AU2007100477B4 - Parasiticide Composition - Google Patents

Description

AUSTRALIA

Patents Act 1990 JUROX PTY LTD COMPLETE SPECIFICATION INNOVATION PATENT Invention Title: Parasiticide Composition The following statement is a full description of this invention including the best method of performing it known to us:-

I

Technical Field This invention relates to organophosphate compositions and in particular to such compositions where the organophosphate is presented in the form of a drench for the prevention or control ofendo- and ecto-parasites in warm blooded animals.

Background Art There are a number of organophosphate insecticides that are known to be useful for the treatment of parasites in warm blooded animals such as domestic and farm animals.

These include naphthalophos, coumaphos, crufomate, metrifonate and haloxon.

Chemically, naphthalophos (also known as naftalofos) is 2-[(diethoxyphosphinyl)oxy]- 1H-benz[de]isoquinoline-1,3(2H)-dione, coumafos is 3-chloro-7diethoxyphosphinothioyloxy-4-methylcoumarin, crufomate is (RS)-(4-tert-butyl-2chlorophenyl methyl methylphosphoramidate), metrifonate (also known as trichlorfon) is dimethyl (RS)-2,2,2-trichloro- -hydroxyethylphosphonate and haloxon is O,O-di-(2chloroethyl)-O-(3-chloro-4-methylcoumarin-7-yl) phosphate.

Naphthalophos for example, is practically insoluble in water but is water dispersible.

In order to maintain an acceptable stability profile, it is generally formulated and stored as a wettable powder that may be dispersed in water or in a water-based formulation immediately prior to use.

The wettable naphthalophos powder is highly poisonous to the user if it comes in contact with the skin or eyes, or if the powder is inhaled. Mixing of the powder into the desired solution is time consuming and provides potential for incorrect preparation that can further result in incorrect dosing of an animal being treated. Once the naphthalophos is added to water, it begins to degrade giving a short shelf-life for the made-up dispersion. The reduced shelf-life can be costly to the user as surplus formulation not used during the initial treatment may not retain sufficient potency for treatment at a later time.

Summary of the Invention The present inventors have recognised the disadvantages of powdered organophosphates and accordingly have sought to provide compositions that are stable and in the form of a suspension. The present inventors have achieved stable solvent- 08/01 2008 TpE 15:02 FAX +61 2 8231 1099 FBRice Co 005/008 00 0 0 3 C based compositions of organophosphates through the finding that certain solvent 0 combinations with organophosphates result in formulations that are stable and are 0 suitable for oral administration to animals.

Accordingly, in a first aspect, the present invention provides a non-aqueous suspension composition consisting essentially of: a parasiticidally effective amount of at least one organophosphate; o one or more organic solvents selected from the group consisting of medium Schain triglycerides, alcohols, Ci-Cis pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters; O one or more stabilising agents; and one or more surfactants.

In a second aspect, the invention provides a method of preventing or controlling endo and ectoparasites in a warm blooded animal, the method comprising orally administering to the animal a non-aqueous suspension composition consisting essentially of: a parasiticidally effective amount of at least one organophosphate; one or more organic solvents selected from the group consisting of medium chain triglycerides, alcohols, C 1

-C

18 pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters; one or more stabilising agents; and one or more surfactants.

In a third aspect the invention further provides use of a non-aqueous suspension composition consisting essentially of: a parasiticidally effective amount of at least one organophosphate; one or more organic solvents selected from the group consisting of medium chain triglycerides, alcohols, Ci-Cg pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters; one or more stabilising agents; and one or more surfactants, in the preparation of an oral composition for prevention or control of ecto and endoparasites in a warm blooded animal.

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.

COMS ID No: ARCS-174445 Received by IP Australia: Time 15:05 Date 2008-01-08 Throughout this specification the phrase "consisting essentially of' or variations thereof will be understood to be open-ended but to exclude elements or ingredients that would materially affect the properties/characteristics of the invention described and claimed herein.

Suitable organophosphates include but are not limited to naphthalophos, coumaphos, crufomate, metrifonate and haloxon. The preferred organophosphate is naphthalophos.

Naphthalophos may be included in the composition in a concentration of up to percent w/v, such as in an amount of from 1 to 30 percent w/v. Preferably, the naphthalophos is included in the composition in an amount of from 10 to 30% w/v, more preferably 10 to 15% w/v and most preferably from 12.5 to 13.5% w/v.

The one or more organic solvents included in the composition are selected from the group consisting of medium chain triglycerides, alcohols, CI.Cis pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters.

Suitable medium chain triglycerides are those with carbon chain link in the order of from 6 to 12.

Suitable alcohols include but are not limited to those with two or more carbon atoms, preferably two to eight carbon atoms such as ethanol, isopropanol, isooctanol and benzyl alcohol.

Suitable Ci CIR pyrrolidones include 2-pyrrolidone and N-methylpyrrolidone.

Suitable glycol ethers include but are not limited to dipropylene glycol monomethylether, butyl icinol and butyl di icinol.

Suitable fatty acid esters include but are not limited to isopropyl myristate, ethyl oleate, and isopropyl palmitate.

Suitable glycerol fatty acid esters include but are not limited to propylene glycol dicaprylate/dicaprate and propylene glycol isocetyth-3-acetate Suitably alkyl ethers include but are not limited to dimethyl isosorbide.

Preferred organic solvents are one or more fatty acid esters and one or more alcohols, such as caprylic/capric triglyceride and benzyl alcohol.

Surprisingly, use of some conventional organic solvents does not prevent the hydrolysis of the organophosphate. Slightly hygroscopic solvents may absorb moisture from the surrounding environment. The absorbed water molecules hydrolyse the organophosphate, degrading the active and significantly shortening the shelf-life of the product.

The total concentration of the solvent in the composition may be in the range of from to 97.5% w/v, preferably from 65 to 85 w/v, more preferably from75 to 80 w/v.

Suitable stabilising agents may be selected from the group consisting of antioxidants, antihydrolytic compounds and glycerol fatty acid esters. Preferred antioxidants include butylated hydroxyanisole, butylated hydroxytoluene and tocopherols. These antioxidants are also antihydrolytic agents. Preferred stabilising agents are glycerol fatty acid esters such as oleochemicals and cpoxidised oleochemicals. Suitable oleochemicals include sunflower oil, palm oil, soybean oil and olive oil. More preferred stabilising agents are epoxidised oleochemicals, such as epoxidised soybean oil.

The stabilising agents in combination with the solvent serve to stabilise the organophosphate against hydrolysis. The stabilising agents act as a water scavenger, reacting with water molecules that may be present in solution before the water can degrade the active.

The total concentration of stabilising agents in the composition may be in the range of from 0.5 to 10% w/v, preferably from 2 to 10 w/v, most preferably from 7 to 9 w/v.

The one or more surfactants included in the composition may be selected from nonionic, anionic, cationic and amphoteric surfactants. Preferably, the surfactants are one or more non-ionic surfactants selected from the group consisting of C 8

-C

10 alkylphenol ethoxylates, C9-C 17 alkyl ethoxylates, C 8

-C

20 alkyl amine ethoxylates, castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester ethoxylates, sorbitan r fatty acid esters and mixtures thereof. More preferred surfactants are C 8

-C

0 alkylphenol ethoxylates and most preferred are C 9 alkylphenol ethoxylates such as Teric N8 (a nonyl phenol ethoxylate with 8 ethoxy groups).

Veterinarily acceptable excipients and adjuvants may be included in the composition such as dyes, flavouring agents, thickening agents, dispersing agents and oils. A person skilled in the art would be well aware of appropriate adjuvants suitable for oral veterinary preparations.

The composition of the present invention may be used for combination therapy as it may include one or more other parasiticides such as those selected from the group consisting of: macrocyclic lactones; salicylanilides; benzimidazoles; imidazothiazoles; and isoquinolines.

Modes for Carrying Out the Invention Example 1 Component Quantity Supplier Function Naphthalophos 135 g/L PRI Active Epoxidised Soybean 80g/L APS stabiliser Oil Teric N8 30 g/L Huntsman surfactant Caprylic/capric q.s. I L Asia Pacific solvent triglyceride A litre of formulation is prepared at room temperature as follows: Transfer 750 mL of caprylic/capric triglyceride to the manufacturing vessel. Whilst stirring the solution, slowly add the epoxidised soybean oil (ESBO). Stir under medium speed until an optically isotropic solution is achieved.

Add Teric N8 to the solution. Stir under medium speed until an optically isotropic solution is achieved.

Whilst stirring the solution at a low speed, slowly add the Naphthalophos, mix the solution at medium speed until the solid active is homogenously suspended within ihe solution.

Homogenise the mixture at high speed for 10 minuted to achieve a uniform mixture.

Allow the solution to settle and make up to 1 litre with caprylic/capric triglyceride.

Example 2 Component Quantity Supplier Function Naphthalophos 130 g/L PRI active Albendazole 25 g/L PRI active Abamectin I g/L Sinca active Benzyl Alcohol 10 g/L Redox Chemicals co-solvent Epoxidised Soybean 80g/L APS stabiliser Oil Sorbitan 30 g/L Huntsman surfactant monostearate Caprylic/capric q.s. 1 L Asia Pacific solvent triglyceride A litre of formulation is prepared at room temperature as follows: Transfer 750 mL of caprylic/capric triglyceride to the manufacturing vessel. Whilst stirring the solution, slowly add the epoxidised soybean oil (ESBO). Stir under medium speed until an optically isotropic solution is achieved.

In a separate container, dissolve the abamectin in benzyl alcohol.

Add the abamectin solution to the solution prepared in Step 1. Mix thoroughly under medium speed.

Add Teric N8 to the solution. Stir under medium speed until an optically isotropic solution is achieved.

Whilst stirring the solution at a low speed, slowly add the Naphthalophos, mix the solution at medium speed until the solid active is homogenously suspended within the solution.

Homogenise the mixture at high speed for 10 minuted to achieve a uniform mixture.

Whilst stirring the solution at a low speed, slowly add the albendazole; mix the solution at medium speed until the solid active is homogenously suspended within the solution.

Homogenise the mixture at high speed for 10 minuted to achieve a uniform mixture Allow the solution to settle and make up to 1 litre with caprylic/capric triglyceride.

Example 3 Component Quantity Supplier Function Naphthalophos 135 g/L PRI active Fenbendazole 25 g/L PRI active Abamectin I g/L Sinca active Benzyl Alcohol 10 g/L Redox Chemicals co-solvent Epoxidised Soybean 80g/L APS stabiliser Oil Teric N8 30 g/L Huntsman surfactant Caprylic/capric q.s. 1 L Asia Pacific solvent triglyceride A litre of formulation is prepared at room temperature as follows: Transfer 750 mL of caprylic/capric triglyceride to the manufacturing vessel. Whilst stirring the solution, slowly add the epoxidised soybean oil (ESBO). Stir under medium speed until an optically isotropic solution is achieved.

In a separate container, dissolve the abamectin in benzyl alcohol.

Add the abamectin solution to the solution prepared in Step 1. Mix thoroughly under medium speed.

Add Teric N8 to the solution. Stir under medium speed until an optically isotropic solution is achieved.

Whilst stirring the solution at a low speed, slowly add the Naphthalophos, mix the solution at medium speed until the solid active is homogenously suspended within the solution.

Homogenise the mixture at high speed for 10 minuted to achieve a uniform mixture.

Whilst stirring the solution at a low speed, slowly add the fenbendazole; mix the solution at medium speed until the solid active is homogenously suspended within the solution.

Homogenise the mixture at high speed for 10 minuted to achieve a uniform mixture Allow the solution to settle and make up to I litre with caprylic/capric triglyceride.

Example 4 Stability Tests An experimental batch of the formulation described in Example I was prepared and stored under real-time conditions (30"C/60% RH) and accelerated conditions (40"C/75% RH) for a period of 3 months. Samples were assessed for appearance, resuspendability and assayed for strength via HPLC. Results are shown in the table below.

Test Parameter Initial 3 Months Off-white liquid Off-white liquid Appearance suspension suspension Re-suspendability Easily re-suspendible Easily re-suspendible Naphthalophos Concentration (30°C/60% 133.5 g/L 138.8 g/L

RH)

Naphthalophos Concentration 133.5 g/L 131.0 g/L Strength (40°C/75% RH) Industrial Applicability Whilst compositions made according to the invention will find the greatest application as a drench for treatment or control of parasitic infestations of sheep, goats and camelids including llamas and alpacas, they are also useful in treating parasitic infestations of other ruminants as well as horses, pigs and dogs.

Claims (4)

1. A non-aqueous suspension composition consisting essentially of: 00 o a parasiticidally effective amount of at least one organophosphate; one or more organic solvents selected from the group consisting of medium chain triglycerides, alcohols, CJ.Crs pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters; Sone or more stabilising agents; and _one or more surfactants. U

2. A composition according to claim 1 wherein the at least one organophosphate is 0 10 selected from the group consisting of naphthalophos, coumaphos, crufomate, metrifonate and haloxon.

3. A composition according to claim I wherein the at least one organophosphate is naphthalophos.

4. A composition according to any one of claims 1 to 3 wherein: the one or more organic solvents is selected from the group consisting of C6-C2 medium chain triglycerides, Ctwo or more alcohols, 2-pyrrolidone, N-methylpyrrolidone, dipropylene glycol monomethylether, butyl icinol, butyl di icinol, isopropyl myristate, ethyl oleate, isopropyl palmitate, propylene glycol dicaprylate/dicaprate, propylene glycol isocetyth-3-acetate, dimethyl isosorbide the one or more stabilising agents is selected from the group consisting ofantioxidants, antihydrolytic compounds and glycerol fatty acid esters, preferably selected from butylated hydroxyanisole, butylated hydroxytoluene, tocopherols, oleochemicals and epoxidised oleochemicals; the one or more surfactants is selected from non-ionic, anionic, cationic and amphoteric surfactants, preferably selected from Cs-Clo alkylphenol ethoxylates, C9-C17 alkyl ethoxylates, C 8 -C 20 alkyl amine ethoxylates, castor oil ethoxylates, lanolin alcohol ethoxylates, sorbitan fatty acid ester ethoxylates and sorbitan fatty acid esters. A method of preventing or controlling endo and ectoparasites in a warm blooded animal, the method comprising orally administering to the animal a non-aqueous suspension consisting essentially of: a parasiticidally effective amount of at least one organophosphate, preferably at least one organophosphate selected from the group consisting of naphthalophos, coumaphos, crufomate, metrifonate and haloxon, more preferably naphthalophos; COMS ID No: ARCS-174445 Received by IP Australia: Time 15:05 Date 2008-01-08 11 one or more organic solvents selected from the group consisting of medium chain triglycerides, alcohols, CI-Cs 8 pyrrolidones, alkyl ethers, glycol ethers, fatty acid esters and glycerol fatty acid esters; one or more stabilising agents; and one or more surfactants.