AU2013100468B4 - Veterinary composition - Google Patents
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- AU2013100468B4 AU2013100468B4 AU2013100468A AU2013100468A AU2013100468B4 AU 2013100468 B4 AU2013100468 B4 AU 2013100468B4 AU 2013100468 A AU2013100468 A AU 2013100468A AU 2013100468 A AU2013100468 A AU 2013100468A AU 2013100468 B4 AU2013100468 B4 AU 2013100468B4
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Abstract
Abstract Disclosed is a stable insecticidal composition comprising an insecticidally effective amount of one or more insect growth regulators (IGR) and a water miscible solvent system to solubilise the IGR.
Description
1 AUSTRALIA Patents Act 1990 JUROX PTY LTD COMPLETE SPECIFICATION INNOVATION PATENT Invention Title: Veterinary composition The following statement is a full description of this invention including the best method of performing it known to us:- 2 Veterinary Composition Cross-Reference to Related Applications 5 The present application claims priority from Australian Provisional Patent Application No 2012902993 filed on 12 July 2012, the content of which is incorporated herein by reference. Technical Field 10 This invention relates to veterinary compositions and in particular to insecticidal compositions comprising an insect growth regulator and a specific solvent system and their use in the prevention and control of insect and parasite infections on animals. Background Art 15 Insect Growth Regulators (IGR's) are well known for their control of a variety of insects. The use of IGR's in insecticidal compositions is considered to address the safety concerns associated with other insecticides, relating to environmental issues and safety to both the user and animal being treated. Most IGR's are known to have low water solubility and are commonly provided in the form of wettable powders, dilute 20 aqueous solutions or suspensions. Insecticidal compositions for external use on animals are generally administered by spray or pour-on techniques to the animal. Wettable powders are dusty and potentially hazardous to any person handling the product during production or administration. They are generally considered to be more cumbersome and time consuming to use as they require "wetting" to achieve a 25 form that is able to be administered to the animal. The known dilute aqueous insecticidal solutions have a low active content and contain a large amount of water. This means that a relatively large volume of the solution is required, making transportation more expensive and storage a burden. Further, stability of the aqueous solution during transportation and storage has been a 30 problem. The known insecticidal suspensions have a number of recognised problems. Caking, settlement and/or clumping over time may occur, requiring that the composition be vigorously shaken and/or mixed thoroughly before use. Uniformity of dosing can be adversely affected by insufficient shaking before use or infrequent 35 shaking during prolonged use during which time the suspension could re-settle. Changes to temperature of known suspension compositions can lead to viscosity 3 changes that make spray-on or pour-on applicators more difficult to use thus increasing the chances of under or over dosing. Further, suspensions can also cause clogging of pour on or spray on apparatus. A need clearly exists for insecticidal compositions comprising IGR's that are 5 easily administered and stable during transportation and storage. Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority 10 date of each claim of this application. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 15 Disclosure of the Invention In work leading up to the present invention, the inventors have found that an insecticidal composition comprising an insect growth regulator (IGR) in solution has improved stability in both the concentrated and diluted form and provides improved 20 uniformity of dosage. Surprisingly, this has been achieved by including into the insecticidal composition a specific water miscible solvent system, comprising methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate and an organic acid. This has been found to provide a stable composition with the IGR in solution. Disclosed herein is a stable insecticidal composition comprising: 25 a) an insecticidally effective amount of one or more insect growth regulators (IGR's); b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and one or more organic acids; 30 c) optionally one or more veterinary acceptable carriers and/or adjuvants . The stable insecticidal composition of the invention is a solution, wherein the active material (IGR) is solubilised therein. Advantageously, this allows the IGR to be uniformly distributed throughout the solution. This means there are no particulates to cake, clump, settle or potentially clog the dosage apparatus. 35 It will be understood that the composition may be in a concentrated or diluted form as discussed below.
4 The insect growth regulator (IGR) may be selected from one or more of the group consisting of dicyclanil, cyromazine, triflumuron, diflubenzuron, fluazuron and methoprene and mixtures thereof. Preferably, the IGR is dicyclanil and/or cyromazine. According to a first aspect, the present invention is directed to a stable 5 insecticidal composition comprising: a) an insecticidally effective amount of one or more insect growth regulators (IGRs) selected from dicyclanil and cyromazine; b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and one or 10 more organic acids; c) optionally one or more veterinary acceptable carriers and/or adjuvants. The IGR may be included in the composition in a concentration of about: 0.1 30% w/v; 0.1-20% w/v; 0.1-12.5; 0.1-10% w/v; 0.1-6% w/v; 0.1-5% w/v; 1-4% w/v; 1 5% w/v; 1-6% w/v; 1-15% w/v; 2-8% w/v; 2-7% w/v; 2-6% w/v; 2-5% w/v; 3-8% w/v; 15 3-6% w/v; 4-12.5% w/v; 4-10% w/v; 4-8% w/v; 4-6% w/v; 4-5% w/v; 5-15% w/v; 5 12.5% w/v; 8-15% w/v; >0-12.5%; >0-12%; 1-12.5% w/v; or 8-10% w/v. In one preferred embodiment, the concentration of IGR is in the range of about 1-1 5%w/v. In another preferred embodiment the concentration of IGR is in the range of about 4 12.5% w/v. 20 In one embodiment the IGR is dicyclanil. In one preferred embodiment, the concentration of dicyclanil is in a range of about >0 to 12.5 %w/v. Any solid form of dicyclanil may be used in preparing the composition of the invention. The composition of the invention does not rely on specific polymorphic crystalline structures of dicyclanil for efficacy or stability. 25 In another embodiment of the invention, the IGR is cyromazine. In one preferred embodiment, the concentration of cyromazine is in the range of about >0 to 12 %w/v. The water miscible solvent system comprises methyl-5-(dimethylamino)-2 methyl-5-oxopentanoate and one or more organic acids. The inventors have found that 30 methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate solubilises the IGR and when in combination with the organic acid provides a stabilised solution containing the IGR. The inventors have recognised that this solvent system is important in providing the required solubility of the IGR and the stability of the resulting composition in both the diluted and undiluted form. Specifically, the inventors have identified that the presence 4A of both methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and one or more organic acids are required in the solvent system to achieve the desired dissolution and stability. Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate is a water soluble polar solvent of low toxicity. The methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate may 5 be included in an amount of about: 0.1-95% w/v; 0.1-85% w/v; 0.1-75% w/v; 0.1-65% w/v; 0.1-55% w/v; 0.1-45% w/v; 0.1-35% w/v; 0.1-25% w/v; 5-25% w/v; 5-35% w/v; 5-45% w/v; 5-55% w/v; 5-65% w/v; 5-75% w/v; 5-80% w/v; or 25-80% w/v. In one embodiment, the concentration of methyl-5-(dimethylamino)-2-methyl-5 oxopentanoate is in the range of about 5-80% w/v, preferably about 25-80% w/v. 10 5 The one or more organic acids included in the composition of the present invention may be selected from the group consisting of CI - C 6 carboxylic acid, C 2 - C 6 dicarboxylic acid, C 4 - C 6 tricarboxylic acid and mixtures thereof. Suitable organic acids include but are not limited to, lactic acid, citric acid, methanoic acid, ethanoic 5 acid, propionic acid, caproic acid, ethandioic acid, hexanedioic acid, pentanoic acid, butanoic acid and mixtures thereof. In one embodiment the organic acid is lactic acid. The amount of organic acids included in the composition may be in the range of about: 2-70% w/v; 2-60% w/v; 2-50% w/v; 3-70% w/v; 3-60% w/v; 3-55% w/v; 5-70% w/v; 5-60% w/v; 5-55% w/v; 10-70% w/v; 10-60% w/v; 10-55% w/v; 15-70% w/v; 15-60% 10 w/v; or 15-55% w/v. In one preferred embodiment, the organic acids are present in an amount of about 3-55% w/v, most preferably about 10-55% w/v. The ratio of methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to organic acid may be in the range of about 21:1 to 1:6, preferably in the range of: about 21:1 to 1:2, about 8:1 to 1:2, or about 6:1 to 1:2, or about 8:1 to 2:1 or about 6:1 to 2:1, or 15 about 7:1, or about 6:1, or about 5:1, or about 4:1, or about 3:1, or about 2:1, or about 1.65:1, or about 1.6:1, or about 1.5:1, or about 1:1, or about 1:1.25, or about 1:2. The composition of the present invention optionally includes one or more veterinary acceptable carriers and/or adjuvants. Typical carriers and/or adjuvants include but are not limited to one or more additional solvents (in addition to the methyl 20 5-(dimethylamino)-2-methyl-5-oxopentanoate and organic acid), one or more surfactants, one or more scourable dyes, one or more preservatives, one or more thickening agents, one or more rain fast improving agents, one or more stabilisers, one or more dispersants and one or more antifoams. The specific amounts of veterinary acceptable carriers and/or adjuvants included in the composition would be readily 25 determined by a person skilled in the art. A person skilled in the art would be well aware of other appropriate adjuvants suitable for topical veterinary preparations. In one embodiment, the one or more carriers and/or adjuvants are present in an amount of about 0-70%w/v. The one or more additional solvents include but are not limited to solvents 30 selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol, N-methyl pyrrolidone, propylene glycol, dipropyleneglycol monomethyl ether, benzyl alcohol, benzyl benzoate, cyclohexanone, butyl di-icinol, ethyl acetate, water and mixtures thereof. Surfactants that may be used include but are not limited to ethoxylated alkyl 35 phenols (such as Terric X1O), ethoxylated sorbitan esters (such as polysorbate 80), 6 acetylated lanolin alcohol and ethoxylated castor oils. Surfactants may be added to the composition to improve the wetting capability of the composition. A scourable dye may be added to the formulation to aid as a quick visual check to determine which animals have been dosed. Suitable scourable dyes that may be used 5 in the composition of the present invention include but are not limited to ponceau red and brilliant blue One or more preservatives may be included such as hydroxybenzoate, benzyl alcohol, sorbic acid, sorbate salts and mixtures thereof. Suitable thickening agents include xanthan gum, colloidal silicon dioxide, 10 cellulose gum, guar gum and Polyvinylpyrrolidone (PVP). PVP's may also be used as a stabiliser. Preferred PVP's are those with a K value of 12 to 97 such as PVP-K15, PVP-K25 (such as Plasdone K25), PVP-K30 and PVP-K90. Suitable rain fast improving agents, including but not limited to Plasdones and cyclodextrins, may be used to improve the ability of the solution to remain on the 15 treated animal in the event of rainfall. One or more dispersants may be included in the composition. Suitable dispersants include but are not limited to magnesium aluminium silicate and colloidal silica. Colloidal silica may simultaneously perform the role of dispersant and thickener. 20 Antifoams may also be included in the composition. Suitable antifoams would be readily determined by a person skilled in the art. The present invention encompasses and includes all pharmaceutically acceptable salts of the compounds discussed herein. For the purpose of commercial products, the compositions of the invention may 25 be formulated as a concentrate, however, the end user will normally employ diluted compositions with a lower concentration of active. Dilution may be carried out with one or more of the solvents as detailed above and/or methyl-5-(dimethylamino)-2 methyl-5-oxopentanoate. Accordingly, the composition disclosed herein encompasses the composition in a concentrated and diluted form. 30 In one preferred embodiment of the invention, the composition further includes propylene glycol and/or water as carriers. The inclusion of one or more carriers effectively provides the composition in a diluted form. The water and propylene glycol are readily interchangeable in the composition of the invention and can be substituted completely or in part for the other. Preferably, in colder conditions, approaching 0"C 35 and below, propylene glycol alone or as a major component of a propylene glycol/water mixture is used.
7 In another embodiment, dilution is carried out with methyl-5-(dimethylamino) 2-methyl-5 -oxopentanoate. One of the advantages of the present invention is that the IGR containing composition is stable in a concentrated and diluted form. 5 One or more synthetic pyrethroids (SP) may also be included in the composition of the present invention. The one or more synthetic pyrethroids (SP) may be selected from the group consisting of alphacypermethrin, cypermethrin, cyhalothrin, deltamethrin, permethrin, bifenthrin, cyfluthrin, their isomers and mixtures thereof. The one or more SP and/or isomers may be included in the composition in a 10 concentration in the range of about 0-20% w/v. In one embodiment the one or more SP and/or isomers are included in the composition in a concentration in the range of about 0.01-10 %w/v; such as about 0.075-5%w/v. The composition of the present invention may further include one or more other parasiticide actives including but not limited to those from the chemical classes of: 15 - SP synergists including but not limited to piperonyl butoxide; - chloronicotinyls including but not limited to chloronicotinyl nitroguanidines such as imidacloprid; -phenylpyrazoles including but not limited to fipronil. The one or more parasiticide actives may be included in the composition in a 20 concentration in the range of about 0-20 %w/v. In one embodiment, the one or more parasiticide actives are included in the composition in a concentration in the range of about 2-8 %w/v. In one embodiment, the present invention provides a stable insecticidal composition comprising: 25 a) an insecticidally effective amount of one or more insect growth regulators (IGR's) selected from dicyclanil and cyromazine in a concentration in the range of about 4-12.5%w/v; b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate in an amount 30 of 25-80%w/v and lactic acid in an amount of about 3- 55%w/v, wherein the ratio of methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to lactic acid is in the range of about 21:1 to 1:2; c) one or more carriers selected from propylene glycol and water or mixtures thereof in an amount of about 0-70%w/v; 35 d) optionally one or more other veterinary acceptable carriers and/or adjuvants; e) optionally one or more synthetic pyrethroids; and 8 f) optionally one or more parasiticide actives selected from the group consisting of SP synergists, chloronicotinyls and phenylpyrazoles. The composition of the present invention has the following advantages: - the composition provides significant improvement in physicochemical stability 5 against other solution composition disclosed in the prior art; - the composition, being a solution, enables greater uniformity of dosage and removes the need to shake the composition as a suspension would require; - the composition can be used in a pour-on or spray-on applicator (drench gun) without concern of particulate clogging the nozzle; 10 - the composition is in the form of a solution which is water miscible, which means it can be easily diluted to the required concentrations; - the composition also has improved stability over previous compositions enabling longer low temperature storage; - as the composition is a solution there is no need to rely on specific polymorphic 15 crystalline structure of the IGR, such as dicyclanil, for efficacy and stability. The inventors have carried out stability studies on compositions according to a preferred embodiment of the invention and have surprisingly found that they are stable in a diluted form over a range of temperatures for up to 2 months. The compositions of the present invention are useful in the treatment and/or 20 control of ectoparasites. The compositions of the invention are effective when used in a variety of animals. For example, ovines (sheep), goats, ruminants (including cattle), dogs, cats and camelids. The inventors have found that a composition according to a preferred embodiment of the invention is safe and as effective as a pioneer formulation, containing the same amount of IGR, in preventing blow fly strike in sheep. 25 The composition of the present invention is suitable for topical administration to an animal for example in the form of a pour-on or a spray-on. In a preferred embodiment, the invention will be used topically to control/prevent ectoparacidic insect larvae infestation on livestock by inhibiting their growth and preventing them from maturing. A typical use of the invention will be to prevent blowfly strike in ovines 30 (sheep). In a second aspect, the present invention is directed to a method of treating parasites in/on an animal, the method comprising administering to the animal an effective amount of the parasiticide composition according to the first aspect of the invention.
9 In a third aspect, the present invention is directed to the use of an effective amount of a composition according to the first aspect for the manufacture of a medicament for the treatment of a parasitic infection in an animal. 5 Modes for Carrying out the Invention Compositions: Example 1: a) concentrated composition 10 Quantity % Component Qu(w/y) Supplier Function (g) (w/v) Dicyclanil 50 Shanghai Pharmatech Active Chemicals Co., Ltd. (IGR) Methyl-5 (dimethylamino)-2- Q.S. to Q.S. Redox Solvent methyl-5- 500mL oxopentanoate Lactic Acid 185 -37 Nuplex Specialties Solvent b) diluted composition Quantity % Component Supplier Function (g) (w/v) Dicyclanil 50 Shanghai Pharmatech Active Chemicals Co., Ltd. (IGR) 5 Methyl-5 (dimethylamino)-2- 305 Redox Solvent methyl-5- 30.5 oxopentanoate Water Q.S. to IL Q'S Jurox Carrier Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 10 1. Mix Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly. 2. Mix in Lactic Acid. 3. Add Water to volume. 5 c) diluted composition Quantity % Component Qu(w/y) Supplier Function (g) (w/v) Dicyclanil 50 Shanghai Pharmatech Active 5 Chemicals Co., Ltd. (IGR) Methyl-5 (dimethylamino)-2- 305 Redox Solvent methyl-5- 30.5 oxopentanoate Propylene Glycol Q.S. to IL Q.S. IMCD Australia Ltd Carrier Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 1. Mix ~200mL of Propylene Glycol with Methyl-5-(dimethylamino)-2-methyl-5 10 oxopentanoate. 2. Mix Dicyclanil in thoroughly. 3. Mix in Lactic Acid. 4. Add Propylene Glycol to volume. 5. Filter through 0.45um Teflon filter. 15 d) diluted composition Quantity % Component Qu(w/y) Supplier Function (g) (w/v) Dicyclanil 50 Shanghai Pharmatech Active 5 Chemicals Co.,Ltd. (IGR) Methyl-5 (dimethylamino)-2- 30.5 305 Redox Solvent methyl-5 oxopentanoate Propylene Glycol 100 10 IMCD Australia Ltd Carrier 11 Water Q.S. to IL Q.S Jurox Carrier Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 1. Mix Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly. 2. Mix in Lactic Acid. 5 3. Add Propylene Glycol. 4. Add Water to volume e) diluted composition Quantity % Component Supplier Function (g) (w/v) Shanghai Active Dicyclanil 50 5 Pharmatech (IGR) Chemicals Co.Ltd. Methyl-5 (dimethylamino)-2- Q.S. to IL Redox Solvent/Carrier methyl-5- Q.S. oxopentanoate Lactic Acid 185 18.5 Nuplex Specialties Solvent 10 Approximately one litre can be prepared following the steps outlined below: 1. Mix 305g Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly. 2. Mix in Lactic Acid. 3. Add Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to volume. 15 Example 2: a) concentrated composition Quantity % Component Qu(w/y) Supplier Function (g) (w/v) Pharmatech Chemicals Active Cyromazine 60 ~12 Co., Ltd.
(IGR)
12 Methyl-5 (dimethylamino)-2- Q.S. to Q.S. Redox Solvent methyl-5- 500mL oxopentanoate Lactic Acid 185 -37 Nuplex Specialties Solvent b) diluted composition Quantity % Component Supplier Function (g) (w/v) Pharmatech Chemicals Active Cyromazine 60 6 Co.,Ltd. (IGR) Methyl-5 (dimethylamino)-2 methyl-5- 305 30.5 Redox Solvent oxopentanoate Q.S. Propylene Glycol Q.S. to IL IMCD Australia Ltd Carrier (~46) Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 5 1. Mix ~200mL of Propylene Glycol with Methyl-5-(dimethylamino)-2-methyl-5 oxopentanoate. 2. Mix Cyromazine in thoroughly. 3. Mix in Lactic Acid. 4. Add Propylene Glycol to volume. 10 c) diluted composition Quantity % Component Qu(w/y) Supplier Function (g) (w/v) Cyromazine 60 6 Shanghai Pharmatech Active Chemicals Co.,Ltd. Methyl-5- 305 Redox Solvent (dimethylamino)-2- 13 methyl-5- 30.5 oxopentanoate Water Q.S. to IL Q'S' Jurox Carrier Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 1. Mix Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Cyromazine thoroughly. 2. Mix in Lactic Acid. 5 3. Add Water to volume. Example 3: a) concentrated composition 10 Quantity % Component Supplier Function (g) (w/v) Shanghai Active Dicyclanil 50 10 Pharmatech (IGR) Chemicals Co.,Ltd. Methyl-5 (dimethylamino)-2- Q.S. to Redox Solvent/carrier methyl-5- 500mL Q.S oxopentanoate Lactic Acid 250 Solvent 50 Nuplex Specialties b) diluted composition Quantity % Component Supplier Function (g) (w/v) Shanghai Active Dicyclanil 50 5 Pharmatech Chemicals Co.Ltd. Methyl-5 (methyla ) Q.S. to IL Redox Solvent/carrier (dimethylamino)-2- 14 methyl-5- Q.S oxopentanoate Lactic Acid 250 Solvent 25 Nuplex Specialties Approximately one litre can be prepared following the steps outlined below: 1. Mix 400g Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly. 5 2. Mix in Lactic Acid. 3. Add Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to volume. Example 4: Quantity % Component Quan (w/y) Supplier Function (g) (w/v) Shanghai Pharmatech Active Dicyclanil 50 5 Chemicals Co., Ltd. (IGR) Parasiticide Shanghai Pharmatech Imidacloprid 70 7 Active Chemicals Co., Ltd. Methyl-5 (dimethylamino)-2- Q.S. to IL Q.S. Redox Solvent methyl-5 oxopentanoate N-methyl pyrrolidone 31 (NMP) 310 Jurox Carrier Lactic Acid 185 18.5 Nuplex Specialties Solvent 10 Approximately one litre can be prepared following the steps outlined below: 1. Mix about 400 mL Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly.
15 2. Mix in Lactic Acid 3. Add NMP and then Imidacloprid, mix well. 3. Add methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to volume. 5 Example 5 (RD0312): Quantity % Component Supplier Function (g) (w/v) Shanghai Pharmatech Active Dicyclanil 50 5 Chemicals Co., Ltd. (IGR) Methyl-5 (dimethylamino)-2- 30.5 305 Redox Solvent methyl-5 oxopentanoate 10 IMCD Australia Ltd Propylene Glycol 100 Carrier Water Q.S. to IL Q.S Jurox Carrier 5 Huntsman Teric X10 50 Surfactant Shanghai Pharmatech Plasdone K25 50 5 Chemicals Co., Ltd. Thickener 0.015 Keith Harris Poncean Red 0.15 Dye Antifoam 3 0.3 Coming antifoam Lactic Acid 185 18.5 Nuplex Specialties Solvent Approximately one litre can be prepared following the steps outlined below: 10 1. Mix 305 g Methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate with Dicyclanil thoroughly.
16 2. Mix in Lactic Acid. 3. Add Propylene Glycol, Teric X1O, Plasdone K25. Mix well. 4. Add approx 250 g water, Poncean Red and Antifoam. Mix well. 3. Add water to volume. 5 Stability Studies: Composition Storage Temperature ("C) Time in Storage % Initial Concentration Example Ib 4 2 Months 95.04 40 2 Months 99.83 60 1 Month 96.10 Example 1.cl -20 2 Months 100.25 0 2 Months 98.71 30 2 Months 100.01 40 2 Months 100.98 60 1 Month 101.37 Example 1A -20 1 Month 99.75 0 1 Month 99.7 30 1 Month 99.41 40 1 Month 99.33 60 1 Month 95.59 Example 13 -20 1 Month 99.22 0 1 Month 98.77 30 1 Month 98.05 40 1 Month 99.53 60 1 Month 96.68 Example 5 0 6 Months 98.91 17 (RD0312) 30 6 Months 98.14 40 6 Months 97.58 The % initial concentration was determined by HPLC analysis. The above stability study demonstrates that the compositions of the invention according to Example 1 are stable at the extreme environmental temperatures of -20'C 5 to 60'C for 1 month and at 4'C to 40'C for a period of 2 months, with the concentration of the composition being essentially unchanged over this period. The above stability study also demonstrates that the compositions of the invention according to Example 5 are stable at the environmental temperatures of 0 0 C to 40'C for 6 months with the concentration of the composition being essentially 10 unchanged over this period. In order to evaluate the efficacy and safety of compositions disclosed herein, the following trial was conducted using Example 4 (RD0312) as described above. Trial - "A pilot study to evaluate the efficacy and safety of formulation RD0312 versus 15 formulations containing the same active ingredient for the prevention of blowfly strike by the Australian green blowfly (Lucilia cuprina) in a larval implant study in Merino sheep". Study Objective 20 RD0312, according to Example 4, was used in this trial in the form of a spray-on formulation for the prevention of blowfly strike in sheep. RD0312 contains dicyclanil 50 g/L. This study was conducted to evaluate the safety and efficacy of formulation RD0312 versus the pioneer formulation containing the same concentrations of 25 dicyclanil for the prevention of blowfly strike by the Australian green blowfly Lucilia cuprina in a larval implant study in Merino sheep. Study methods 30 The study Test Site was a sheep farm on the North Island of New Zealand. A weather station positioned on the farm recorded conditions throughout the study including temperature and rainfall. A five group, single treatment parallel study design was used.
18 On Day 0, a total of thirty-five (35) healthy male Merino sheep aged approximately 18 - 24 months and weighing 40 - 50kg were included in the study, ranked on live weight, and block allocated into three (3) treatment groups (Table 1). All sheep were shorn to leave the equivalent of 2 weeks wool growth. Untreated sheep were turned out to 5 pasture immediately. Sheep were treated as per the label instructions for the pioneer product, using a new spray-on applicator per treatment group. Sheep were kept in covered yards in their individual treatment groups for 24 hours, then were turned out to pasture. 10 Table 1. Treatment groups and larval implant schedule. Treatment Group Number of sheep (number of Treatment Weeks to be implanted & sheep) assessed I (n=15) Untreated 12, 15, 18, 20 and 24 6 2 (n=10) Pioneer Product 12, 15, 18, 20 and 24 6 3 (n=10) RD0312 12, 15, 18, 20 and 24 6 Larval implant challenges commenced in Week 12, as per the schedule in Table 1. Approximately 100 first instar L. cuprina larvae, reared on slices of lamb liver in an 15 insectary, were transferred to damp cotton wool which was then affixed above a superficial skin abrasion created by manual excoriation. Two implants were created on each sheep on either side of the spine per implant period. Implants were assessed at 24 hours and the cotton wool discarded; implants were then assessed at 48 and 72 hours for treatments that were giving some control. The state of the implant was described by 20 a blinded observer and classified as 'controlled' or 'active strike'. Active strikes were shorn, larvae removed and the wound treated with inert powder. 25 19 Results No evidence of local (dermal) or systemic adverse reactions to RD0312 was seen. Superficial skin lacerations present from shearing were not aggravated by treatment 5 application and healed as expected. Table 2. Results of larval implant challenge assessments up until Week 12. 6 sheep received 2 implants each = total of 12 implant sites per assessment. Larval implants 10 were assessed at 24 and 48 hours, and assessments were extended to 72 hours as the treatments were giving control. Week Hours post RD0312 Pioneer Product implant Active Controlled Active Controlled Week 12 72 0 12 1 11 Larval development was slow owing to cool overnight temperatures. Larval implant 15 challenge sites in untreated control sheep developed to very active strike post implantation by 48 hours. Very active strike was characterized by progression of a large number (>50) of larvae to second instar and later developmental stages, which were actively burrowing into the skin tissue and creating significant trauma and discomfort to the sheep. 20 A controlled site was one where all larvae were either dead, or where a small number (<10) of arrested development or moribund larvae which had not created further tissue trauma were present. RD0312 and the pioneer product were both effective at preventing blowfly strike at Week 12, with a final assessment being made at 72 hours (Table 2). 25 Also disclosed herein are the following embodiments noted as items A-DD 20 ITEMS: A. The steps, features, integers, compositions and/or compounds disclosed herein or indicated in the specification of this application individually or collectively, and any 5 and all combinations of two or more of said steps or features. B. A stable insecticidal composition comprising: a) an insecticidally effective amount of one or more insect growth regulators (IGRs); b) a water miscible solvent system to solubilise the IGR, wherein the solvent 10 system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and one or more organic acids; c) optionally one or more veterinary acceptable carriers and/or adjuvants . C. The stable insecticidal composition of item B wherein the insect growth regulator (IGR) is selected from one or more of the group consisting of dicyclanil, 15 cyromazine, triflumuron, diflubenzuron, fluazuron and methoprene and mixtures thereof, preferably, the IGR is dicyclanil and/or cyromazine. D. The stable insecticidal composition of items B-C wherein the IGR is included in the composition in a concentration of about 0.1-30% w/v, preferably about 1-15%w/v, more preferably about 4-12.5% w/v. 20 E. The stable insecticidal composition of any one of items B-D, wherein the IGR is dicyclanil in a concentration of up to about 12.5 %w/v. F. The stable insecticidal composition of any one of items B-D, wherein the IGR is cyromazine in concentrations up to about 12 %w/v. G. The stable insecticidal composition of any one of items B-F, wherein the 25 methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate is in an amount of about 0.10 95% w/v, preferably about 5-80%w/v, most preferably about 25-80% w/v. H. The stable insecticidal composition of any one of items B-G, wherein the one or more organic acids is selected from the group consisting of C 1 - C 6 carboxylic acid, C 2 - C 6 dicarboxylic acid, C 4 - C 6 tricarboxylic acid and mixtures thereof, preferably one 30 or more selected from the group consisting of lactic acid, citric acid, methanoic acid, ethanoic acid, propionic acid, caproic acid, ethandioic acid, hexanedioic acid, pentanoic acid, butanoic acid and mixtures thereof, preferably, the organic acid is lactic acid. I. The stable insecticidal composition of any one of items B-H, wherein the one or more organic acids are in an amount of about 2-70%w/v, preferably about 3-55%w/v, 35 most preferably about 10-55%w/v.
21 J. The stable insecticidal composition of any one of items B-I, wherein the ratio of methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to organic acid is in the range of about 21:1 to 1:6, preferably: about 21:1 to 1:2, or about 8:1 to 1:2, or about 6:1 to 1:2, or about 8:1 to 2:1 or about 6:1 to 2:1, or about 7:1, or about 6:1, or about 5:1, or or 5 about 4:1, or about 3:1, or about 2:1, or about 1.65:1, or about 1.6:1, or about 1.5:1, or about 1:1, or about 1:1.25, or about 1:2. K. The stable insecticidal composition of any one of items B-J, wherein the veterinary acceptable carriers and/or adjuvants are selected from one or more of the following: one or more solvents, one or more surfactants, one or more scourable dyes, 10 one or more preservatives, one or more thickening agents, one or more rain fast improving agents, one or more stabilisers, one or more dispersants and water. L. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include one or more solvents selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol, 15 N-methyl pyrrolidone, propylene glycol, dipropyleneglycol monomethyl ether, benzyl alcohol, benzyl benzoate, cyclohexanone, butyl di-icinol, ethyl acetate, water and mixtures thereof, preferably the solvent is propylene glycol and/or water. M. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include one or more surfactants selected 20 from the group consisting of polysorbate 80, ethoxylated alkyl phenols, ethoxylated sorbitan esters, acetylated lanolin alcohol and ethoxylated castor oil. N. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include a scourable dye selected from the group consisting of ponceau red and brilliant blue 25 0. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include one or more preservatives selected from the group consisting of hydroxybenzoate, benzyl alcohol, sorbic acid, sorbate salts and mixtures thereof. P. The stable insecticidal composition of any one of items B-K, wherein the 30 veterinary acceptable carriers and/or adjuvants include thickening agents selected from one or more of the group consisting of xanthan gum, colloidal silicon dioxide, cellulose gum, guar gum and polyvinylpyrrolidone (PVP). Q. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include polyvinylpyrrolidone (PVP)..
22 R. The stable insecticidal composition of any one of items B-K, wherein the veterinary acceptable carriers and/or adjuvants include one or more rain fast improving agents selected form the group consisting of plasdones and cyclodextrins. S. The stable insecticidal composition of any one of items B-K, wherein the 5 veterinary acceptable carriers and/or adjuvants include one or more dispersants selected from the group consisting of magnesium aluminium silicate and colloidal silica. T. The stable insecticidal composition of any one of items B-J, wherein the composition is in the form of a concentrate. TT. The stable insecticidal composition of T, wherein the composition is diluted 10 with methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and /or one or more solvents selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol, N-methyl pyrrolidone, propylene glycol, dipropyleneglycol monomethyl ether, benzyl alcohol, benzyl benzoate, cyclohexanone, butyl di-icinol, ethyl acetate and water. 15 U. The stable insecticidal composition of any one of items B-T, wherein the composition further includes one or more synthetic pyrethroids (SP) selected from the group consisting of alphacypermethrin, cypermethrin, cyhalothrin, deltamethrin, permethrin, bifenthrin, cyfluthrin, their isomers and mixtures thereof. V. The stable insecticidal composition of any one of items B-U, wherein the 20 composition further includes one or more synthetic pyrethroids (SP) and/or isomers in a concentration of about 0.01-20% w/v, more preferably about 0.075-5%w/v. W. The stable insecticidal composition of any one of items B-V, wherein the composition further includes one or more other parasiticide actives selected from the chemical classes of SP synergists, chlomicotinyl nitroguanidings and phenylpyrazoles, 25 preferably selected from one or more of the group consisting of piperonyl butoxide, imidacloprid and fipronil. X. A stable insecticidal composition comprising: a) an insecticidally effective amount of one or more insect growth regulators (IGR's) selected from dicyclanil and cyromazine in a concentration in the range of 30 about 4-12.5%w/v; b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate in an amount of 25- 80%w/v and lactic acid in an amount of about 3- 55%w/v, wherein the ratio of methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate to lactic acid is in the range of 35 about 21:1 to 1:2; 23 c) one or more carriers selected from propylene glycol and water or mixtures thereof in an amount of about 0-70%w/v d) optionally one or more other veterinary acceptable carriers and/or adjuvants; e) optionally one or more synthetic pyrethroids (SP) and/or isomers in a 5 concentration of about 0-20% w/v; and f) optionally one or more parasiticide actives selected from the chemical classes of SP synergists, chlornicotinyl and phenylpyrazoles in a concentration of about 0-20% w/v; Y. A method of treating parasites in/on an animal, the method comprising 10 administering to the animal an effective amount of the insecticidal composition according to any one of items B-X. Z. The method according to item Y wherein the parasites are ectoparasites. AA. The method according to items Y or Z wherein the composition is administered topically in the form of a pour-on or a spray-on. 15 BB. Use of an effective amount of a composition according to any one of items B-X for the manufacture of a medicament for the treatment of a parasitic infection on an animal. CC. The use according to item BB wherein the parasitic infection is an ectoparasitic infection. 20 DD. The method according to any one of items Y-AA or the use according to item BB or CC wherein the animal is selected from one or more of the group consisting of ovines (sheep), goats, ruminants (including cattle), dogs, cats and camelids. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without 25 departing from the broad general scope of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.
Claims (6)
1. A stable insecticidal composition comprising: a) an insecticidally effective amount of one or more insect growth regulators (IGRs) selected from dicyclanil and cyromazine; 5 b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate and one or more organic acids; c) optionally one or more veterinary acceptable carriers and/or adjuvants.
2. The stable insecticidal composition of claim 1 wherein the one or more organic 10 acids is selected from the group consisting of Ci - C 6 carboxylic acid, C 2 - C 6 dicarboxylic acid, C 4 - C 6 tricarboxylic acid and mixtures thereof; and the veterinary acceptable carriers and/or adjuvants are selected from: one or more solvents selected from the group consisting of: polyethylene glycol, tetraglycol, ethanol, benzyl alcohol, N-methyl pyrrolidone, propylene glycol, dipropyleneglycol monomethyl ether, benzyl 15 alcohol, benzyl benzoate, cyclohexanone, butyl di-icinol, ethyl acetate, water and mixtures thereof; one or more surfactants, one or more scourable dyes, one or more preservatives, one or more thickening agents, one or more rain fast improving agents, one or more stabilisers, one or more dispersants and one or more antifoams.
3. The stable insecticidal composition of claim 1 or 2 wherein the IGR is included 20 in the composition in a concentration of 0.1-30% w/v; the methyl-5-(dimethylamino)-2 methyl-5-oxopentanoate is in an amount of 0.10-95% w/v; the one or more organic acids are in an amount of 2-70%w/v; and the ratio of methyl-5-(dimethylamino)-2 methyl-5-oxopentanoate to organic acid is in the range of 21:1 to 1:6.
4. The stable insecticidal composition of any one of claims 1-3, wherein the 25 composition further includes one or more: synthetic pyrethroids (SP) and/or isomers; parasiticide actives selected from the chemical classes of SP synergists, chlomicotinyl nitroguanidings and phenylpyrazoles.
5. A stable insecticidal composition according to any one of claims 1-4 comprising: 30 a) an insecticidally effective amount of one or more insect growth regulators (IGR's) selected from dicyclanil and cyromazine in a concentration in the range of 4
12.5%w/v; b) a water miscible solvent system to solubilise the IGR, wherein the solvent system comprises methyl-5-(dimethylamino)-2-methyl-5-oxopentanoate in an amount 35 of 25- 80%w/v and lactic acid in an amount of 3- 55%w/v, wherein the ratio of methyl 24 25 5-(dimethylamino)-2-methyl-5-oxopentanoate to lactic acid is in the range of about 21:1 to 1:2; c) one or more carriers selected from propylene glycol and water or mixtures thereof in an amount of 0-70%w/v 5 d) optionally one or more other veterinary acceptable carriers and/or adjuvants; e) optionally one or more: synthetic pyrethroids (SP) and/or isomers in a concentration of 0-20% w/v; and f) optionally one or more parasiticide actives selected from the chemical classes of SP synergists, chloronicotinyl nitroguanidines and phenylpyrazoles in a 10 concentration of 0-20% w/v. 25
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Vidal et al, A New Environmentally Friendly Solvent of Low Toxicity for Crop Protection Formulations, Journal of ASTM International, July 2011, Vol. 8, No. 6, Pages 1-8 * |
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