amount of the RTL lipophilic substance in the dry composition ranges 3-60 wt.%, or ranges 3-80 wt.%, or ranges 30-80 wt.%, or ranges 50-80 wt.%.
  • the amount of the RTL lipophilic substance in the dry composition is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, or at least 80 wt.% of the total weight of the composition.
  • water-immiscible refers to a property of chemical substances, compounds and molecular entities that are characterized by low water solubility.
  • Low water solubility can also be referred to as a substance that is characterized by water solubility of less than 10 mg/L or less than 10 ppm.
  • the present invention is not limited to plant extracts that include water-immiscible components; therefore, the plant extract may include components characterized by moderate water solubility (i.e., 10-1,000 mg/L or 10-1,000 ppm) and by high water solubility (more than 1,000 mg/L or 1,000 ppm).
  • the lipophilic substance used in forming the dry powdered composition is characterized by comprising a water-immiscible component content, or lipophilic component content of at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, or at least 95 wt.% of a water- immiscible component with respect to the total weight of the plant extract.
  • the lipophilic substance is an oily (liquid) extract of a plant.
  • the lipophilic substance is a mixture of molecular entities, such as in the case of a plant extract
  • the lipophilicity of the most lipophilic element of the liquid mixture is taken as the lipophilicity of the RTL lipophilic substance (mixture) as a whole.
  • the lipophilicity of the plant extract is taken from the partition coefficient of the most water-immiscible component of the plant extract, or the average partition coefficient of the major water-immiscible components of the extract.
  • the present invention provides a general solution to the problem of providing an edible formulation of phytochemicals originating from plant extract (whole extract, partial extract or otherwise) and having low aqueous solubility, and more specifically, providing an edible (drinkable) formulation of phytochemicals originating from an oily liquid plant extract.
  • the formulations provided herein are useful in a wide spectrum of applications, including nutrition, pharmaceutical, cosmetics, recreation and leisure.
  • the present invention is suitable for preparing a dry rehydratable powder ready for re-emulsification in hot or cold water from any plant extract having any water- insoluble phytochemicals.
  • Bioactive phytochemicals from plant materials can be extracted by various extraction techniques.
  • Most of the conventional/classical/traditional techniques are based on the extracting power of different solvents in use and the application of heat and/or mixing.
  • the existing classical techniques are, without limitation, soxhlet extraction, maceration and hydrodistillation.
  • the major challenges of conventional extraction are longer extraction time, requirement of costly and high purity solvent, evaporation of the huge amount of solvent, low extraction selectivity and thermal decomposition of thermo labile compounds.
  • new and promising extraction techniques have been introduced. These techniques are referred as nonconventional extraction techniques.
  • Some of the most promising techniques are ultrasound assisted extraction, enzyme-assisted extraction, microwave-assisted extraction, pulsed electric field assisted extraction, supercritical fluid extraction and pressurized liquid extraction. Some of these techniques are considered as “green techniques” as they comply with standards set by the US Environmental Protection Agency. These include less hazardous chemical synthesis; designing safer chemicals, safe solvents auxiliaries, design for energy efficiency, use of renewable feedstock, reduce derivatives, catalysis, design to prevent degradation, atom economy, and time analysis for pollution prevention and inherently safer chemistry for the prevention of accident.
  • the plant extract having low water-solubility bioactive phytochemicals is a whole cannabis extract.
  • Whole cannabis medicinal extract (CME) has been used for many years as a medicinal and recreational agent. Oral consumption of water-based cannabis extract beverages is limited due to the poor water solubility of the lipophilic phytocannabinoids and other entourage phytochemicals.
  • enhancement of solubility of CME for water-based preparations is a goal sought by many, and achieved by the provisions of the present invention.
  • the present invention provides a solution to the problems associated with forming stable aqueous-based edible (and drinkable) colloids from oily (fatty liquid) plant extracts which include water-immiscible oily components.
  • component refers to one or more compounds that form a part of the plant extract, whereas the plant extract may include water-miscible components as well.
  • the amount of the oily plant extract in the dry composition is derived from the amount of the plant extract used to form the original colloid.
  • the amount of the plant extract ranges 5-60 wt.%, and more preferably is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, or at least 60 wt.% of the total weight of the composition.
  • the plant extract used in forming the dry powdered composition is characterized by comprising a water-immiscible or and/or oily lipophilic component content of at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, or at least 95 wt.% of a water- immiscible component with respect to the total weight of the plant extract.
  • the plant extract is an oily extract that is generally water-immiscible and/or lipophilic.
  • the use of a plant extract rather than isolated active compounds is justified and advantageous when considering the “entourage effect”.
  • the entourage effect is a proposed mechanism by which cannabis compounds other than tetrahydrocannabinol (THC), such as found in a whole cannabis extract, act synergistically with it to modulate the overall psychoactive effects of the plant.
  • THC tetrahydrocannabinol
  • the phrase entourage effect was introduced in 1999; while originally identified as a novel method of endocannabinoid regulation by which multiple endogenous chemical species display a cooperative effect in eliciting a cellular response, the term has evolved to describe the polypharmacy effects of combined cannabis phytochemicals or whole plant extracts.
  • Other cannabinoids, terpenoids, and flavonoids may be part of an entourage effect.
  • Cannabinoids generally have a very low solubility in water and are highly lipophilic. Consequently, these materials cannot readily be absorbed orally and, therefore, a large quantity is required to have a medicinal effect.
  • CBD cannabidiol
  • CBD has a solubility of only 0.7 pg/mL (0.7 ppm), and tetrahydrocannabinol (THC) 2.8 pg/mL.
  • tetrahydrocannabinol is characterized by a LogPow of 7.2 log units, cannabinol (CBN) by LogP 5.58, cannabidiol (CBD) 7.75, cannabicyclol (CBL) 4.96, cannabitriol (CBT) 8.04, cannabielsoin (CBE) 7.64, cannabigerol (CBG) 8.59, cannabichromene (CBC) 8.28, and cannabivarin (CBDV) is characterized by a LogP ow of 6.98 log units.
  • the plant extract is a cannabis extract, comprising at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, or at least 90 wt.% of water- immiscible/lipophilic components.
  • Exemplary RTL lipophilic substance originating from plants, which can be rendered into a dry powder that can be rehydrated into a stable colloid include, without limitation, a cannabinoid or a mixture thereof, a vitamin or a mixture thereof, and an essential oil or a mixture thereof.
  • examples of RTL lipophilic substances include various oily (liquid fatty) total extracts, such as, without limitation, Amaranth Seed extract from Amaranthus caudatus, arnica flower extract from Arnica montana, black cumin seed oil from Nigella sativa, calendula extract from Calendula officinalis, carrot root extract from Daucus carota, chia seed extract from Salvia hispanica, cocoa select extract from Theobroma cacao, coconut extract from Cocos nucifera, coffee extract from Coffea arabica, fenugreek extract from Trigonella foenumgraecum, oat extract from Avena sativa, pomegranate seed extract from Punica granatum, raspberry seed extract from Rubus idaeus, rhatany root extract from Krameria lappacea, rice bran extract from Oryza sativa, rose hip seed extract from Rosa canina, sandalwood seed extract from Santalum spicatum,
  • ingredients of the dry composition are extracted primarily from natural substances, and include stabilizers, thickeners and surfactants that have been approved as direct additives than may be incorporated into foods to provide structure, viscosity, stability and other qualities, such as forming stable and rehydratable colloids.
  • Thickeners, stabilizers and gelling agents are classified separately but overlap in functionality. When dissolved or added to foods, they create stiffness, stabilize emulsions/colloids or form gels.
  • Thickeners range from flavorless powders to gums and are chosen for their ability to work in a variety of chemical and physical conditions. Variables affecting choice of thickener include pH, frozen state, clarity and taste. Starches, pectin and gums are the most common commercial thickeners used in soups, sauces and puddings. Thickening agents also are used in treating medical conditions, such as dysphagia, to make swallowing easier and reduce the risk of aspiration.
  • Stabilizers are substances that increase stability and thickness by helping foods remain in a colloid and retain physical characteristics. Ingredients that normally do not mix, such as oil and water, often need stabilizers. Many low-fat foods are dependent on stabilizers. Lecithin, agar- agar, carrageenan and pectin are common in ice cream, margarine, dairy products, salad dressings and mayonnaise.
  • Gelling agents also function as stabilizers and thickeners to provide thickening without stiffness through the formation of gel in jellies, jams, desserts, yogurts and candies. Gums, starches, pectin, agar-agar and gelatin are common gelling agents.
  • Thickeners, stabilizers and gelling agents must be authorized by the Food and Drug Administration before use in edible products.
  • Standards for food additives are clearly defined with strict criteria, and there must be a documented need for their use before approval is granted. Maximum usage levels vary depending on the additive and the food in which it is used. For example, stabilizers in frozen dairy desserts, fruit and water ices and in confections and frostings cannot exceed 0.5 percent by weight of the final edible product.
  • Emulsifier, flavoring adjuvant, stabilizer or thickener in baked goods have the same 0.5 percent by weight limit with respect to the weight of the final edible product.
  • the composition includes a non-gelling thickening agent.
  • the present inventors have surprisingly found that the type of carrageenan which is the lease commercially used for of the family due to its non-gelling property, namely lambda carrageenan (k-carrageenan), allows the formation of dry and rehydratable dry powdered product that is superior to those obtained with other emulsifying, gelling, and/or thickening agents, including other types of carrageenan.
  • k-carrageenan lambda carrageenan
  • Carrageenans (E number E407) constitute family of natural polysaccharides that are extracted from red edible seaweeds. These large, highly flexible carbohydrate molecules form curling helical structures, which gives them the ability to form a variety of different gels at roomtemperature, for which they are widely used in the food and other industries as gelling, thickening and stabilizing agents.
  • the term “carrageenans” represent one of the three major classes of industrial algal polysaccharides. These water soluble, linear, and sulfated polysaccharides are characterized by alternating P-1-3- and a-l-4-linked galactose residues, with additional substitute residues such as xylose, glucose, methyl esters, and pyruvate groups.
  • Carrageenans are classified by the types of sulfate bonds they contain, including kappa (K- ), iota (r-), lambda (X), and other types. This sub-division mostly represents their distinguished functionality and thus distinguished utility in foods, pharmaceuticals, cosmetics and other industrial uses.
  • K-Carrageenans are mainly composed of D-galactose-4-sulfate and 3,6-anhydro- D-galactose, and the sulfate content of commercial K-CGN is approximately 22 %.
  • the gelling properties of K-CGN have led to its wide adoption in the food and pharmaceutical industries.
  • Kappa-carrageenan yields a strong gel often described as firm and brittle in the presence of potassium ions.
  • the kappa structure is a linear polysaccharide with one sulfate group per two galactose molecules and assumes a helical network that is only strengthened with potassium present.
  • Kappa needs to be solubilized in hot water, but the sodium salts of kappa- carrageenan can be soluble in cold water. The resulting gels are not freeze-thaw stable.
  • Kappa- carrageenan is used in dairy applications with success because it complexes with kappa-casein to form a pourable gel formation.
  • K-carrageenan is used to stabilize air bubbles.
  • processed cheese it can be used to reduce the amount of natural cheese without changing manufacturability or finished product texture.
  • Kappa-carrageenan is also commonly used in meat processing. It enables higher moisture content in meat products like sausages and cooked hams, which results in better yields and improved slicing. In low-fat meat products, using it will result in eating qualities which mimic full fat meat products.
  • Kappa-2 is a weak kappa-carrageenan from a kappa/iota hybrid.
  • the lota-carrageenan structure is also a linear polysaccharide which assumes a helical conformation but with two sulfate groups per two galactose molecules.
  • Iota forms a soft elastic gel especially in the presence of calcium ions (EU) and the resulting gel strength is ionic strength dependent.
  • EU calcium ions
  • iota-carrageenan forms gels with freeze-thaw stability and is less likely to undergo syneresis.
  • the iota form is soluble in hot water, and only the sodium salts of iota-carrageenan are soluble in cold water.
  • Iota-carrageenan gels have the ability to break apart during mechanical action and reform once the mechanical action stops, which is known as thixotropy. This property is helpful in cold- filled products.
  • low usage levels of iota-carrageenan are used to suspend particulates within salad dressings and other beverages like soy milk.
  • iota creates a stronger gel and is used in products like pet foods to create gravy.
  • lambda-carrageenan With a flat structure, lambda-carrageenan has three sulfate groups per two galactose molecules, which does not form a helical structure like the kappa or iota varieties.
  • lambda is a non-gelling polysaccharide mainly used to thicken solutions.
  • iota which uses calcium ions to set
  • lambda-carrageenan does not require ions to achieve a viscous solution.
  • the lambda form is also the only carrageenan which is cold-soluble without being a sodium salt.
  • lambda creates a viscous but pseudoplastic solution, or shearthinning, under mechanical action.
  • liquids like dairy products, syrups, beverages, tomato sauce and salad dressings, lambda can enable a full bodied, creamy texture.
  • Kappa, iota, and lambda carrageenans exhibit distinct characteristics influencing the texture and functionality of the final product. For instance, kappa carrageenan produces a rigid, brittle gel, iota carrageenan forms a softer, elastic gel, and lambda carrageenan contributes thickening properties without gel formation.
  • the non-gelling thickening agent is lambda carrageenan (k-carrageenan).
  • the amount of non-gelling thickening agent depends on the amount of the RTL lipophilic substance, the content of the water-immiscible component therein, and the concentration of other ingredients of the composition, with which the non-gelling agent may produce a favorable synergistic effect, expressed in the properties of the original and regenerated colloid.
  • the amount of X-carrageenan as the non-gelling agent in the dry composition is derived from the amount of the non-gelling thickening agent used to form the original colloid.
  • the amount of the non-gelling agent ranges 5-25 wt.% or 10-25 wt.% of the total weight of the composition.
  • the amount of the non-gelling agent ranges is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, or at least 25 wt.% of the total weight of the composition.
  • the composition includes a surfactant.
  • the surfactant is required to be non-toxic, and compatible with the water-immiscible component of the RTL lipophilic substance (e.g., oily plant extract) and the RTS lipid discussed hereinbelow.
  • the lipid and/or the nongelling thickening agent k-carragccnan act in synergy the surfactant in terms of forming a colloid with the RTL lipophilic substance, which is expressed in the stability of the colloid and the rehydratability (the capacity to rehydrate into a colloid upon mixing with an aqueous media under mild conditions) of the dry composition into a stable drinkable colloid.
  • surfactant s few candidates, which include the same members of the natural triterpene glycoside family, and in particular, saponin.
  • suitable surfactants may include methyl-P-cyclodextrin, P-cyclodextrin, lecithin, and the like, or any combination thereof.
  • a triterpene glycoside (a saponin) is selected as a surfactant/solubility enhancer, based on its superior synergistic effect with the other ingredients of the composition, particularly its interaction with the lipid, and more specifically, with stearin.
  • Saponins may be introduced into the original colloid in the form of an extract of Quillaja saponaria and/or Quillaja brasiliensis, which contain natural triterpene glycosides (saponins).
  • the saponin is glycyrrhizinic acid or a salt thereof. In some embodiments, the composition is essentially devoid of glycyrrhizinic acid or any salt thereof.
  • the amount of the surfactant in the dry composition is derived from the amount of the surfactant used to form the original colloid, and depends on the amount of lipophilic substance, the content of the water-immiscible component therein, and the concentration of other ingredients of the composition. In some embodiments, the amount of the surfactant in the original colloid ranges about 1-15 wt.%, 5-15 wt.%, 8-10 wt.%, 2-8 wt.%, 3-7 wt.%, or 4-6 wt.% of the total weight of said original colloid.
  • the original colloid may include at least about 2 wt.%, at least about 5 wt.%, at least about 8 wt.%, at least about 10 wt.%, at least about 12 wt.%, or at least 15 wt.% of the total weight of the composition.
  • Solid lipid
  • the composition further includes a room-temperature solid (RTS) lipid ingredient, also referred to herein as an RTS lipid.
  • RTS room-temperature solid
  • the role of the lipid is to participate in the mechanism that turns the water-immiscible components from the RTL lipophilic substance into fine particulates during the step of removing water from the original colloid.
  • the requirements from the RTS lipid ingredient in the composition provided herein limit the selection of lipids to those that possess a delicate balance between safety (edibility), odor/taste, melting point and hydrophobicity.
  • a suitable lipid is required to be a good solvent for the water- immiscible component of the plant extract, have a melting point in the limited range of 40-100 °C (room-temperature solid), non-toxic and conducive to forming colorless, odorless, and tasteless edible compositions.
  • the lipid should act synergistically with the surfactant, another ingredient of the composition provided herein, making the selection of a suitable lipid even more limited.
  • the lipid is a room-temperature solid lipid, having a melting point that ranges 40-100 °C or 50-90 °C, which is safe for human consumption (non-toxic).
  • the lipid may include, for example, various types of glycerides and/or various types of fatty acids.
  • various types of glycerides may be selected from, but not limited to: triglycerides, medium-chain triglyceride, short-chain triglyceride, partial glyceride, glyceryl tristearate, glyceryl stearate, and the like, or any combination thereof.
  • various types of fatty acids may be selected from, but not limited to: polyoxyethylated fatty alcohol, polyoxyethylated fatty acid, polyoxyethylated fatty acid, esters of fatty acids, and RT-solid forms of vegetable oil, oleic acid, linoleic acid, olive oil, soybean oil, grape seed oil, sunflower oil, peanut oil, com oil, canola oil, coconut oil, and the like, or any combinations thereof, whereas each possibility is a separate embodiment.
  • the lipid is stearin (glyceryl tristearate), trilaurin, tripalmitin, trimyristin, triolein, any fatty acid characterized by a melting point above RT.
  • the lipid is stearin, which acts in synergy with the preferred surfactant and the preferred thickening agent.
  • to act in synergy it is meant in terms of forming a colloid with the plant extract, which is expressed in the stability of the colloid and the rehydratability (the capacity to rehydrate into a colloid upon mixing with an aqueous media under mild conditions) of the dry composition into a stable colloid.
  • the amount of the RTS lipid in the dry composition is derived from the amount of the RTS lipid used to form the original colloid.
  • the original colloid may include RTS lipid in an amount of about 2-40 wt.%, 3-30 wt.%, 4-20 wt.%, 4.5-5 wt.%, 6-18 wt.%, 8-15 wt.%, 10-15, 15-25 wt.%, or 10-30 wt.% of the total weight of the composition.
  • the original colloid may include an RTS lipid in an amount of at least about 2 wt.%, at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, or at least 25 wt.% of the total weight of the composition.
  • Glucomannan (E number E425) is a water-soluble polysaccharide dietary fiber, being a hemicellulose component in the cell walls of some plant species, such as Konjac plant. It is a major source of mannan oligosaccharide (MOS) found in nature, the other being galactomannan, which is insoluble. Glucomannan from the Konjac plant is a glucose-mannose polysaccharide in which 5-10 % of the sugars are acetylated. The molecule is structurally related to glucomannan from guar gum.
  • MOS mannan oligosaccharide
  • Glucomannans are linear copolymers of P-d-glucopyranose (about 30 %) and its 2-epimer, P-d-mannopyranose (about 70 %), joined by ( l ⁇ 4)-linkagcs to form linear chains with DPs ranging from less than 100 to several thousand.
  • the backbone has (1— >6)- linked P-d-galactopyranosyl substituents and is generally esterified with acetyl groups.
  • the shape of the glucomannan polymer is similar to cellulose and it has therefore been suggested that the chains may associate strongly with surfaces of cellulose microfibrils.
  • Glucomannans are extractable from walls with alkaline borate solutions that act by complexing with the mannopyranosyl units.
  • glucomannan has a property to lower the surface tension of the mixture of K-carrageenan gel and glucomannan to form a more elastic gel and lower the brittleness property of K-carrageenan gel so that the gel is made stronger.
  • the mixture of K-carrageenan and Konjac can produce good gels as there is a synergistic relationship in the formation of gels so as to produce gels with higher gel strength, better texture, and better elasticity.
  • Konjac as a gelling agent, has a unique ability to form reversible and irreversible gels at different conditions.
  • Konjac can form a gel by heating it to 85 °C under alkaline conditions (pH 9-10), forming a gel that is heat resistant (irreversible) and remained stable under reheating at a temperature of 100 °C and even at a temperature of 200 °C.
  • glucomannan can replace some of the k-carrageenan in the composition to some extent, while still producing colloid that are conducive to the drying and rehydration objective.
  • the amount of glucomannan in the composition ranges 10-25 wt.% of the total weight of the composition, whereas in some embodiments, glucomannan can replace some of the k-carrageenan, up to 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, or replacement of 90 % of the k-carrageenan in the composition.
  • the amount of the additive in general is in the range of 1-5 wt.% of the total weight of the dry ingredients of the composition.
  • the ingredients, components and agents which are mentioned herein as excluded from the composition provided herein are excluded from the ingredients that are added to the plant extract and not from the plant extract itself.
  • the composition provided herein is essentially devoid of an animal-based (sourced from animals) ingredient.
  • dry of hydrated forms of any milk, dairy, non-diary milk and/or plant-based and/or animal-based proteins are excluded from the composition provided herein.
  • the composition is essentially devoid of milk, and specifically essentially devoid of a protein, except for naturally occurring proteins present in the plant extract.
  • gelling agents, plant and/or animal-based gelling agents are excluded from the composition provided herein. That includes gelatin, with is expressively excluded from the composition provided herein, such that the composition is essentially devoid of gelatin.
  • glucomannan Expressively excluded from the exclusion of gelling agents is glucomannan, which is known as capable of forming stable gels. The exclusion of glucomannan from the exclusion of gelling agents is based on the favorable interaction of glucomannan with the non-gelling agent /.-carrageenan, which is assumed to be synergistically exceptional.
  • polyphenols are excluded from the composition provided herein.
  • the composition is essentially devoid of a polyphenol such as phenolic acids, flavonoids, stilbenes, and lignans, except for naturally occurring polyphenols present in the plant extract.
  • the composition provided herein is essentially devoid of simple sugars, such as, for example, glucose, fructose, galactose, sucrose, lactose, maltose, as well as essentially devoid of sugar alcohols, such as, for example, xylitol, sorbitol, erythritol, lactitol, mannitol, maltitol, trehalose and isomaltitol, except for naturally occurring sugars and sugar alcohols that are present in the lipophilic substance (e.g., plant extract).
  • simple sugars such as, for example, glucose, fructose, galactose, sucrose, lactose, maltose
  • sugar alcohols such as, for example, xylitol, sorbitol, erythritol, lactitol, mannitol, maltitol, trehalose and isomaltitol, except for naturally occurring sugars and sugar alcohols
  • the composition provided herein is essentially devoid of synthetic surfactants, such as poloxamers (e.g., PluronicTM, KolliphorTM, and SynperonicTM), and others, such as colfosceril, pumactant, lucinactant and beractant.
  • synthetic surfactants such as poloxamers (e.g., PluronicTM, KolliphorTM, and SynperonicTM), and others, such as colfosceril, pumactant, lucinactant and beractant.
  • the composition provided herein is essentially devoid of synthetic substances.
  • the dry powder composition is capable of being rehydrated to afford a colloid, using water or another aqueous solution, jointly referred to herein as an aqueous medium, wherein the colloid afforded by rehydrating the dry powdered composition provide herein is referred to as an “regenerated colloid”, which is an aqueous edible/drinkable colloid.
  • the regenerated colloid of the present invention is easily afforded by simply mixing the dry composition with an aqueous medium, using any mixing tool.
  • the regeneration of the colloid is effected by using cold aqueous media, aqueous media at room-temperature, or warm (30-90 °C) aqueous media, and the mixing can be effected using any mixing means, including household utensil or stirrer. Mixing, shaking or stirring the dry composition with the aqueous medium in any container, including household shaker, may be effected manually, or by using a power tool.
  • the regenerated colloid can be identical or similar to the original colloid, which has been freeze-dried to afford the dry powder composition.
  • the regenerated colloid is afforded by rehydrating the dry powder composition with less or more water than the content of water in the original colloid, then regenerated colloid will have a higher or a lower concentration of the plant extract, respectively.
  • the regenerated colloid is afforded by rehydrating the dry powder composition with an aqueous solution that includes solute, the regenerated colloid will have higher, similar or lower concentration of the plant extract in addition to the solutes originating from the added aqueous solution.
  • the water or aqueous solution can be at room-temperature, or heated to 30-80 °C.
  • the aqueous solution can include preservatives, antioxidants, coloring agents, flavoring/taste agents, pH-modulating agents, nutritional additives/supplements, pharmaceutical agent and drugs, and the likes.
  • the original and regenerated colloid are each a homogeneous mixture wherein the particles do not settle out on standing (stable colloid).
  • a stable regenerated colloid results when the dry powder composition in turned into a colloid wherein the suspended droplets and/or particles have an average side ranging between 1 and 1000 nanometers in diameter (not to be confused with the parameters of the dry powder that generates the colloid), dispersed in the aqueous medium (water or an aqueous solution). Colloids can be distinguished from solutions as they exhibit light scattering.
  • the regenerated colloids are characterized by:
  • Process of preparation starts by preparing two liquid compositions, a lipophilic mixture that includes the RTL lipophilic substance of interest mixed with a small amount of molten RTS lipid and other optional lipophilic ingredients, and an aqueous mixture that includes X-carrageenan, a surfactant and other optional water-soluble ingredients.
  • the two mixtures are heated and mixed together, and the combined mixtures are added to hot water in excess of about 4X the volume of the combined mixtures, and the resulting mixture is homogenized to form a colloid.
  • the colloid is thereafter freeze-dried to afform the dry powder.
  • FIG. 1 presents a flowchart of the basic steps in the process of preparing the dry powder provided herein.
  • the heat can be employed also to melt waxy lipophilic substances, rendering this type of lipophilic substances suitable for the formulating dry powders therefrom according to some embodiments of the present invention.
  • the lipophilic substance is a liquid at mild temperatures ranging from 40-70 °C
  • the process of preparing the dry powder composition includes the step of mixing and heating both the waxy lipophilic substance with the room-temperature solid lipid to a temperature at which both ingredients liquify.
  • treating a medical condition encompasses alleviating, at least to some degree, at least one symptom associated with the medical condition.
  • the dry powder composition originating from dehydration of a colloid of a lipophilic substance having low aqueous solubility, can be rehydrated and consumed as an edible colloid, whereas the contents of the colloid can be regarded as an oral administration of the bioactive agent(s) in the lipophilic substance.
  • the lipophilic substance is a plant extract
  • the colloid can be used to treat medical or cosmetic condition which is treatable by active agents in the plant extract.
  • the colloid can be used to treat medical conditions that are ameliorated by cannabinoids.
  • lipophilic substances that are known for their nutraceutical, therapeutic, and/or recreational activity can be formulated as a dry powder, according to embodiments of the present invention, and become more bioavailable due to the transformation from an oily substance into a drinkable colloid.
  • a method of treating a medical condition in a subject in need thereof which is effected by orally administering the regenerated colloid provided herein to the subject.
  • Also provided herein is a use of the dry powder composition provided herein, in the preparation of a regenerated colloid , as provided herein, for the treatment of a medical condition in a subject in need thereof which is treatable by at least one of the bioactive agents in the lipophilic substance.
  • the medical condition treatable by the composition provided herein include, without limitation, pain, insomnia, depression, anxiety, PTSD, multiple sclerosis, migraines, fibromyalgia, seizures, Alzheimer’s disease, dementia, Parkinson’s disease, Crohn’s disease, and glaucoma.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • the phrases “substantially devoid of” and/or “essentially devoid of” in the context of a certain substance refer to a composition that is totally devoid of this substance or includes less than about 5, 1, 0.5 or 0.1 percent of the substance by total weight or volume of the composition.
  • the phrases "substantially devoid of” and/or “essentially devoid of” in the context of a process, a method, a property or a characteristic refer to a process, a composition, a structure or an article that is totally devoid of a certain process/method step, or a certain property or a certain characteristic, or a process/method wherein the certain process/method step is effected at less than about 5, 1, 0.5 or 0.1 percent compared to a given standard process/method, or property or a characteristic characterized by less than about 5, 1, 0.5 or 0.1 percent of the property or characteristic, compared to a given standard.
  • exemplary is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range.
  • the phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
  • process and “method” refer to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, material, mechanical, computational and digital arts.
  • Ethanol extraction of high-THC cannabis sativa was used as an exemplary lipophilic substance, according to embodiments of the present invention.
  • X-carrageenan was obtained from Modernist Pantry, SKU 1060-50;
  • Glyceryl tristearate (69498-250G-F; GT, Sigma- Aldrich);
  • Cannabis extract loading efficiency was calculated according to the formula in Equation 1:
  • Cannabis powder (approximately 4 mg) was dissolved in 500 pl hot water (80 °C, HPLC grade), then precipitated with 4.5 ml ethanol followed by vortex for 1 hour. The suspension was filtered through 0.22 pm PTFE-filters to remove polymeric debris and analyzed for cannabinoid concentration by HPLC . Solubility test
  • Cannabis emulsions were prepared by pouring water at different temperatures (25 °C, 50 °C, and 80 °C) over dry particles. To determine cannabinoid content in the emulsion, 1 ml of supernatant was withdrawn after 15 minutes. The obtained supernatant was freeze-dried, dissolved in 1 ml ethanol, filtered, and then analyzed for cannabinoid content by HPLC.
  • Colloid droplet size and/or solid particle size distribution will be measured with a Malvern Master Sizer 3000.
  • Colloid stability refers to the ability of colloids to resist changes in its physicochemical properties over time. Colloid stability will be assessed by:
  • glyceryl tristearate 50 mg of cannabis extract (high-THC) and 5 mg of glyceryl tristearate (stearin) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • 25 mg of X-carrageenan was dissolved in 10 ml of water at room-temperature, after 10 minutes the vail was heated to 80 °C and 10 mg of maltodextrin and 10 mg of saponin were added to the mixture.
  • the solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized using a homogenizer three times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, and soluble in hot and cold water up to concentration of more than 10 mg/mL.
  • Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • X-carrageenan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (17 mg) and saponin (80 mg) were added to the mixture.
  • the solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added up to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
  • Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml, and homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
  • Cannabis extract (high-CBD) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, soluble in hot and cold water.
  • the dry mixture dissolved also under simulated gastric fluid.
  • Formulation L-C-M-G-l (glucomannan) Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • glucomannan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, soluble in hot and cold water. Did not dissolve as quickly as the L-carrageenan formulation.
  • Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • glucomannan (11.25 mg) and L-carrageenan (11.25 mg) were dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (125 mg) and glyceryl tristearate (131.2 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carrageenan (62.5 mg) was dissolved in hot water (80 °C, 10 ml). After the k-carrageenan dissolved, saponin (3.75 mg) was added to the mixture. When all the components dissolved completely the solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carrageenan (24 mg) was dissolved in RT water (5 ml). After the k- carrageenan dissolved, saponin (9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in a hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying and the solid mixture.
  • Formulation Pl pea protein
  • Cannabis extract (high-THC) (62.5 mg) and glyceryl tristearate (65.6 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • pea protein 31.25 mg was dissolved in RT water (5 ml).
  • saponin 1.9 mg was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Formulation P2 pea protein
  • Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • pea protein 24 mg was dissolved in RT water (5 ml). After the protein dissolved, saponin (9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in a hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (62.5 mg) and glyceryl tristearate (65.6 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • rice protein 31.25 mg was dissolved in RT water (5 ml). After the protein dissolved, saponin (1.9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in the hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • Isomaltose (24 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carragccnan (24 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carragccnan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (18 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Cannabis extract (high-THC) (50mg) and oleic acid (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • X-carrageenan (25 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (10 mg) and saponin (10 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Lecithin (waxy material) (55 mg) and glyceryl tristearate (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate and lecithin.
  • X-carrageenan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (17 mg) and saponin (80 mg) were added to the mixture.
  • the solution was added to the first vial containing the lecithin and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added up to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • the dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
  • a superior non-gelling thickener is L-carragccnan, supplemented or not with glucomannan. It is also noted that some compositions that used a triglyceride (e.g., glyceryl tristearate) as a RTS lipid performed better than some compositions that used a fatty acid (e.g., oleic acid) instead, and further noted that some compositions that used maltodextrin performed better than some compositions that contained no maltodextrin.
  • a triglyceride e.g., glyceryl tristearate
  • a fatty acid e.g., oleic acid
  • Formulation medium chain triglycerides (/.-carrageenan)
  • Oregano oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • X-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • Formulation vitamin D oil (/.-carrageenan)
  • Vitamin D oil 55 mg
  • glyceryl tristearate 4.5 mg
  • k-carrageenan 22.5 mg
  • RT water 10 ml
  • maltodextrin 9 mg
  • saponin 9 mg
  • Black Seed oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture.
  • the solution was added to the first vial and the mixture was vortexed and heated repeatedly.
  • the mixture was poured to a beaker and hot water was added to 40 ml.
  • the mixture was homogenized 3 times for
  • Flux Seed oil 55 mg
  • glyceryl tristearate 4.5 mg
  • k-carrageenan 22.5 mg
  • RT water 10 ml
  • maltodextrin 9 mg
  • saponin 9 mg
  • Formulation Omega 3 oil (/.-carrageenan) Omega 3 oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate.
  • X-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
  • PK Pharmacokinetic properties evaluation of a solid self-emulsifying delivery formulation for oral delivery of whole cannabis plant extract was evaluated following single dose oral administration in Sprague Dawley (SD) rats. In separate studies, blood plasma levels of the major active compounds THC and CBD were assessed over a 2 hours period. The results were compared to a control group, administered with olive oil-based commercial formulation.
  • Water-based cannabis beverage was prepared by pouring hot tap water (30 mL, 80 °C) over dry powder (120 mg) of exemplary Formulation L-C-M3.
  • oil-based beverage was prepared by dissolving the whole-plant cannabis extract (60 mg) in olive oil (OO, 30 mL). Both formulations were at a concentration of 2 mg/mL CME extract in liquid.
  • Test Item and the Control were orally administered according to group allocation. Blood samples were collected from three/four animals at each of the following time points: Baseline [on “Day -1”], 10, 20, 40, 60, 90, 120 min (THC and CBD) and 180 min (CBD only) post dosing. Each rat was bled three to four times (the last one being terminal bleeding).
  • Formulation L-C-M3 containing 53 % w/w of high-THC cannabis extract and 53.5 % of high-CBD cannabis extract was prepared. When mixed with hot water for beverage preparation, a homogeneous emulsion was obtained within a few seconds.
  • the SE cannabis beverage was orally administered to SD rats to evaluate the ability of the formulation to improve the bioavailability and decrease the onset of action of the lipophilic cannabinoids in the extract. PK results
  • SE powder cannabis formulation
  • control olive oil formulations
  • a formulation according to some embodiments of the present invention comprising THC as one of the lipophilic substances, can be tested for subjective psychoactive effect to provide information as for the onset time, time to reach peak effect, and total duration, along with general indication of taste, and overall impression.
  • the trial is conducted with a panel of human volunteers (e.g., 10 eligible members).
  • the average age of the test subjects is about 35-45 years, composed of women and men.
  • a regenerated colloid prepared from the test formulation on site by mixing about 0.5-1 grams of the dry powder with 500 mL of warm water.
  • Each subject is given about 30-70 mL of the prepared, ensuing consumption of at least 15-25 mg of THC per person.
  • all users are provided with a monitoring form, to be filled every five minutes, thus following up on the subjective effects of the drink consumption. Additionally, open questions with regards to the overall impression of the drink are answered.
  • Astaxanthin is a powerful antioxidant, known for its various therapeutic properties including anti-inflammatory and antimicrobial activities. Oral consumption of ATX, specifically in beverages, is limited due to its poor water solubility.
  • PK pharmacokinetic
  • ATX -rich oleoresin blood plasma levels of ATX from ATX -rich oleoresin were assessed over a 4 hours period. The results were compared to a control group, administered with olive oil-based commercial ATX formulation.
  • the following example showed significant improvement in bioavailability in comparison to the traditional ATX resin oil-based product currently used in the production of ATX-based food supplements.
  • the exemplary dry powder rendering of ATX is based on natural ingredients and is also suitable for vegan diets.
  • a dry powder ATX formulation containing 15 % w/w of ATX extract was prepared based on the L-C-M3 formulation presented above, exchanging the cannabis extraction with ATX. When mixed with hot water for beverage preparation, a homogeneous emulsion was obtained within a few seconds. The regenerated ATX colloid was orally administered to SD rats to evaluate the ability of the formulation to improve the bioavailability and decrease the onset of action of the lipophilic ATX in the extract.
  • Water-based ATX beverage (regenerated colloid) was prepared by mixing 1000 mg of the dry powder in hot tap water (60 mL, 70 °C) and cooling the regenerated colloid to 37 °C.
  • oil-based beverage was prepared by dissolving ATX resin (150 mg) in olive oil (OO, 60 mL). Both liquid formulations exhibited ATX concentration of 2 mg/mL.
  • Test Item and the Control were orally administered according to group allocation.
  • Blood samples were collected from three/four animals at each of the following timepoints: Baseline [on Day (-1)], 10, 20, 40, 60, 120, 180, 240 min (post dosing. Blood samples were collected through the sub-mandibular vein (about 500 pL per sample) into K3EDTA tubes. The tubes were gently inverted several times to ensure mixing and immediately placed on wet ice. K3EDTA tubes were then centrifuged for plasma preparation within 30 min after sampling (2000xg for 10 min) at 4 °C. Plasma was frozen and stored in appropriately labeled test-tubes at (-60°C) to (-90 °C). 1 BL sample and all PK samples from 10 to 120 minutes were transferred on ice to the analytical lab for quantification.

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Abstract

Provided herein is a dry powdered formulation containing up to 55 wt.% of a lipophilic substance, which is rehydratable to form a stable edible colloid upon manual mixing with warm water.

Description

REHYDRATABLE INGESTIBLE PLANT-BASED FORMULATION
RELATED APPLICATION
This application claims the benefit of priority of US Provisional Application No. 63/432,421 filed on December 14, 2022, the contents of which are incorporated by reference as if fully set forth herein.
FIELD AND BACKGROUND OF THE INVENTION
The present invention, in some embodiments thereof, relates to an edible formulations, and more particularly, but not exclusively, to dry formulations of water-insoluble lipophilic substances that can be rehydrated in an aqueous carrier to form an edible colloid.
Oral administration and delivery, and ingestion of bioactive agents (e.g., drugs, vitamins, etc.) is by far the most convenient and thus the most popular route of administration, overcoming most of the drawbacks of intravenous administration, including extravasation of drug or blood, catheter infections, and thrombosis, all of which can be prevented by administering the bioactive orally. Nonetheless, oral administration is limited by problems related to physico-chemical properties of the bioactive, including poor solubility, low permeability, instability, and rapid metabolism, all of which decrease oral bioavailability.
Some bioactive agents are characterized by poor aqueous solubility, which limits oral bioavailability. These bioactive agents have low solubility which leads to low dissolution and limits absorption. This poor solubility not only gives low oral bioavailability but also leads to high inter- and intra-subject variability and lack of dose proportionality. Also, some of these bioactive agents have enhanced bioavailability when co-administered along with food. In order to formulate such bioactive agents in a safe and efficacious form, a balance must be maintained between bioavailability, toxicity and disposition within the body. Various techniques like micronization, complexation with cyclodextrins, solid dispersions, permeation enhancers, lipids and surfactants have been reported to overcome some solubility and permeability issues.
Substances originating from plants are used in many applications, including food, food supplement, medicine, cosmetics and pleasure (taste, color, shape). Plants are a source of nutritional and medicinal products for millennia, with many useful drugs developed from plant sources. However, the quality and concentration of substances and functionality, e.g., color, taste or humidity of plants, varies depending on the origin of species, the geographic localization, seasonality, the nature of the soil, growing conditions, harvest date, etc. Further, natural plants can comprise undesired substances or be contaminated, e.g., with bacterial loads, pesticides, heavy metals, mycotoxins and toxic substances. Still further, the desired substances from a natural plant can in many cases not be easily extracted during digestion, e.g., the lycopene trapped in the skin of tomatoes.
While processed plants can be consumed in different forms, e.g., fresh, dehydrated, cooked, fermented or concentrated (extracts), once of the more convenient and controllable forms of consumption is a form that can be quantified and delivered easily, without compromising the efficacy and bioavailability of the desired bioactive agents of the plant.
Oral administration of plant extracts is oftentimes characterized by lower bioavailability, long onset time, uncontrolled effect duration and instability of the extract. Some of the disadvantages of oral consumption are low bioavailability due to poor solubility of the desired active substances in water, and decomposition of active substances.
WO 2021/084527 to some of the present inventors, the contents of which are incorporated herein by reference, provides solid self-emulsifying cannabis plant extract formulations, methods for their preparation and uses thereof. The provisions of WO 2021/084527 are based on a plant extract formulation comprising whole cannabis plant extract, a solid carrier and a lipidic component wherein upon rehydrating the solid formulation in liquid, the cannabis plant extract is self-emulsified within the liquid.
U.S. Patent No. 11,013,715 provides compositions, having nanosized droplets, wherein the nanosized droplets may contain a cannabinoid oil, a dietically acceptable carrier oil, a surfactant, and water. Also disclosed herein are methods of making and using the same.
Apricity, Inc. claims to provide nano-sized hydrophilic (water-attractant) emulsifier to encapsulate active cannabinoids by enveloping the oil-based cannabinoids, thereby producing a water-soluble formulation that is safe, reliable, and extremely effective. Apricity, Inc. technology is said to be applicable for any cannabinoid (CBD, CBG, THC, CBC, etc.) or terpene.
WO 2021026366 provides compositions comprising cannabinoids and active ingredients and/or excipients and methods of producing the compositions.
WO 2021/003091 provides beverage compositions comprising a mixture of: (a) an emulsion of about 2 wt % of a cannabinoid; about 2-10 wt % of a carrier oil; about 2-24 wt % of an amphipathic glycoside; and about 64-94 wt % of water; and (b) a polyphenol or tannin rich beverage base, wherein the beverage composition does not precipitate over an extended time. Also disclosed herein are methods of making and using the same.
WO 20201/50616 provides solid, micellar compositions, comprising micelles of one or more cannabinoid acids and a metal, wherein the cannabinoid acids are in a salt form, the salt form has a monovalent counter ion, and the micelles are free of added surfactants, are disclosed, as well as processes for obtaining the same, and methods of treating a number of disorders using the same.
WO 2021/138597 provides a water-soluble cannabinoid-containing solid dispersion and method of preparation thereof; the solid dispersion comprises one or more cannabinoids as active ingredients, a hydrophilic polymeric carrier, an antioxidant and optionally the palatability- improving agent. The solid dispersion is suitable for oral delivery application in form of solid material or an aqueous colloidal dispersion or for transdermal delivery application.
WO 2022/066936 provides beverages including an active emulsion and a blank emulsion, wherein the blank emulsion is used as a sacrificial agent to retain the active emulsion's potency within an infused beverage.
WO 2020/035850 discloses a water-dispersible solid formulation of a cannabinoid or a cannabis extract, present in the form of a nanoemulsion, and upon dispersion in water said formulation produces droplets of a submicron size with an average size of up to about 500 nm, as well as methods of making thereof, and therapeutic applications in humans for treating disorders and broader application for a range of medical conditions.
WO 2022/024126 discloses compositions that increase oral bioavailability of beneficial edible lipophilic substances such as edible oils, oil-soluble vitamins, and nutraceuticals.
Yet, there is still a long-felt need for an aqueous formulation of room-temperature liquid lipophilic substances that is based on safe and plant-based materials, and that is easy to prepare and consume by mixing an edible dry powder containing significant amount of the lipophilic substance, which is rehydratable such that it can form a stable drinkable colloid upon manual mixing with water and maintains the benefits of the bioactive agents therein.
SUMMARY OF THE INVENTION
The present invention provides a highly effective rendering of non-soluble lipophilic substances into easy-to-use drinkable formulation that can be prepared by an end user utilizing everyday tools and methods. Specifically, the invention provides dry powder compositions prepared from lipophilic substances, such as oily plant extracts, that can be dissolved/suspended/emulsified into edible aqueous colloids (a drink), while improving the bioavailability and the efficiency of the active ingredients in the substance, compared to other modes of administration of the same.
Following is a non-exclusive list including some examples of embodiments of the invention. The invention also includes embodiments which include fewer than all the features in an example and embodiments using features from multiple examples, also if not expressly listed below.
Thus, according to an aspect of some embodiments of the present invention, there is provided a dry powder composition, which includes: a room-temperature liquid (RTL) lipophilic substance;
X-carrageenan (lambda-carrageenan); a surfactant; and a room-temperature solid (RTS) lipid; wherein:
X-carrageenan constitutes 10-25 wt.% of the composition; the RTL lipophilic substance constitutes 3-80 wt.% of the composition; the surfactant constitutes 8-10 wt.% of the composition; and the RTS lipid constitutes 3-60 wt.% of the composition; the dry powder composition is characterized by at least one of: an average particle size that ranges 1 - 5,000 pm; a water activity of less than 0.5; and a humidity of less than 10 %.
In some embodiments, the dry powder composition provided herein is a dehydration residue of an original colloid, that forms a regenerated colloid upon mixing the dry powder composition with an aqueous medium.
In some embodiments, the dry powder composition provided herein is essentially devoid of a gelling agent that is not naturally occurring in the lipophilic substance; for example, devoid of gelatin.
In some embodiments, the dry powder composition provided herein is essentially devoid of a polyphenol that is not naturally occurring in the lipophilic substance.
In some embodiments, the dry powder composition provided herein is essentially devoid of an animal-based ingredient that is not naturally occurring in the lipophilic substance.
In some embodiments, the dry powder composition provided herein includes maltodextrin.
In some embodiments, the dry powder composition provided herein includes glucomannan.
In some embodiments, glucomannan constitutes 10-25 wt.% of the total weight of the composition.
In some embodiments, glucomannan together with the X-carrageenan constitutes 10-25 wt.% of the total weight of the composition. In some embodiments, the RTS lipid is a triglyceride.
In some embodiments, the triglyceride is stearin (glyceryl tristearate).
In some embodiments, the surfactant is added to the original colloid as an extract of Quillaja saponaria and/or Quillaja brasiliensis containing natural triterpene glycosides (saponins).
In some embodiments, the surfactant is a triterpene glycoside (a saponin).
In some embodiments, the dry powder composition provided herein further includes an additive, such as, for a non-limiting example, a food preservative, an antioxidant, an anticaking agent, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food supplement, and a pharmaceutical agent.
In some embodiments, the lipophilic substance is an oily plant extract.
In some embodiments, the oily plant extract is a cannabis plant extract.
In some embodiment the lipophilic substance is a wax, namely a solid that melts at 40-70 °C, which liquifies during the preparation of the dry powder composition, as presented herein.
In some embodiments, the dry powder composition provided herein consists of generally recognized as safe (GRAS) ingredients, and the composition is an edible composition.
According to another aspect of some embodiments of the present invention there is provided a dry powder composition, which includes: from 45 to 55 wt.% of an oily cannabis extract as an RTL lipophilic substance; from 20 to 25 wt.% of /.-carrageenan as a non-gelling thickening agent; from 8 to 10 wt.% saponin as a surfactant; from 4 to 5 wt.% glyceryl tristearate as a RTS lipid; and from 8 to 10 wt.% maltodextrin.
According to another aspect of some embodiments of the present invention there is provided a regenerated colloid that includes the dry powder composition as provided herein, and an aqueous medium.
In some embodiments, the aqueous medium is water, or an edible/drinkable aqueous solution.
In some embodiments, additional ingredients in the aqueous solution may be, for a nonlimiting example, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food additive/supplement, and a pharmaceutical agent.
In some embodiments, the regenerated colloid provided herein is afforded by mixing the dry powder composition as provided herein, with the aqueous medium, for example at roomtemperature, or with the aqueous medium heated, for example, to about 30-90 °C, thereby obtaining the regenerated colloid (or generating the colloid from the dry powder). In some embodiments, mixing the dry powder is effected by manual stirring using a household container and a household utensil.
In some embodiments, the regenerated colloid as provided herein is characterized by at least one of: a particle size of less than 1000 nm; and a loading efficiency of at least 90 % of the active ingredients compared to the original colloid.
In some embodiments, the regenerated colloid is for use in the treatment of a medical condition in a subject in need thereof, which is treatable by at least one bioactive agent in the RTL lipophilic substance.
According to another aspect of some embodiments of the present invention, there is provided a process of preparing the dry powder composition as provided herein, which is effected by: mixing the lipophilic substance with the room-temperature solid lipid at a temperature equal or higher than a melting point of the lipid to thereby obtain a lipophilic mixture; mixing under heat the non-gelling thickening agent and the surfactant in water to thereby obtain an aqueous mixture; combining (stirring) the lipophilic mixture and the aqueous mixture to thereby obtain a biphasic mixture; adding hot water to the bi-phasic mixture and homogenizing the hot water and the bi-phasic mixture to thereby obtain the original colloid; and freeze-dry the original colloid to thereby afford the dry powder composition.
In some embodiments, the process further includes adding optional lipophilic ingredients to the lipophilic mixture, and/or adding optional water-soluble ingredients to the aqueous mixture.
According to yet another aspect of some embodiments of the present invention, there is provided a method of treating a medical condition in a subject in need thereof, that includes orally administering the regenerated colloid as provided herein, prepared from the dry powder composition provided herein.
According to yet another aspect of some embodiments of the present invention, there is provided a use of the dry powder composition provided herein, in the preparation of the regenerated colloid for the treatment of a medical condition in a subject in need thereof.
In some embodiments, the lipophilic substance is a cannabis extract, and the medical condition is selected from the group consisting of pain, insomnia, depression, anxiety, PTSD, multiple sclerosis, migraines, fibromyalgia, seizures, Alzheimer’s disease, dementia, Parkinson’s disease, Crohn’s disease, and glaucoma.
Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS:
Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.
In the drawings:
FIG. 1 presents a flowchart of the basic steps in the process of preparing the dry powder provided herein;
FIGs. 2A-B present plasma concentration-time profiles of THC (A) and CBD (B), following oral administration of powder cannabis formulation (SE) and olive oil formulations (control) in rats (mean ± SE, n=3 for THC, n=4 for CBD); and
FIG. 3 presents a comparative plot, showing the plasma concentration-time profiles of ATX following oral administration of a regenerated colloid prepared using a dry powder ATX formulation (self-emulsifying formulation) and olive oil formulations (control) in rats (mean ± SE, n=4 ).
DESCRIPTION OF SOME SPECIFIC EMBODIMENTS OF THE INVENTION
The present invention, in some embodiments thereof, relates to an edible formulations, and more particularly, but not exclusively, to dry formulations of water-insoluble lipophilic substances that can be rehydrated in an aqueous carrier to form an edible colloid.
Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.
While seeking to improve the stability and regeneration of colloids of/from dry rehydratable lipophilic plant liquid extract formulation, the present inventors have surprisingly found that forming a colloid of a room-temperature liquid (RTL) lipophilic (oily) plant extract with a non-gelling carbohydrate of an edible algae source, and subsequently drying the colloid affords a powder that can be mixed with water to regenerate the colloid while preserving the amount and activity of the bioactive agents in the lipophilic substances originating from the plant extract.
Upon further investigation of this finding, it was established that many RTL lipophilic substances can be rendered as a dry powder composition from an original colloid, which can be rehydrated to form a regenerated colloid of the RTL lipophilic substances. These regenerated colloids can be ingested as a form of oral delivery vehicle, which have been shown to exhibit high oral bioavailability, especially compared to other modes of administration of the same lipophilic substances.
A dry powder of a rehydratable colloid:
While experimenting with various carriers that can generate a stable (long-lasting) colloid using generally recognized as safe (GRAS) ingredients, it was found that a non-gelling thickening agent would serve as a preferred carrier since the transformation from colloid to powder and back to colloid upon adding water is hampered when a gel is formed during any of the transformations.
Thus, according to an aspect of some embodiments of the present invention, there is provided dry powder composition being the dehydration residue of an original colloid, which includes: a room-temperature liquid (RTL) lipophilic substance, a non-gelling thickening agent, a surfactant, and a room-temperature solid (RTS) lipid.
In some embodiments thereof, the present invention is drawn to a dry powder that is obtained from drying (dehydrating) a colloid or an emulsion - a powder that can be rehydrated to form (regenerate) the colloid it originated from when mixing the powder with the same amount of water that was evaporated, or any colloid that comprises the components of the original colloid when the powder is rehydrated with any aqueous medium. In the context of the present invention, the dry and rehydratable powder is referred to herein as a “rehydratable dry powdered colloid”, a “rehydratable colloid”, a “rehydratable dry powder composition”, or simply a “dry powder composition”.
While stemming from an aqueous mixture of water-soluble, water-insoluble and amphiphilic ingredients and substances, the dry powder composition of the present invention is characterized primarily by the capacity to rehydrate to generate a colloid upon mixing the dry powder in an aqueous media, such as water. The dry powder composition is obtained by dehydrating an aqueous mixture that is referred to herein as the original aqueous mixture, or the original colloid.
The original aqueous mixture is characterized by being a colloid of a lipophilic substance, and more specifically, a room-temperature liquid lipophilic substance. In the context of the present invention, the term “colloid” refers to a mixture of a compound or a plurality of compounds that can be in solid, liquid or gas state, and a liquid. A colloid is generally a homogeneous noncrystalline substance consisting of large molecules or complexes, or ultramicroscopic particles of a substance (the substance may comprise a plurality of different types of compounds) dispersed through a second substance that is a liquid, whereas the dispersed particles do not settle down spontaneously (stable). The four major categories of colloids include: Sol - a colloidal suspension which has solid particles distributed in a liquid; Emulsion - a colloidal suspension containing a combination of two liquids; Foam - this forms when gas particles get trapped in a liquid or a solid; and Aerosol - forms when solid or liquid particles distribute throughout the air.
The terms colloid and emulsion are often used synonymously but it should be kept in mind that emulsions result when immiscible liquids are mixed whereas in a colloid solution it can be a liquid or solid dispersion in another liquid. In other words, an emulsion can be termed as a colloid but not all colloids are emulsions.
In addition, there are three forms of colloids; multimolecular colloids, macromolecular colloids, and micelles. This classification categorizes colloids according to the particle size and behavior of those particles in a colloid. A multimolecular colloid forms if the molecules of a compound aggregate when the compound is dissolve in a suitable solvent. In a macromolecular colloid, the individual particles are large enough for the mixture to be called a colloid. In micelles, it contains an aggregate of molecules in a colloidal solution, such as those formed by detergents/surfactants in a spherical manner.
In the context of the present invention, the rehydratable dry powder composition is a result of dehydrating an original aqueous mixture, which falls under the definition of a colloid, as defined hereinabove. According to some embodiments of the present invention, the rehydratable dry powder composition is a result of dehydrating a sol-type or an emulsion-type colloid, and is further characterized by the capacity to rehydrate to form a sol-type or an emulsion-type colloid. The colloid that is afforded by rehydrating the dry powder composition provided herein is referred to herein interchangeably as an “edible colloid” or a “regenerated colloid”.
In the context of the present invention, the rehydratable dry powder composition provided herein forms a sol-type or an emulsion-type colloid upon rehydration thereof in an aqueous medium, which can be water or any aqueous solution or carrier. Hence, the dry powder composition provided herein can rehydrate to afford a regenerated colloid that is essentially identical in composition (and possibly concentration) to the original colloid when rehydrated with water, or a different colloid when rehydrated with any aqueous solution, adding ingredients that were not part of the original colloid.
The term “dehydration residue” refers to the product obtained from a solution, a suspension or a colloid, which has been subjected to a drying process, wherein most of or essentially all the liquid carrier has been removed. In the context of the present invention, the drying process may include room-temperature drying, drying under heating, and freeze drying. In some embodiments, the dehydration residue is obtained by subjecting the original colloid to freeze-drying.
Due to the unique formulation of substances and their relative concentrations (ratio), as provided herein, the rehydratable dry powder composition is characterized by chemical, physical and mechanical stability, low hygroscopic nature, and long-term rehydratablilty.
Water activity (aw) is the partial vapor pressure of water in a solution divided by the standard state partial vapor pressure of water. In the field of food science, the standard state is most often defined as pure water at the same temperature. Using this particular definition, pure distilled water has a water activity of exactly 1 (one). Water activity is the thermodynamic activity of water as solvent and the relative humidity of the surrounding air after equilibration. As temperature increases, aw typically increases, except in some products with crystalline salt or sugar. Water activity is equal to equilibrium relative humidity divided by 100: (aw = ERH/100) wherein ERH is the equilibrium relative humidity (%).
Moisture contents of the powder provided herein can be determined by drying the powder in an oven at a temperature of at least about 50, 60, 70, 80 or 90 °C until consecutive constant weights are obtained, and optionally followed by 1- or 2-hours interval weighting, which gave variation less than 0.3 %. Moisture content expressed as % of moisture in wet basis.
Bulk (dry) density of the powder provided herein can be measured by gently adding a few (e.g., 2) grams of powder to an empty graduated cylinder (e.g., 10 mL) and holding the cylinder in a vibrator for a few moments (e.g., 1 min). The volume is then recorded and used to calculate the bulk density in g/mL.
Rehydration rate of the powder provided herein can be determined by adding a few grams (e.g., 2 g) of powder into distilled water (e.g., a 50 mL) at room-temperature (e.g., 25 °C) in a low form glass beaker (e.g., 100 mL). The mixture is agitated on a hot plate/stirrer at a given speed (e.g., 900 rpm) using a magnetic stirrer bar with a given size (e.g., 2-7 mm), and the time in seconds required for the powder to be completely rehydrated is recorded.
Hygroscopicity is the ability of a substance (e.i., the powder) to absorb moisture from high relative humidity environment. In the case of the powders provided herein, carbohydrates and sugars may be responsible for significant interaction with the water molecules due to the polar terminals present in these molecules. Hygroscopicity of the powder provided herein can be determined by placing a few grams (e.g., 2 g) of the powder in the flow-path of air having a known and steady humidity level (air bubbled through a saturate solution of a salt having about 75-85 % relative humidity), and thereafter calculating the increase in weight of the sample after a given time interval(s) to express hygroscopicity in percent of the weight of the hygroscopic moisture per gram of dry solid sample.
Other parameters which can be used to characterize the dry powder provided herein, include degree of caking, dispersibility, flowability and other parameters used to define a powder, particularly when intended for storage and rehydration. These parameters can be measured and determined by any method known in the art, such as, for example, the methodologies presented by Jaya, S. et al. [Journal of Food Engineering, 2004, 63, pp. 125-134].
The dry powder composition, according to embodiments of the present invention, is a dehydration residue of an original colloid, which characterized by at least one of: an average particle size that ranges 1 - 5,000 pm, a moisture content (humidity) of less than 1 %, less than 2 %, less than 3 %, less than 4 %, less than 5 %, less than 6 %, less than 7 %, less than 8 %, less than 9 %, or less than 10 % humidity (water) in the dry composition; and a water activity of less than 0.2, less than 0.3, less than 0.4, less than 0.5, less than 0.6, less than 0.8, less than 0.9, or less than 1.
The dry powder composition, according to embodiments of the present invention, is further characterized by a degree of caking of less than 50 %, less than 60 %, less than 70 %, less than 80 % or less than 90 %. According to some preferred embodiments, the degree of caking is less than 50 %. Caking of powders used in the food and pharmaceutical industries can be assessed and quantitated using any method known in the art; for example, see Freeman, T. et al., “Measurement and Quantification of Caking in Powders”, Procedia Engineering, 2015, 102, pp. 35-44, D01:10.1016/j.proeng.2015.01.104.
An angle of repose (related to flowability of powders) that ranges 20-80 °, and
An average particles size (diameter) that ranges 1-5000 pm (micron).
According to embodiments of the present invention, the original colloid, the dry composition derived therefrom, and the regenerated colloid, as discussed hereinbelow, contain GRAS and edible ingredients, and are therefore also edible (fit, suitable and approved for human consumption by eating or drinking).
The amount of each of the ingredients of the composition is given below as a percent by weight of the ingredient out of the total weight of the non- water (dry) ingredients on the composition.
Lipophilic Substance:
The composition provided herein is essentially a delivery vehicle for edible substances that, given in a particular formulation, can be absorbed into the body by oral administration and ingestion, and preferably a vehicle for edible lipophilic substances that do not or hardly dissolve in water. In other words, the dry composition provided herein constitutes a formulation of a lipophilic substance which can easily turned into an ingestible colloid that can be prepared by the user in as much effort as required to prepare a cup of instant coffee.
Lipophilicity refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents, and is oftentimes estimated in values of the partition coefficient of a given substance. A partition coefficient can be determined empirically, such as the n-octanol-water partition coefficient, or Kow, which is a partition coefficient for the two-phase system consisting of n-octanol and water. Kow is also frequently referred to by the symbol P, and it is called n- octanol-water partition ratio and reported in log units as LogPow. The partition coefficient LogP can also be calculated based on molecular descriptors and observational data (CLogP). In the context of the present invention the lipophilicity of a substance can be determined empirically or estimated computationally, and stated in terms of LogP. In the context of the present invention, the term “LogP” encompasses experimental (LogPow) and/or calculated (CLogP), as well a distribution coefficient (D; LogD), and other representation of lipophilicity expresses in log units and that is commonly used to denote lipophilicity in quantitative terms.
The term “lipophilic substance”, as used herein according to embodiments of the present invention, is a molecular entity, a complex of molecules, a macromolecule, a nanoparticle, an oily extract or a mixture of substances that is essentially lipophilic as a mixture even if it contains some water-soluble components. A greater challenge arises when the formulation is for a lipophilic substance that is a liquid at room- temperature. The present invention is particularly useful for turning a room-temperature liquid lipophilic substance into a dry and rehydratable powder, which can be ingested as an aqueous colloid by simply mixing the powder in water using any household kitchen utensils and dishes. Hence, in some embodiments of the present invention, the lipophilic substance is a roomtemperature liquid lipophilic substance, or for short, “RTL lipophilic substance”, which is a lipophilic substance that liquifies above 14 °C, or above 16 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C, or above 30 °C. In some embodiments, the lipophilic substance used to form the dry powder provided herein, is a liquid above a 14-30 °C in its isolated form (not as part of the colloid or the powder presented herein) - such lipophilic substance is also referred to herein as an RTL lipophilic substance.
In some embodiments, the lipophilic substance is a wax at room-temperature, which melts at relatively low temperatures (40-70 °C), such as used in the process of preparing the dry powder composition provided herein. A waxy lipophilic substance can also be rendered liquid by adding thereto a small amount of oil, or a small amount of an organic solvent, thereby liquidating the wax without heating. The organic solvent can be an edible (GRAS) substance, and/or a substance that can easily be evaporated off the composition during the preparation process.
According to embodiments of the present invention, the lipophilic substance is characterized by a partition coefficient (LogP) of at least 1, 2, 3, 4, 5, 6, 7, 8, or 9 log units. Preferably, the partition coefficient of the lipophilic substance is greater than 5, and more preferably, the partition coefficient of the lipophilic substance is greater than 6. According to some embodiments of the present invention, the partition coefficient of the lipophilic substance is greater than 7 log units.
For additional non-limiting examples, the RTL lipophilic substance is, or contains tetrahydrocannabinol (THC) having a LogPow of 7.2 log units, astaxanthin (a keto-carotenoid; LogP 6.8) and D-alpha-tocopherol (Vitamin E; LogP 10.7).
Once of the objectives of the present invention is to deliver a relatively large amount of the lipophilic substance to the user, which means that the loading capacity of the composition is high, particularly when compared to other compositions that attempt to emulsify lipophilic substances. It is noted herein that the amount of the RTL lipophilic substance in the dry composition correlates to the amount of the RTL lipophilic substance used to form the original colloid. The amount of the RTL lipophilic substance in the dry composition, according to some embodiments of the present invention, which is also referred to as the payload, ranges 3-60 wt.%, or ranges 3-80 wt.%, or ranges 30-80 wt.%, or ranges 50-80 wt.%. According to some embodiments of the present invention, the amount of the RTL lipophilic substance in the dry composition is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, or at least 80 wt.% of the total weight of the composition.
Similar to lipophilicity, the term “water-immiscible” refers to a property of chemical substances, compounds and molecular entities that are characterized by low water solubility. Low water solubility can also be referred to as a substance that is characterized by water solubility of less than 10 mg/L or less than 10 ppm. The present invention is not limited to plant extracts that include water-immiscible components; therefore, the plant extract may include components characterized by moderate water solubility (i.e., 10-1,000 mg/L or 10-1,000 ppm) and by high water solubility (more than 1,000 mg/L or 1,000 ppm).
According to some embodiments of the present invention, the lipophilic substance used in forming the dry powdered composition, is characterized by comprising a water-immiscible component content, or lipophilic component content of at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, or at least 95 wt.% of a water- immiscible component with respect to the total weight of the plant extract.
Plant extract:
In some embodiments, the lipophilic substance is an oily (liquid) extract of a plant. In embodiments wherein the lipophilic substance is a mixture of molecular entities, such as in the case of a plant extract, the lipophilicity of the most lipophilic element of the liquid mixture is taken as the lipophilicity of the RTL lipophilic substance (mixture) as a whole. Thus, in a plant extract that includes a plurality of compounds and bioactive agents, the lipophilicity of the plant extract is taken from the partition coefficient of the most water-immiscible component of the plant extract, or the average partition coefficient of the major water-immiscible components of the extract.
The present invention provides a general solution to the problem of providing an edible formulation of phytochemicals originating from plant extract (whole extract, partial extract or otherwise) and having low aqueous solubility, and more specifically, providing an edible (drinkable) formulation of phytochemicals originating from an oily liquid plant extract. The formulations provided herein are useful in a wide spectrum of applications, including nutrition, pharmaceutical, cosmetics, recreation and leisure.
In traditional medicine whole plants or mixtures of plants are used rather than isolated compounds. There is evidence that crude plant extracts often have greater in vitro or/and in vivo antiplasmodial activity than isolated constituents at an equivalent dose. There is evidence for several different types of positive interactions between different components of plants used in the treatment of various medical conditions. Pharmacodynamic synergy has been demonstrated between the alkaloids and between various traditionally combined plant extracts. Pharmacokinetic interactions occur, for example between constituents of Artemisia annua tea so that its artemisinin is more rapidly absorbed than the pure drug. Some plant extracts may have an immunomodulatory effect as well as a direct antimicrobial effect. Several extracts contain multidrug resistance inhibitors, although none of these has been tested clinically in the treatment of several medical conditions. Some plant constituents are added mainly to attenuate the side-effects of others, for example ginger to prevent nausea.
The present invention, according some embodiments thereof, is suitable for preparing a dry rehydratable powder ready for re-emulsification in hot or cold water from any plant extract having any water- insoluble phytochemicals.
Bioactive phytochemicals from plant materials can be extracted by various extraction techniques. Most of the conventional/classical/traditional techniques are based on the extracting power of different solvents in use and the application of heat and/or mixing. In order to obtain bioactive agents from plants, the existing classical techniques are, without limitation, soxhlet extraction, maceration and hydrodistillation. The major challenges of conventional extraction are longer extraction time, requirement of costly and high purity solvent, evaporation of the huge amount of solvent, low extraction selectivity and thermal decomposition of thermo labile compounds. To overcome these limitations of conventional extraction methods, new and promising extraction techniques have been introduced. These techniques are referred as nonconventional extraction techniques. Some of the most promising techniques are ultrasound assisted extraction, enzyme-assisted extraction, microwave-assisted extraction, pulsed electric field assisted extraction, supercritical fluid extraction and pressurized liquid extraction. Some of these techniques are considered as “green techniques” as they comply with standards set by the US Environmental Protection Agency. These include less hazardous chemical synthesis; designing safer chemicals, safe solvents auxiliaries, design for energy efficiency, use of renewable feedstock, reduce derivatives, catalysis, design to prevent degradation, atom economy, and time analysis for pollution prevention and inherently safer chemistry for the prevention of accident.
The skilled artisan would appreciate the various plants, phytochemicals, and plant extraction technique, all of which are relevant to the present invention by providing the means to obtain plant extract in any form (liquid or dry) and composition (whole plant, partial plant or purified phytochemicals). An exemplary review of the various pant extraction techniques can be found “Techniques for extraction of bioactive agents from plant materials: A review” by Azmir, J. et al., Journal of Food Engineering, 2013, 117, pp. 426-436.
According to some embodiments, the plant extract having low water-solubility bioactive phytochemicals, is a whole cannabis extract. Whole cannabis medicinal extract (CME) has been used for many years as a medicinal and recreational agent. Oral consumption of water-based cannabis extract beverages is limited due to the poor water solubility of the lipophilic phytocannabinoids and other entourage phytochemicals. Thus, enhancement of solubility of CME for water-based preparations is a goal sought by many, and achieved by the provisions of the present invention.
The present invention provides a solution to the problems associated with forming stable aqueous-based edible (and drinkable) colloids from oily (fatty liquid) plant extracts which include water-immiscible oily components. The term “component” refers to one or more compounds that form a part of the plant extract, whereas the plant extract may include water-miscible components as well.
The amount of the oily plant extract in the dry composition is derived from the amount of the plant extract used to form the original colloid. Preferably, the amount of the plant extract ranges 5-60 wt.%, and more preferably is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, or at least 60 wt.% of the total weight of the composition.
According to some embodiments of the present invention, the plant extract used in forming the dry powdered composition, is characterized by comprising a water-immiscible or and/or oily lipophilic component content of at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, at least 25 wt.%, at least 30 wt.%, at least 40 wt.%, at least 50 wt.%, at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, or at least 95 wt.% of a water- immiscible component with respect to the total weight of the plant extract. In some embodiments, the plant extract is an oily extract that is generally water-immiscible and/or lipophilic.
In the context of some embodiments of the present invention, the use of a plant extract rather than isolated active compounds, is justified and advantageous when considering the “entourage effect”. In the example of cannabis, the entourage effect is a proposed mechanism by which cannabis compounds other than tetrahydrocannabinol (THC), such as found in a whole cannabis extract, act synergistically with it to modulate the overall psychoactive effects of the plant. The phrase entourage effect was introduced in 1999; while originally identified as a novel method of endocannabinoid regulation by which multiple endogenous chemical species display a cooperative effect in eliciting a cellular response, the term has evolved to describe the polypharmacy effects of combined cannabis phytochemicals or whole plant extracts. The phrase now commonly refers to the compounds present in cannabis supposedly working in concert to create "the sum of all the parts that leads to the magic or power of cannabis". Other cannabinoids, terpenoids, and flavonoids may be part of an entourage effect.
Cannabinoids generally have a very low solubility in water and are highly lipophilic. Consequently, these materials cannot readily be absorbed orally and, therefore, a large quantity is required to have a medicinal effect. As an example, cannabidiol (CBD) has a solubility of only 0.7 pg/mL (0.7 ppm), and tetrahydrocannabinol (THC) 2.8 pg/mL. In lipophilicity terms tetrahydrocannabinol (THC) is characterized by a LogPow of 7.2 log units, cannabinol (CBN) by LogP 5.58, cannabidiol (CBD) 7.75, cannabicyclol (CBL) 4.96, cannabitriol (CBT) 8.04, cannabielsoin (CBE) 7.64, cannabigerol (CBG) 8.59, cannabichromene (CBC) 8.28, and cannabivarin (CBDV) is characterized by a LogPow of 6.98 log units.
In some embodiments, the plant extract is a cannabis extract, comprising at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, or at least 90 wt.% of water- immiscible/lipophilic components.
Exemplary RTL lipophilic substance originating from plants, which can be rendered into a dry powder that can be rehydrated into a stable colloid include, without limitation, a cannabinoid or a mixture thereof, a vitamin or a mixture thereof, and an essential oil or a mixture thereof. According to some embodiments, examples of RTL lipophilic substances include various oily (liquid fatty) total extracts, such as, without limitation, Amaranth Seed extract from Amaranthus caudatus, arnica flower extract from Arnica montana, black cumin seed oil from Nigella sativa, calendula extract from Calendula officinalis, carrot root extract from Daucus carota, chia seed extract from Salvia hispanica, cocoa select extract from Theobroma cacao, coconut extract from Cocos nucifera, coffee extract from Coffea arabica, fenugreek extract from Trigonella foenumgraecum, oat extract from Avena sativa, pomegranate seed extract from Punica granatum, raspberry seed extract from Rubus idaeus, rhatany root extract from Krameria lappacea, rice bran extract from Oryza sativa, rose hip seed extract from Rosa canina, sandalwood seed extract from Santalum spicatum, seabuckthorn berry fruit pulp or seed extract from Hippophae rhamnoides, tomato seed extract from Solanum lycopersicum, and wheatgerm extract from Triticum aestivum. A non-gelling thickening agent:
In the context of embodiments of the present invention, some or all the ingredients of the dry composition are extracted primarily from natural substances, and include stabilizers, thickeners and surfactants that have been approved as direct additives than may be incorporated into foods to provide structure, viscosity, stability and other qualities, such as forming stable and rehydratable colloids. Thickeners, stabilizers and gelling agents are classified separately but overlap in functionality. When dissolved or added to foods, they create stiffness, stabilize emulsions/colloids or form gels.
Thickeners range from flavorless powders to gums and are chosen for their ability to work in a variety of chemical and physical conditions. Variables affecting choice of thickener include pH, frozen state, clarity and taste. Starches, pectin and gums are the most common commercial thickeners used in soups, sauces and puddings. Thickening agents also are used in treating medical conditions, such as dysphagia, to make swallowing easier and reduce the risk of aspiration.
Stabilizers are substances that increase stability and thickness by helping foods remain in a colloid and retain physical characteristics. Ingredients that normally do not mix, such as oil and water, often need stabilizers. Many low-fat foods are dependent on stabilizers. Lecithin, agar- agar, carrageenan and pectin are common in ice cream, margarine, dairy products, salad dressings and mayonnaise.
Gelling agents also function as stabilizers and thickeners to provide thickening without stiffness through the formation of gel in jellies, jams, desserts, yogurts and candies. Gums, starches, pectin, agar-agar and gelatin are common gelling agents.
Thickeners, stabilizers and gelling agents must be authorized by the Food and Drug Administration before use in edible products. Standards for food additives are clearly defined with strict criteria, and there must be a documented need for their use before approval is granted. Maximum usage levels vary depending on the additive and the food in which it is used. For example, stabilizers in frozen dairy desserts, fruit and water ices and in confections and frostings cannot exceed 0.5 percent by weight of the final edible product. Emulsifier, flavoring adjuvant, stabilizer or thickener in baked goods have the same 0.5 percent by weight limit with respect to the weight of the final edible product.
As discussed hereinabove, the formation of a gel during the process of producing the dry powder composition, or during the rehydration thereof, is undesired. Hence, according to embodiments of the present invention, the composition includes a non-gelling thickening agent.
As discussed hereinabove, the present inventors have surprisingly found that the type of carrageenan which is the lease commercially used for of the family due to its non-gelling property, namely lambda carrageenan (k-carrageenan), allows the formation of dry and rehydratable dry powdered product that is superior to those obtained with other emulsifying, gelling, and/or thickening agents, including other types of carrageenan.
Carrageenans (E number E407) constitute family of natural polysaccharides that are extracted from red edible seaweeds. These large, highly flexible carbohydrate molecules form curling helical structures, which gives them the ability to form a variety of different gels at roomtemperature, for which they are widely used in the food and other industries as gelling, thickening and stabilizing agents. The term “carrageenans” represent one of the three major classes of industrial algal polysaccharides. These water soluble, linear, and sulfated polysaccharides are characterized by alternating P-1-3- and a-l-4-linked galactose residues, with additional substitute residues such as xylose, glucose, methyl esters, and pyruvate groups.
Carrageenans are classified by the types of sulfate bonds they contain, including kappa (K- ), iota (r-), lambda (X), and other types. This sub-division mostly represents their distinguished functionality and thus distinguished utility in foods, pharmaceuticals, cosmetics and other industrial uses. K-Carrageenans are mainly composed of D-galactose-4-sulfate and 3,6-anhydro- D-galactose, and the sulfate content of commercial K-CGN is approximately 22 %. In addition, the gelling properties of K-CGN have led to its wide adoption in the food and pharmaceutical industries.
There are three main commercial classes of carrageenan - the highly used kappa (K- carrageenan), the iota (i- carrageenan), and the lease used lambda (k-carrageenan).
Kappa-carrageenan (K-carrageenan) yields a strong gel often described as firm and brittle in the presence of potassium ions. The kappa structure is a linear polysaccharide with one sulfate group per two galactose molecules and assumes a helical network that is only strengthened with potassium present. Kappa needs to be solubilized in hot water, but the sodium salts of kappa- carrageenan can be soluble in cold water. The resulting gels are not freeze-thaw stable. Kappa- carrageenan is used in dairy applications with success because it complexes with kappa-casein to form a pourable gel formation. This link allows particles like cocoa in chocolate milk or whey proteins in other dairy products to remain suspended. In ice cream, K-carrageenan is used to stabilize air bubbles. In processed cheese, it can be used to reduce the amount of natural cheese without changing manufacturability or finished product texture. Kappa-carrageenan is also commonly used in meat processing. It enables higher moisture content in meat products like sausages and cooked hams, which results in better yields and improved slicing. In low-fat meat products, using it will result in eating qualities which mimic full fat meat products.
With known synergies, kappa-carrageenan is often paired with locust bean gum and guar gum (a blend often seen in ice cream) to produce a softer gel with better stability. Kappa-2 is a weak kappa-carrageenan from a kappa/iota hybrid.
Like kappa, the lota-carrageenan structure is also a linear polysaccharide which assumes a helical conformation but with two sulfate groups per two galactose molecules. Iota forms a soft elastic gel especially in the presence of calcium ions (EU) and the resulting gel strength is ionic strength dependent. Unlike kappa, iota-carrageenan forms gels with freeze-thaw stability and is less likely to undergo syneresis. The iota form is soluble in hot water, and only the sodium salts of iota-carrageenan are soluble in cold water.
Iota-carrageenan gels have the ability to break apart during mechanical action and reform once the mechanical action stops, which is known as thixotropy. This property is helpful in cold- filled products. Within food applications, low usage levels of iota-carrageenan are used to suspend particulates within salad dressings and other beverages like soy milk. At higher usage levels, iota creates a stronger gel and is used in products like pet foods to create gravy.
With a flat structure, lambda-carrageenan has three sulfate groups per two galactose molecules, which does not form a helical structure like the kappa or iota varieties. As a result of structure, lambda is a non-gelling polysaccharide mainly used to thicken solutions. Unlike kappa, which uses potassium ions to set, and iota, which uses calcium ions to set, lambda-carrageenan does not require ions to achieve a viscous solution. The lambda form is also the only carrageenan which is cold-soluble without being a sodium salt.
In food applications, lambda creates a viscous but pseudoplastic solution, or shearthinning, under mechanical action. In liquids, like dairy products, syrups, beverages, tomato sauce and salad dressings, lambda can enable a full bodied, creamy texture.
Substituting one type of carrageenan for another is a nuanced process that requires careful consideration of the specific properties of each variant. Kappa, iota, and lambda carrageenans exhibit distinct characteristics influencing the texture and functionality of the final product. For instance, kappa carrageenan produces a rigid, brittle gel, iota carrageenan forms a softer, elastic gel, and lambda carrageenan contributes thickening properties without gel formation. These differences result in significant textural variations, as seen when substituting kappa with iota carrageenan in a pudding, leading to a softer consistency, or when replacing iota with kappa carrageenan in a beverage, resulting in increased thickness and gel-like attributes. Additionally, carrageenans play a role in stabilizing emulsions and preventing syneresis, and their specific functionalities depend on type and molecular weight. Given this complexity, it is not trivial to interchange carrageenan types without thoughtful consideration, and it is not evident that such substitutions are obvious. Adjustments to the formula or processing conditions may be necessary to achieve the desired results, emphasizing the need for a meticulous approach to carrageenan selection in food product development. Thus, according to some embodiments of the present invention, the non-gelling thickening agent is lambda carrageenan (k-carrageenan).
The amount of non-gelling thickening agent depends on the amount of the RTL lipophilic substance, the content of the water-immiscible component therein, and the concentration of other ingredients of the composition, with which the non-gelling agent may produce a favorable synergistic effect, expressed in the properties of the original and regenerated colloid. The amount of X-carrageenan as the non-gelling agent in the dry composition is derived from the amount of the non-gelling thickening agent used to form the original colloid. Preferably, the amount of the non-gelling agent ranges 5-25 wt.% or 10-25 wt.% of the total weight of the composition. In some embodiments, the amount of the non-gelling agent ranges is at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, or at least 25 wt.% of the total weight of the composition.
Surfactant:
According to some embodiments of the present invention, the composition includes a surfactant. In the context of the present invention, the surfactant is required to be non-toxic, and compatible with the water-immiscible component of the RTL lipophilic substance (e.g., oily plant extract) and the RTS lipid discussed hereinbelow. In some embodiments, the lipid and/or the nongelling thickening agent k-carragccnan act in synergy the surfactant in terms of forming a colloid with the RTL lipophilic substance, which is expressed in the stability of the colloid and the rehydratability (the capacity to rehydrate into a colloid upon mixing with an aqueous media under mild conditions) of the dry composition into a stable drinkable colloid. These requirements limit the selection of the surfactant to s few candidates, which include the same members of the natural triterpene glycoside family, and in particular, saponin. Other suitable surfactants may include methyl-P-cyclodextrin, P-cyclodextrin, lecithin, and the like, or any combination thereof.
According to some embodiments, a triterpene glycoside (a saponin) is selected as a surfactant/solubility enhancer, based on its superior synergistic effect with the other ingredients of the composition, particularly its interaction with the lipid, and more specifically, with stearin. Saponins may be introduced into the original colloid in the form of an extract of Quillaja saponaria and/or Quillaja brasiliensis, which contain natural triterpene glycosides (saponins).
In some embodiments, the saponin is glycyrrhizinic acid or a salt thereof. In some embodiments, the composition is essentially devoid of glycyrrhizinic acid or any salt thereof.
The amount of the surfactant in the dry composition is derived from the amount of the surfactant used to form the original colloid, and depends on the amount of lipophilic substance, the content of the water-immiscible component therein, and the concentration of other ingredients of the composition. In some embodiments, the amount of the surfactant in the original colloid ranges about 1-15 wt.%, 5-15 wt.%, 8-10 wt.%, 2-8 wt.%, 3-7 wt.%, or 4-6 wt.% of the total weight of said original colloid. In some embodiments, the original colloid may include at least about 2 wt.%, at least about 5 wt.%, at least about 8 wt.%, at least about 10 wt.%, at least about 12 wt.%, or at least 15 wt.% of the total weight of the composition. Solid lipid:
According to some embodiments of the present invention, the composition further includes a room-temperature solid (RTS) lipid ingredient, also referred to herein as an RTS lipid. Without being bound by any particular theory, it is assumed that the role of the lipid is to participate in the mechanism that turns the water-immiscible components from the RTL lipophilic substance into fine particulates during the step of removing water from the original colloid.
The requirements from the RTS lipid ingredient in the composition provided herein limit the selection of lipids to those that possess a delicate balance between safety (edibility), odor/taste, melting point and hydrophobicity. A suitable lipid is required to be a good solvent for the water- immiscible component of the plant extract, have a melting point in the limited range of 40-100 °C (room-temperature solid), non-toxic and conducive to forming colorless, odorless, and tasteless edible compositions. Without being bound by any particular theory, it is further assumed that the lipid should act synergistically with the surfactant, another ingredient of the composition provided herein, making the selection of a suitable lipid even more limited.
Hence, according to some embodiments of the invention, the lipid is a room-temperature solid lipid, having a melting point that ranges 40-100 °C or 50-90 °C, which is safe for human consumption (non-toxic). The lipid may include, for example, various types of glycerides and/or various types of fatty acids. In some embodiments, various types of glycerides may be selected from, but not limited to: triglycerides, medium-chain triglyceride, short-chain triglyceride, partial glyceride, glyceryl tristearate, glyceryl stearate, and the like, or any combination thereof. In some embodiments, various types of fatty acids may be selected from, but not limited to: polyoxyethylated fatty alcohol, polyoxyethylated fatty acid, polyoxyethylated fatty acid, esters of fatty acids, and RT-solid forms of vegetable oil, oleic acid, linoleic acid, olive oil, soybean oil, grape seed oil, sunflower oil, peanut oil, com oil, canola oil, coconut oil, and the like, or any combinations thereof, whereas each possibility is a separate embodiment.
According to some embodiments, the lipid is stearin (glyceryl tristearate), trilaurin, tripalmitin, trimyristin, triolein, any fatty acid characterized by a melting point above RT. Preferably, the lipid is stearin, which acts in synergy with the preferred surfactant and the preferred thickening agent. As discussed herein, to act in synergy it is meant in terms of forming a colloid with the plant extract, which is expressed in the stability of the colloid and the rehydratability (the capacity to rehydrate into a colloid upon mixing with an aqueous media under mild conditions) of the dry composition into a stable colloid.
The amount of the RTS lipid in the dry composition is derived from the amount of the RTS lipid used to form the original colloid. In some embodiments, the original colloid may include RTS lipid in an amount of about 2-40 wt.%, 3-30 wt.%, 4-20 wt.%, 4.5-5 wt.%, 6-18 wt.%, 8-15 wt.%, 10-15, 15-25 wt.%, or 10-30 wt.% of the total weight of the composition. In some embodiments, the original colloid may include an RTS lipid in an amount of at least about 2 wt.%, at least 5 wt.%, at least 10 wt.%, at least 15 wt.%, at least 20 wt.%, or at least 25 wt.% of the total weight of the composition.
Glucomannan:
As discussed hereinabove, another surprisingly useful substance, conducive to the formation of a dry and rehydratable powdered product, and a stable regenerated colloid, is glucomannan. It is assumed that this water-soluble polysaccharide, having prominent filmforming ability, biocompatibility, biodegradability, and thickening performance, acts in synergy with the non-gelling agent, and in particularly with k-carrageenan, to form a dry composition that form a more stable regenerated colloid.
Glucomannan (E number E425) is a water-soluble polysaccharide dietary fiber, being a hemicellulose component in the cell walls of some plant species, such as Konjac plant. It is a major source of mannan oligosaccharide (MOS) found in nature, the other being galactomannan, which is insoluble. Glucomannan from the Konjac plant is a glucose-mannose polysaccharide in which 5-10 % of the sugars are acetylated. The molecule is structurally related to glucomannan from guar gum.
Glucomannans are linear copolymers of P-d-glucopyranose (about 30 %) and its 2-epimer, P-d-mannopyranose (about 70 %), joined by ( l ^4)-linkagcs to form linear chains with DPs ranging from less than 100 to several thousand. In some examples, the backbone has (1— >6)- linked P-d-galactopyranosyl substituents and is generally esterified with acetyl groups. The shape of the glucomannan polymer is similar to cellulose and it has therefore been suggested that the chains may associate strongly with surfaces of cellulose microfibrils. Glucomannans are extractable from walls with alkaline borate solutions that act by complexing with the mannopyranosyl units.
The inclusion of glucomannan in the presently disclosed formulation was not trivial, since the underlying basis of using a non-gelling agent was to afford a colloid that can be dried and rehydrated, and the formation of a gel is unconducive to this objective. Indeed, glucomannan has a property to lower the surface tension of the mixture of K-carrageenan gel and glucomannan to form a more elastic gel and lower the brittleness property of K-carrageenan gel so that the gel is made stronger. The mixture of K-carrageenan and Konjac can produce good gels as there is a synergistic relationship in the formation of gels so as to produce gels with higher gel strength, better texture, and better elasticity. In the literature it is stated that konjac, as a gelling agent, has a unique ability to form reversible and irreversible gels at different conditions. Konjac can form a gel by heating it to 85 °C under alkaline conditions (pH 9-10), forming a gel that is heat resistant (irreversible) and remained stable under reheating at a temperature of 100 °C and even at a temperature of 200 °C.
Nonetheless, while searching for improved dry and rehydratable compositions, according to embodiments of the present invention, it was surprisingly found the synergy that forms stronger gels from the combination of glucomannan and K-carrageenan, is reversed when k-carragccnan is used instead of K-carrageenan; namely, when K-carrageenan is replaced with k-carrageenan, the result form combining carrageenan with glucomannan is a synergistic non-gelling effect that affords a more stable and homogeneous colloid using plant extracts characterized by a high content of water- immiscible components.
It was further found that glucomannan can replace some of the k-carrageenan in the composition to some extent, while still producing colloid that are conducive to the drying and rehydration objective. Generally, the amount of glucomannan in the composition ranges 10-25 wt.% of the total weight of the composition, whereas in some embodiments, glucomannan can replace some of the k-carrageenan, up to 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, or replacement of 90 % of the k-carrageenan in the composition.
Optional ingredients:
Many herbal compounds including quercetin, genistein, naringin, sinomenine, glycyrrhizin and nitrile glycoside, as well as piperine, along with its isomer chavicine, have demonstrated capability to enhance the bioavailability of various bioactive agents, including those originating from plants.
These additives and others are contemplated within the scope of some embodiments of the present invention. The amount of the additive in general, is in the range of 1-5 wt.% of the total weight of the dry ingredients of the composition.
Excluded from the composition and colloids:
It is noted that the ingredients, components and agents which are mentioned herein as excluded from the composition provided herein, are excluded from the ingredients that are added to the plant extract and not from the plant extract itself. In other words, when stating that a certain family of substances are exclude from the composition provided herein, or when stating the composition provided herein is essentially devoid of a certain family of substances, it does not mean that the excluded substances are not naturally occurring and therefore present in the plant extract. In some embodiments of the present invention, the composition provided herein is essentially devoid of an animal-based (sourced from animals) ingredient.
In some embodiments of the present invention, dry of hydrated forms of any milk, dairy, non-diary milk and/or plant-based and/or animal-based proteins are excluded from the composition provided herein. In some embodiments, the composition is essentially devoid of milk, and specifically essentially devoid of a protein, except for naturally occurring proteins present in the plant extract.
In some embodiments of the present invention, gelling agents, plant and/or animal-based gelling agents are excluded from the composition provided herein. That includes gelatin, with is expressively excluded from the composition provided herein, such that the composition is essentially devoid of gelatin. Expressively excluded from the exclusion of gelling agents is glucomannan, which is known as capable of forming stable gels. The exclusion of glucomannan from the exclusion of gelling agents is based on the favorable interaction of glucomannan with the non-gelling agent /.-carrageenan, which is assumed to be synergistically exceptional.
In some embodiments of the present invention, polyphenols are excluded from the composition provided herein. In some embodiments, the composition is essentially devoid of a polyphenol such as phenolic acids, flavonoids, stilbenes, and lignans, except for naturally occurring polyphenols present in the plant extract.
In some embodiments of the present invention, the composition provided herein is essentially devoid of simple sugars, such as, for example, glucose, fructose, galactose, sucrose, lactose, maltose, as well as essentially devoid of sugar alcohols, such as, for example, xylitol, sorbitol, erythritol, lactitol, mannitol, maltitol, trehalose and isomaltitol, except for naturally occurring sugars and sugar alcohols that are present in the lipophilic substance (e.g., plant extract).
In some embodiments of the present invention, the composition provided herein is essentially devoid of synthetic surfactants, such as poloxamers (e.g., Pluronic™, Kolliphor™, and Synperonic™), and others, such as colfosceril, pumactant, lucinactant and beractant.
In some embodiments of the present invention, the composition provided herein is essentially devoid of synthetic substances.
Regenerated colloid:
According to embodiments of the present invention, the dry powder composition is capable of being rehydrated to afford a colloid, using water or another aqueous solution, jointly referred to herein as an aqueous medium, wherein the colloid afforded by rehydrating the dry powdered composition provide herein is referred to as an “regenerated colloid”, which is an aqueous edible/drinkable colloid. The regenerated colloid of the present invention is easily afforded by simply mixing the dry composition with an aqueous medium, using any mixing tool. Preferably, the regeneration of the colloid is effected by using cold aqueous media, aqueous media at room-temperature, or warm (30-90 °C) aqueous media, and the mixing can be effected using any mixing means, including household utensil or stirrer. Mixing, shaking or stirring the dry composition with the aqueous medium in any container, including household shaker, may be effected manually, or by using a power tool.
In the context of the present invention, if pure water is used to rehydrate the dry powder composition provided herein, then the regenerated colloid can be identical or similar to the original colloid, which has been freeze-dried to afford the dry powder composition. In embodiments where the regenerated colloid is afforded by rehydrating the dry powder composition with less or more water than the content of water in the original colloid, then regenerated colloid will have a higher or a lower concentration of the plant extract, respectively. In embodiments where the regenerated colloid is afforded by rehydrating the dry powder composition with an aqueous solution that includes solute, the regenerated colloid will have higher, similar or lower concentration of the plant extract in addition to the solutes originating from the added aqueous solution.
The water or aqueous solution can be at room-temperature, or heated to 30-80 °C. The aqueous solution can include preservatives, antioxidants, coloring agents, flavoring/taste agents, pH-modulating agents, nutritional additives/supplements, pharmaceutical agent and drugs, and the likes.
The original and regenerated colloid are each a homogeneous mixture wherein the particles do not settle out on standing (stable colloid). A stable regenerated colloid results when the dry powder composition in turned into a colloid wherein the suspended droplets and/or particles have an average side ranging between 1 and 1000 nanometers in diameter (not to be confused with the parameters of the dry powder that generates the colloid), dispersed in the aqueous medium (water or an aqueous solution). Colloids can be distinguished from solutions as they exhibit light scattering.
According to embodiments of the present invention, the regenerated colloids are characterized by:
An average particle (suspended solid and/or emulsified liquid droplet) size of less than 1000 nm, less than 800 nm, less than 600 nm, or less than 400 nm, and
A loading efficiency of at least 90 %, at least 80 %, at least 90 %, at least 70 %, at least 60 %, or at least 50 % of the active ingredients.
Process of preparation: Generally, the process starts by preparing two liquid compositions, a lipophilic mixture that includes the RTL lipophilic substance of interest mixed with a small amount of molten RTS lipid and other optional lipophilic ingredients, and an aqueous mixture that includes X-carrageenan, a surfactant and other optional water-soluble ingredients. The two mixtures are heated and mixed together, and the combined mixtures are added to hot water in excess of about 4X the volume of the combined mixtures, and the resulting mixture is homogenized to form a colloid. The colloid is thereafter freeze-dried to afform the dry powder.
FIG. 1 presents a flowchart of the basic steps in the process of preparing the dry powder provided herein.
Since heat is employed in the process of preparing the dry powder composition provided herein, both for melting the RTS lipid constituent and for dissolving and mixing X-carrageenan, surfactant(s) and other optional ingredients, the heat can be employed also to melt waxy lipophilic substances, rendering this type of lipophilic substances suitable for the formulating dry powders therefrom according to some embodiments of the present invention. Hence, in some embodiments, the lipophilic substance is a liquid at mild temperatures ranging from 40-70 °C, and the process of preparing the dry powder composition includes the step of mixing and heating both the waxy lipophilic substance with the room-temperature solid lipid to a temperature at which both ingredients liquify.
Method of treatment and Uses:
It is noted herein that in the context of the present invention, treating a medical condition encompasses alleviating, at least to some degree, at least one symptom associated with the medical condition.
In the context of the present invention, the dry powder composition, originating from dehydration of a colloid of a lipophilic substance having low aqueous solubility, can be rehydrated and consumed as an edible colloid, whereas the contents of the colloid can be regarded as an oral administration of the bioactive agent(s) in the lipophilic substance.
In some embodiments, the lipophilic substance is a plant extract, and the colloid can be used to treat medical or cosmetic condition which is treatable by active agents in the plant extract. For example, in embodiments in which the lipophilic substance is a cannabis extract, the colloid can be used to treat medical conditions that are ameliorated by cannabinoids.
Along the same line, other lipophilic substances that are known for their nutraceutical, therapeutic, and/or recreational activity can be formulated as a dry powder, according to embodiments of the present invention, and become more bioavailable due to the transformation from an oily substance into a drinkable colloid. According to an aspect of some embodiments of the present invention, there is provided a method of treating a medical condition in a subject in need thereof, which is effected by orally administering the regenerated colloid provided herein to the subject. Also provided herein is a use of the dry powder composition provided herein, in the preparation of a regenerated colloid , as provided herein, for the treatment of a medical condition in a subject in need thereof which is treatable by at least one of the bioactive agents in the lipophilic substance.
In some embodiments of the present invention, the medical condition treatable by the composition provided herein include, without limitation, pain, insomnia, depression, anxiety, PTSD, multiple sclerosis, migraines, fibromyalgia, seizures, Alzheimer’s disease, dementia, Parkinson’s disease, Crohn’s disease, and glaucoma.
It is expected that during the life of a patent maturing from this application many relevant processes for inkjet printing antiviral NPs-containing inkjet inks will be developed and the scope of the above terms is intended to include all such new technologies a priori.
As used herein the term “about” refers to ± 10 %.
The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".
The term “consisting of’ means “including and limited to”.
The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
As used herein, the phrases "substantially devoid of" and/or "essentially devoid of" in the context of a certain substance, refer to a composition that is totally devoid of this substance or includes less than about 5, 1, 0.5 or 0.1 percent of the substance by total weight or volume of the composition. Alternatively, the phrases "substantially devoid of" and/or "essentially devoid of" in the context of a process, a method, a property or a characteristic, refer to a process, a composition, a structure or an article that is totally devoid of a certain process/method step, or a certain property or a certain characteristic, or a process/method wherein the certain process/method step is effected at less than about 5, 1, 0.5 or 0.1 percent compared to a given standard process/method, or property or a characteristic characterized by less than about 5, 1, 0.5 or 0.1 percent of the property or characteristic, compared to a given standard.
The term “exemplary” is used herein to mean “serving as an example, instance or illustration”. Any embodiment described as “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.
The words “optionally” or “alternatively” are used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.
As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.
Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.
As used herein the terms “process” and "method" refer to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, material, mechanical, computational and digital arts.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements. Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental and/or calculated support in the following examples.
EXAMPLES
Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.
Example 1
Materials and Methods
Ethanol extraction of high-THC cannabis sativa was used as an exemplary lipophilic substance, according to embodiments of the present invention;
X-carrageenan was obtained from Modernist Pantry, SKU 1060-50;
Glyceryl tristearate (69498-250G-F; GT, Sigma- Aldrich);
Maltodextrin was obtained from Cook Stock, Israel; and
Quillaja Saponin Extract was obtained from Pioneer Biotech.
Cannabis extract loading efficiency
Cannabis extract loading efficiency (CELE) was calculated according to the formula in Equation 1:
_ Actual cannabis extract content ,
CELE = - xlOO Eq. 1
Theoretical cannabis extract content
Actual cannabis extract content was obtained by the following process: Cannabis powder (approximately 4 mg) was dissolved in 500 pl hot water (80 °C, HPLC grade), then precipitated with 4.5 ml ethanol followed by vortex for 1 hour. The suspension was filtered through 0.22 pm PTFE-filters to remove polymeric debris and analyzed for cannabinoid concentration by HPLC . Solubility test
Cannabis emulsions were prepared by pouring water at different temperatures (25 °C, 50 °C, and 80 °C) over dry particles. To determine cannabinoid content in the emulsion, 1 ml of supernatant was withdrawn after 15 minutes. The obtained supernatant was freeze-dried, dissolved in 1 ml ethanol, filtered, and then analyzed for cannabinoid content by HPLC.
Simulated Gastric Fluid In order to evaluate the solubility of the cannabis powder in gastric conditions, 12.5 mg of the powder of the exemplary formulation referred to hereinbelow as “L-C-M3-high CBD-a” was dissolved in acidic media of pH 1.5 at 37 °C. This media contains 0.38 grams of hydrochloric acid (HCL) and 100 mg of sodium chloride (NaCl), as well as 100 ml of water.
Characterization methods
Morphological analysis of solid self-emulsifying lipophilic substance delivery formulation will be investigated by scanning electron microscopy.
Colloid droplet size and/or solid particle size distribution will be measured with a Malvern Master Sizer 3000.
Colloid stability refers to the ability of colloids to resist changes in its physicochemical properties over time. Colloid stability will be assessed by:
• Visual observation,
• Microscopy observation,
• Turbidity/ light scattering.
Example 2
Exemplary Formulations
Formulation L-C-Ml ( -carrageenan)
50 mg of cannabis extract (high-THC) and 5 mg of glyceryl tristearate (stearin) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, 25 mg of X-carrageenan was dissolved in 10 ml of water at room-temperature, after 10 minutes the vail was heated to 80 °C and 10 mg of maltodextrin and 10 mg of saponin were added to the mixture.
The solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized using a homogenizer three times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, and soluble in hot and cold water up to concentration of more than 10 mg/mL.
Formulation L-C-M2 ( -carrageenan)
Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, X-carrageenan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (17 mg) and saponin (80 mg) were added to the mixture. The solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added up to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
Formulation L-C-M3 ( -carrageenan)
Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial containing the cannabis extract and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml, and homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
The most stable formulation of L-C-Ml to L-C-M3, as estimated visually by inspecting visible homogeneity, and the formation of sediments at the bottom of the vessel.
Formulation L-C-M3-high-CBD -a ( -carrageenan)
Cannabis extract (high-CBD) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water. The dry mixture dissolved also under simulated gastric fluid.
Formulation L-C-M-G-l (glucomannan) Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, glucomannan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water. Did not dissolve as quickly as the L-carrageenan formulation.
Formulation L-C-M-G-2 (glucomannan)
Cannabis extract (high-THC) (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, glucomannan (11.25 mg) and L-carrageenan (11.25 mg) were dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water. Dissolved faster than Formulation L-C-M-G-l.
As a proof of concept and to show the criticality of selecting non-gelling thickeners, as oppose to the substances used in the formulations disclosed in WO 2021/084527, the following are examples of formulations that were neither homogeneous nor dissolved well in water. Formulation Cl (k-carrageenan)
Cannabis extract (high-THC) (125 mg) and glyceryl tristearate (131.2 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (62.5 mg) was dissolved in hot water (80 °C, 10 ml). After the k-carrageenan dissolved, saponin (3.75 mg) was added to the mixture. When all the components dissolved completely the solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture looked homogenous and soluble in warm water, insoluble in cold water. Formulation C2 (k-carrageenan)
Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (24 mg) was dissolved in RT water (5 ml). After the k- carrageenan dissolved, saponin (9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in a hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying and the solid mixture.
The dry mixture seems homogenous, soluble in warm water and some solubility in cold water; however, the emulsion remain stable only for a short time, presumably since k-carrageenan tends to form gels in these conditions, and that tendency led to short-time stability.
Formulation Pl (pea protein )
Cannabis extract (high-THC) (62.5 mg) and glyceryl tristearate (65.6 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, pea protein (31.25 mg) was dissolved in RT water (5 ml). After the protein dissolved, saponin (1.9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in the hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
During homogenizing phase separation could be seen, also there were residues of oil on the homogenizer.
Formulation P2 (pea protein )
Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, pea protein (24 mg) was dissolved in RT water (5 ml). After the protein dissolved, saponin (9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in a hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble only in warm water (but a thin layer of oily phase was seen on the top). Formulation R1 (rice protein)
Cannabis extract (high-THC) (62.5 mg) and glyceryl tristearate (65.6 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, rice protein (31.25 mg) was dissolved in RT water (5 ml). After the protein dissolved, saponin (1.9 mg) was added to the mixture. When all the components dissolved completely the solution was heated in the hot water bath. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
During homogenizing complete phase separation could be seen, also there were residues of oil on the homogenizer and the beaker.
Formulation 12 ( isomaltose )
Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial. Isomaltose (24 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble only partially in warm water
Formulation L-C2 ( -carrageenan)
Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carragccnan (24 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble and stable in hot water, soluble in water at RT but after few minutes phase separation has been observed.
Formulation L-C3 ( -carrageenan)
Cannabis extract (high-THC) (60 mg) and glyceryl tristearate (15 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carragccnan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and saponin (18 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble only in hot water, less stable then L-C2. Formulation L-CO3 ( -carrageenan)
Cannabis extract (high-THC) (50mg) and oleic acid (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, X-carrageenan (25 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (10 mg) and saponin (10 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The mixture did not solidify completely.
Formulation L-C-Lecititin (X-carrageenan)
Lecithin (waxy material) (55 mg) and glyceryl tristearate (5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate and lecithin. In a different vial, X-carrageenan (15 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (17 mg) and saponin (80 mg) were added to the mixture. The solution was added to the first vial containing the lecithin and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added up to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
The dry mixture seems homogenous, soluble in hot and cold water up to concentration of more than 10 mg/mL.
Table 1 consolidates the formulations presented hereinabove.
Table 1
Figure imgf000037_0001
Figure imgf000038_0001
As can be seen in Table 1, in order to afford a dry powder composition with the desired properties, a superior non-gelling thickener is L-carragccnan, supplemented or not with glucomannan. It is also noted that some compositions that used a triglyceride (e.g., glyceryl tristearate) as a RTS lipid performed better than some compositions that used a fatty acid (e.g., oleic acid) instead, and further noted that some compositions that used maltodextrin performed better than some compositions that contained no maltodextrin.
Formulation medium chain triglycerides (/.-carrageenan)
Medium chain triglycerides oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying. Formulation oregano oil (/.-carrageenan)
Oregano oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, X-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
Formulation vitamin D oil (/.-carrageenan)
Vitamin D oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for
1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying. Formulation Black Seed oil (/.-carrageenan )
Black Seed oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for
1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying. Formulation Flux Seed oil (A-carrageenan)
Flux Seed oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, k-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for
1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying. Formulation Omega 3 oil (/.-carrageenan) Omega 3 oil (55 mg) and glyceryl tristearate (4.5 mg) were placed in a closed vial and heated in a water bath at 80 °C until complete melting of the glyceryl tristearate. In a different vial, X-carrageenan (22.5 mg) was dissolved in RT water (10 ml), after 10 minutes the vail was heated to 80 °C and maltodextrin (9 mg) and saponin (9 mg) was added to the mixture. The solution was added to the first vial and the mixture was vortexed and heated repeatedly. The mixture was poured to a beaker and hot water was added to 40 ml. The mixture was homogenized 3 times for 1.5 min with a break of 10 sec during each cycle. The water was then removed by freeze-drying.
Example 3
Pharmacokinetic studies in rats
Pharmacokinetic (PK) properties evaluation of a solid self-emulsifying delivery formulation for oral delivery of whole cannabis plant extract was evaluated following single dose oral administration in Sprague Dawley (SD) rats. In separate studies, blood plasma levels of the major active compounds THC and CBD were assessed over a 2 hours period. The results were compared to a control group, administered with olive oil-based commercial formulation.
Beverage preparation:
Water-based cannabis beverage was prepared by pouring hot tap water (30 mL, 80 °C) over dry powder (120 mg) of exemplary Formulation L-C-M3. As a control, oil-based beverage was prepared by dissolving the whole-plant cannabis extract (60 mg) in olive oil (OO, 30 mL). Both formulations were at a concentration of 2 mg/mL CME extract in liquid.
In-vivo procedures and examination:
Animals were weighed during acclimation and before dosing (on Day 1). On Day (-1), one day before the Test Item and Control administrations, blood was collected from three animals, to prepare plasma for determination of baseline levels. In the morning of “Day 1”, six hours before the dosing, the animals' access to the food was restricted. The animals had free access to water.
On Day 1, the Test Item and the Control were orally administered according to group allocation. Blood samples were collected from three/four animals at each of the following time points: Baseline [on “Day -1”], 10, 20, 40, 60, 90, 120 min (THC and CBD) and 180 min (CBD only) post dosing. Each rat was bled three to four times (the last one being terminal bleeding).
Blood samples were collected through the sub-mandibular vein (about 500 pL per sample) into K3EDTA tubes. The tubes were gently inverted several times to ensure mixing and immediately placed on wet ice. K3EDTA tubes were then centrifuged for plasma preparation within 30 min after sampling (2000xg for 10 min) at 4 °C. Plasma was frozen and stored in appropriately labeled test-tubes at (-60 °C) to (-90 °C). 1 BL sample and all PK samples from 10 to 120 minutes were transferred on ice to the analytical lab for quantification.
During the study, the animals were periodically observed for toxicity signs. Termination via CO2 asphyxiation was performed after the last bleeding of each animal.
Powder potency:
Formulation L-C-M3 containing 53 % w/w of high-THC cannabis extract and 53.5 % of high-CBD cannabis extract was prepared. When mixed with hot water for beverage preparation, a homogeneous emulsion was obtained within a few seconds. The SE cannabis beverage was orally administered to SD rats to evaluate the ability of the formulation to improve the bioavailability and decrease the onset of action of the lipophilic cannabinoids in the extract. PK results
Results of concentrations of THC, and CBD in plasma were provided by LCMS and are presented in FIGs. 2A-B.
FIGs. 2A-B present plasma concentration-time profiles of THC (A) and CBD (B), following oral administration of powder cannabis formulation (SE) and olive oil formulations (control) in rats (mean ± SE, n=3 for THC, n=4 for CBD).
As can be seen in FIGs. 2A-B, higher Cmax (maximal concentration in plasma), faster Tmax (time to reach Cmax) and greater exposure were obtained for both THC and CBD test groups in comparison to the control groups. The exposure of the formulation THC and CBD versus the respective control groups via AUC analyses were greater than 5-fold higher (2369 vs. 434.5) for the THC, and greater than 12-fold higher (4229 vs. 349.1) for the CBD, implicating improved bioavailability was obtained.
Faster onset of action and greater exposure were obtained using the exemplary rehydrated cannabis extract formulation (SE) in comparison to conventional oral administration of oil-based cannabis product. The results demonstrate the potential of the formulation to improve the systemic exposure of the active cannabinoid components and decrease the duration of time it takes for a cannabinoid to reach the circulation and express its effects.
Example 4
THC formulation trial with human volunteers General objective
A formulation according to some embodiments of the present invention, comprising THC as one of the lipophilic substances, can be tested for subjective psychoactive effect to provide information as for the onset time, time to reach peak effect, and total duration, along with general indication of taste, and overall impression.
Suggested method
The trial is conducted with a panel of human volunteers (e.g., 10 eligible members). The average age of the test subjects is about 35-45 years, composed of women and men. A regenerated colloid prepared from the test formulation on site by mixing about 0.5-1 grams of the dry powder with 500 mL of warm water. Each subject is given about 30-70 mL of the prepared, ensuing consumption of at least 15-25 mg of THC per person. During the experiment, all users are provided with a monitoring form, to be filled every five minutes, thus following up on the subjective effects of the drink consumption. Additionally, open questions with regards to the overall impression of the drink are answered.
Expected result
It is expected that the psychoactive effect timeline resulting from the experiment will indicate a consumption experience which is closer (and even comparable) to those of THC consumption via smoking and vaporizing, a desired feature in edible formulations.
Example 5
Astaxanthin formulation for oral consumption
Astaxanthin (ATX) is a powerful antioxidant, known for its various therapeutic properties including anti-inflammatory and antimicrobial activities. Oral consumption of ATX, specifically in beverages, is limited due to its poor water solubility. In this study, a dry self-emulsifying ATX resin powder formulation was evaluated for its pharmacokinetic (PK) properties (onset time and bioavailability) following single dose oral administration in Sprague Dawley rats. In separate studies, blood plasma levels of ATX from ATX -rich oleoresin were assessed over a 4 hours period. The results were compared to a control group, administered with olive oil-based commercial ATX formulation.
The following example showed significant improvement in bioavailability in comparison to the traditional ATX resin oil-based product currently used in the production of ATX-based food supplements. The exemplary dry powder rendering of ATX is based on natural ingredients and is also suitable for vegan diets.
Dry powder formulation:
A dry powder ATX formulation containing 15 % w/w of ATX extract was prepared based on the L-C-M3 formulation presented above, exchanging the cannabis extraction with ATX. When mixed with hot water for beverage preparation, a homogeneous emulsion was obtained within a few seconds. The regenerated ATX colloid was orally administered to SD rats to evaluate the ability of the formulation to improve the bioavailability and decrease the onset of action of the lipophilic ATX in the extract.
Beverage preparation:
Water-based ATX beverage (regenerated colloid) was prepared by mixing 1000 mg of the dry powder in hot tap water (60 mL, 70 °C) and cooling the regenerated colloid to 37 °C. As a control, oil-based beverage was prepared by dissolving ATX resin (150 mg) in olive oil (OO, 60 mL). Both liquid formulations exhibited ATX concentration of 2 mg/mL.
In-vivo procedures and examination:
Animals were weighed during acclimation and before dosing (on Day 1). On Day (-1), one day before the Test Item and Control administrations, blood was collected from three animals, to prepare plasma for determination of baseline levels. In the morning of Day 1, six hours before the dosing, the animals' access to the food was restricted. The animals had free access to water.
On Day 1, the Test Item and the Control were orally administered according to group allocation. Blood samples were collected from three/four animals at each of the following timepoints: Baseline [on Day (-1)], 10, 20, 40, 60, 120, 180, 240 min (post dosing. Blood samples were collected through the sub-mandibular vein (about 500 pL per sample) into K3EDTA tubes. The tubes were gently inverted several times to ensure mixing and immediately placed on wet ice. K3EDTA tubes were then centrifuged for plasma preparation within 30 min after sampling (2000xg for 10 min) at 4 °C. Plasma was frozen and stored in appropriately labeled test-tubes at (-60°C) to (-90 °C). 1 BL sample and all PK samples from 10 to 120 minutes were transferred on ice to the analytical lab for quantification.
PK results:
Results of concentrations of ATX in plasma were measured using LCMS and are presented in FIG. 3.
FIG. 3 presents a comparative plot, showing the plasma concentration-time profiles of ATX following oral administration of a regenerated colloid prepared using a dry powder ATX formulation (self-emulsifying formulation) and olive oil formulations (control) in rats (mean ± SE, n=4 ).
As can be seen in FIG. 3, higher Cmax (maximal concentration in plasma), faster Tmax (time to reach Cmax), faster onset time (detection of ATX in plasma) and greater exposure (total amount of ATX that reached the blood system) were observed in the test group that consumed the regenerated colloid compared to the control group that consumed the ATX in olive-oil solution. The exposure of the ATX formulation vs the control group via AUC analysis (area under the curve analysis) exhibited a >5.8-fold increase in the test group (80.8 vs.13.9), implicating improved bioavailability was obtained.
Conclusions
Faster onset of action and greater exposure were obtained using the dry powdered based regenerated colloid formulation in comparison to conventional oral administration of oil-based ATX product. These results demonstrate the potential of the dry powder composition provided herein in improving systemic exposure of the astaxanthin components and decrease the duration of time it takes for the astaxanthin to reach the circulation and express its effects.
Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.
It is the intent of the applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.

Claims

WHAT IS CLAIMED IS:
1. A dry powder composition: a room-temperature liquid (RTL) lipophilic substance;
X-carrageenan (lambda-carrageenan); a surfactant; and a room-temperature solid (RTS) lipid; wherein said X-carrageenan constitutes 10-25 wt.% of the composition; said RTL lipophilic substance constitutes 3-80 wt.% of the composition; said surfactant constitutes 8-10 wt.% of the composition; and said RTS lipid constitutes 3-60 wt.% of the composition.
2. The dry powder composition of claim 1, characterized by at least one of: an average particle size that ranges 1 - 5,000 pm; a water activity of less than 0.5; and a humidity of less than 10 %.
3. The dry powder composition of claim 1, being a dehydration residue of an original colloid, that forms a regenerated colloid upon mixing the dry powder composition with an aqueous medium.
4. The dry powder composition of claim 3, essentially devoid of a gelling agent that is not naturally occurring in said lipophilic substance.
5. The dry powder composition of claim 1, essentially devoid of a polyphenol that is not naturally occurring in said lipophilic substance.
6. The dry powder composition of claim 1, essentially devoid of an animal-based ingredient that is not naturally occurring in said lipophilic substance.
7. The dry powder composition of any one of claims 1-6, further comprising maltodextrin.
8. The dry powder composition of any one of claims 1-7, further comprising glucomannan.
9. The dry powder composition of claim 8, wherein said glucomannan constitutes 10- 25 wt.% of the total weight of the composition.
10. The dry powder composition of claim 9, wherein said glucomannan together with said X-carrageenan constitutes 10-25 wt.% of the total weight of the composition.
11. The dry powder composition of any one of claims 1-10, wherein said roomtemperature solid lipid is a triglyceride.
12. The dry powder composition of claim 11, wherein said triglyceride is stearin (glyceryl tristearate).
13. The dry powder composition of any one of claims 1-12, wherein said surfactant is added to said original colloid as an extract of Quillaja saponaria and/or Quillaja brasiliensis containing natural triterpene glycosides (saponins).
14. The dry powder composition of any one of claims 1-13, wherein said surfactant is a triterpene glycoside (a saponin).
15. The dry powder composition of any preceding claim, further comprising an additive selected from the group consisting of a food preservative, an antioxidant, an anticaking agent, a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food supplement, and a pharmaceutical agent.
16. The dry powder composition of any preceding claim, wherein said lipophilic substance is an oily plant extract.
17. The dry powder composition of claim 16, wherein said oily plant extract is a cannabis plant extract.
18. The dry powder composition of any preceding claim, consisting of generally recognized as safe (GRAS) ingredients, and the composition is an edible composition.
19. A dry powder composition comprising: from 45 to 55 wt.% of an oily cannabis extract as an RTL lipophilic substance; from 20 to 25 wt.% of X-carrageenan as a non-gelling thickening agent; from 8 to 10 wt.% saponin as a surfactant; from 4 to 5 wt.% glyceryl tristearate as a RTS lipid; and from 8 to 10 wt.% maltodextrin.
20. A regenerated colloid comprising the composition of any preceding claim and an aqueous medium.
21. The regenerated colloid of claim 20, wherein said aqueous medium is water, or an edible aqueous solution.
22. The regenerated colloid of claim 21, wherein solutes in said aqueous solution are selected from group consisting of a flavoring agent, a teste agent, a colorant, a pH adjusting agent, a food additive/supplement, and a pharmaceutical agent.
23. The regenerated colloid of any one of claims 20-22, afforded by mixing the composition with said aqueous medium at room-temperature or with said aqueous medium heated to about 30-90 °C, thereby regenerating said colloid.
24. The regenerated colloid of any one of claims 20-23 , wherein said mixing is effected by manual stirring using a household container and a household utensil.
25. The regenerated colloid of any one of claims 20-24, characterized by at least one of: a particle size of less than 1000 nm; and a loading efficiency of at least 90 % of the active ingredients compared to the original colloid.
26. The regenerated colloid of any one of claims 20-25, for use in the treatment of a medical condition in a subject in need thereof, treatable by at least one bioactive agent in said RTL lipophilic substance.
27. A process of preparing the dry powder composition of any one of claims 1-18, comprising: mixing said lipophilic substance with said room-temperature solid lipid at a temperature equal or higher than a melting point of said lipid to thereby obtain a lipophilic mixture; mixing under heat said non-gelling thickening agent and said surfactant in water to thereby obtain an aqueous mixture; combining under vigorous stirring said lipophilic mixture and said aqueous mixture to thereby obtain a bi-phasic mixture; adding hot water to said bi-phasic mixture and homogenizing said hot water and said biphasic mixture to thereby obtain the original colloid; and freeze-dry said original colloid to thereby afford the dry powder composition.
28. The process of claim 27, further comprising adding optional lipophilic ingredients to said lipophilic mixture, and/or adding optional water-soluble ingredients to said aqueous mixture.
29. A method of treating a medical condition in a subject in need thereof, comprising orally administering the regenerated colloid of any one of claims 20-26.
30. Use of the dry powder composition of any one of claims 1-18, in the preparation of the regenerated colloid of any one of claims 20-26 for the treatment of a medical condition in a subject in need thereof.
31. The method of claim 29 or the use of claim 30, wherein said lipophilic substance is a cannabis extract, and said medical condition is selected from the group consisting of pain, insomnia, depression, anxiety, PTSD, multiple sclerosis, migraines, fibromyalgia, seizures, Alzheimer’s disease, dementia, Parkinson’s disease, Crohn’s disease, and glaucoma.
PCT/IL2023/051264 2022-12-14 2023-12-13 Rehydratable ingestible plant-based formulation WO2024127397A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025880A1 (en) * 2017-08-04 2019-02-07 Alsec Alimentos Secos S.A.S. Cannabis oil nanoparticles micro-encapsulated in powder
WO2021084527A1 (en) * 2019-10-28 2021-05-06 Israel Plastics and Rubber Center Ltd. Self-emulsifying cannabis extract

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019025880A1 (en) * 2017-08-04 2019-02-07 Alsec Alimentos Secos S.A.S. Cannabis oil nanoparticles micro-encapsulated in powder
WO2021084527A1 (en) * 2019-10-28 2021-05-06 Israel Plastics and Rubber Center Ltd. Self-emulsifying cannabis extract

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TUVIKENE R.: "Handbook of Hydrocolloids", 27 November 2020, WOODHEAD PUBLISHING, article "Carrageenans", pages: 767 - 804 *

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