AU2009233634A1 - Anthelminitic Compostion - Google Patents

Description

Regulation 3 2 AUSTRALIA PATENTS ACT, 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT ORIGINAL Name of Applicant: JAYCHEM INDUSTRIES LIMITED Actual Inventors: SAMPLONIUS, Katherine Jane Address for service in A PARK, Level 11, 60 Marcus Clarke Street, Canberra ACT Australia: 2601, Australia Invention Title: Anthetuniniti Composition The following cement is full description of this invention, including the best method of perfonning it known to us. - 1- FIELDS OF THE INVENTION The present invention relates to pesticidal compositions, tir preparation and their use. More particularly the present invention relates to non-aqueous formulations for topical administration that includes at least two different active ingrecijents. BACKGROUND IEvery anthelmintic has different chemical properties including different solubilities and different requiretoments for stability A common problern with combining anthelhn antics is that the combination results in an unstable product. Various different routes of administration of anthelmintic Compositions are known, such as orally (PO), subcutaneously (SC) parenterally, and via pour-on administration. Anthelmintic formulations are devised to be appropriate for their particular route of administration. Pour on, or topical (transdermal), routes of administration are generally water based or have combinations of anthelmintics having matching stability characteristics. For example, New Zealand Patent 336139/336213/336014 and New Zealand patent 515772 disclose a stable biecidal composition comprising two separate phases (an oil and a waver phase), and wherein the anthelmintics are soluble in either of the two phases depending on their soluhility characteristics. It is an object of the present invention to provide an anthelmintic composition, or an anthelmintic composition useful in the treatment of pesticidal infection, or to at least provides the public with a useful choice. Other ohjecrs of the invention may become apparent from the following description which is given by way of exarnple only. All percentages are expressed as wv relative to the total composition except where otherwise stated. As used herein, reference to "levamisole" refers to the base form of levamisole (i.e. (6S)-6-phenyl-2,3,5,6-tettahydroimidazo[2,1 -b][ ,3]thiazole), and not the phosphate nor salt (e.g. HCL) forms. 2 SUMMARY OF THE INVENTION Ini one aspect the invention relates to a stable mix of two or more immiscible anthelmintics present in a nonaqueous solvent, wherein one of the anthelinntics is levamisole, and the anthelinntic composition forms a stable suspension for transdermal application. In a further aspect the invention relates to a substantially anhydrous anthelininuc composition comprising: a lipophilic imidazothiazole a non-water-soluble actve " an anhydrous veterinarily acceptable carried, and wherein the composition is applied transdermally. In a further aspect the invention relates to a substantially anhydrous antheimintie Composition comprising: a lipophilic imridazothiazoic " a non-water-soluble benzimridazole, " an anhydrous veterinarily acceptable carrier, and wherein the composition is applied transderinally. In a further aspect the invention relates to a substantiallv anhydrous anthelnintic composition comprising: * about I to about 40% wv/v of a imidazodiazole about 0.1 to about 4 0/g w/v of a non-water-soluble beunzimidazole, " an anhydrous veterinarily acceptable carrier, and wherein the composition is applied tranSledermally. In one embodiment the anhydrous anthelmintic composition comprises about 3 to about 20% w/v of an imidazothiazolc, and about 2 to about 30% w/v of a benzimdazole in a micronised form. Preferably the imidazoihiazole is levamisole. In a further aspect the invention relates to a substantially anhydrous anthelmintic composition comprisig: - levamnisole, at least one non-water-soluble benzimidazole, - a substantially anhydrous veterinarily acceptable carrier, and 3 wherein the composition is applied transdermlly. In a further aspect the invention relates to a substantially anhydrous anthelmintic comllposltiol, as a tnInsdermnii pour-on, conpasig: about I to 4 about 0% w/v of levarnisole, " about 0.1 to about 40% w/v of at least one non-water-soluble benziniidazole, and " a substantially anhydrous veterinarily acceptable carrier, and wherein the composition is applied transdermally. In some embodiments the composition includes a permeation enhancer. In some embodiments the inidazothiazole (e.g. levanisole) is present at about 1, 5, 10, 15, 20, 25, 30, 35 or about 40% w/v. In some embodiments the non-water-soluble active (e.g. benzimidazolc) is present at about 0.1, 1, 5, 10, 15, 20, 25, 30, 35 or about 40% Nv/v. In one embodiment the permeation enhancer is present at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 21. 25, 26,2 7. 28, 29 or about 30%/., w/v. Preferably the permeation enhancer is transcutal CG. In some embodiments the non-water-soluble benzimuidazole has a particle size of less than about 30 p In soue embodiments the composition incLides " optionally an anti-caking agent, e optionally at least one aerosol. In a furtiaer aspect the invention relates to a method of making an anthelnintic composition for transdermal application, the method comprising the steps of: 1. providing a mix of an imidazothiazole (preferably levamisole) with a carrier, 2. muicronising a second active (preferably a non-water-soluble benzinidazole) and adding to the mix of said active and said solvent, 3. adding optimal components, 4. mixing to form a suspension. Any of the following embodiments may individuaBy relate to any of the above aspects. 4 In soeic embodiments the veterinarily acceptable anhydrous carrier is for inanmmals. Preferable the veterinary acceptable anhydrous carrier is for sheep, cattle, deer, pigs, horses. In some embodiments of the present invention said anhydrous carrier is present from about 20 to about 75% w/v. More preferably said anhydrous carrier is present at between about 40 to about 60% w/v. In some embodiments the non-levamisole active (e.g. the non-water-soluble benzimidazole) is suspended in said pesticidal composition without a requirement to be held in an aqueous cartier at arly stage. In some embodiments the benzimidazole is selected from one or more of albendazole, oxfendazole, melbendazole, fenbendazole and trchkbendazole. In Some embodiments of the present invention the composition also includes an active selected from the macrocyclic lactone family of anthelminrics (e.g. moxidectin, ivemrectin and abamectin). In some embodimerts of the present invention the composiLon also includes an active selected from the salicylanilide family of anthelmintics (e.g. brotianide, clioxanide, closantel, nicosanide etc). In some embodiments of the present invention said composition includes a further active selected from one or rnore of a tetrhydropyimidinns, an orgInophospliae, piperazine, dieth ylcarbamazine, prazquaite], cpsiprantel, clorsulon, bunamidine, or nitroscanate. In some embodiments of the preseiI ivetion the non-lev amisole active (e.g. the non-water-soluble benzimidazole) has a particle size of about 5 to about 30 microns. More preferably the particle size is less than about 10 microns. In some embodiments of the present invention the anhydrous carrier is an organic solvent. Preferably said organic solvenit is glycol or "n alcohol diglycol, isopropanol, dipropylene glycol mononethyl ether. In some embodiments of the present invention the non-aqueous solvent is a glycol. More preferably the solvent is butyl diglycol. In some embodiments of the present invention butyl diglycol is present at 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 411, 12, 43, 14, 15, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60% w/v. Preferably the butyl diglycol is present at approximately 51% w/v. 5 In sorne cmbodinents the compositon includes an emollient. A preferable emn.loielit is crodamol CAP, isopropyl l)aimitate, capryic/capric triglyceride. n sonc embodiments the composition includes a pernnation enhancer. Preferable permeation enhancers include dimethyl isosorbide orthoxy diglycol. In soic cimbodlinients said composition includes any one or more of the Following: " anti-cake(s) " acrosol(s) antheinintic(s), e anti-freeze(s), m thickening agentss, " anti-flocculant(s). In some embodiments said emulsifying agent is Tween 80. In some embodirents said aerosol is silicon dioxide. In some embodiments said anti-caking agent is present at between about I to about 5% w/v. More preferably it is present at approximately 2% we/v. Preferably said an ti-caking agent is silicon dioxide In yet a further aspect of the invention consists in a stable non-aqueous anthelmintic composition so made. In still a further aspect of the present invention consists in the Luse of an anthelmintic compositioni of any of the kinds previously defined. Preferred forms of the present invention may also comprise such additives as: - antiflocculants, - mninerals/jvitamins, thickening agents, - anti-freezes, - an antimicrobial, - pH stabiliser. Preferred components in the concentration ranges and examples as set out in Table L. 6 Table 1. Table showing formulations of the present invention. Ingredient Comp. A Comp. B Comp. C Albendazole 15 15 15 Levamisole Base 10 10 10 Butyl diglycol 51 59 40 CrOd amol CAp 10 15 10 Tween 80 1 2 Transcutol CG 15 Isopropyl palmitare - DPM - 25 Specification Comp. A Comp. B Comp. C pH 7.98-8.83 8.15-9 Specific Gravity 0.962-1.064 0.9535-1.0573 Sldl.2@410 rpm 152-168 eps 152-168 cps Other aspects of the invention may become apparent from the following description which is given by way of exampic only and with reference to the accompanying drawings. As used herein the term "'Inhydrous" is used interchangeably with "non-aqueous" A nhydrous means without water. The term "comprising" as used in this specification and claims means "consisting at least in part of'. When interpreting statements in tlis specification and claims which include tiat term, the features, prefaced by' that term in each statement, all need to be present but other features can also be present. Related terms such as "comprise" and "conprsed" are to be interpreted in the same manner. It is intended that reference to a range of numbers disclosed herein (for example, 1 to 10) also incorporates reference to all rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9 and 10) antd also any range of rational numbers within that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7). To those skilled in the art to which the invention relates, many changes in construction and widely differing embodiments and applications of the invention will suggest 7 themselves without departing from the scope of the invention as defined in the appended claims. The disclosures and the descriptions herein are purely illustrative and are not intended to be in any sense limiting. DETAILED DESCRIPTION Ihe present invention relates to a substantially anhydrous anthelmintic composition comprising an organic phase having a nicronised particulate material suspended therein. It should be appreciated that in one embodiment, the invention is directed to having two or more actives, each having different solubilities, in a single anhydrous phase, that is admnisterd transdernmaly- This can he achieved hy micronisng the active or actives that do not form a stable suspension in the anhydrous phase. A further embodiment relates to an anhydrous anthelinntic composition comprising about 3 to about 20% w/v of a imidazothiazole, about 2 to about 30% W/V of a non-water soluble active (preferably in a micronised form), and an anhydrouis veterinarily acceptable carrier. Preferably the irnidazothiazole is levamisole. Preferably the non-water-soluble active is present in a micronised form, or has a particle size of at least less than about 30 p-tm. More preferably the non water-soluble active is a benzimidazole. In a further enbodinent there is provided a substantially anhydrous antheihintic comptiosin comprising: * a lipophilic inmidazothiazole a non-water-soluble active, an anhydrous veterinarily acceptable carrier, and wherein the composition is applied ttansdermally. In a further emlbodilmient there is provided a substantially anhydrous anthlminltic composition coming: a lipophilic inidazothiazole " a non-water-soluble benzimidazole, " an anhydrous veterinarily acceptable carrier, and wherein the composition is applied tansdermally. In a further embodiment there is provided a substantially anhydrous anthehintic composman comparing: * about 1 to about 40% w/v of a imidazothiazole 8 " about 0.1 to about 40% w/v of a non-water-soluble benzimidazole, * an anhydrous vererinarily acccptalC carrier, and wherein the composition is applied transdermally. In a further cinbodiment there is provided an anhydrous anthclintic composition cormprises about 3 to about 20% w/v of an imidazothiazole, and about 2 to about 30% w/v of a benzirnidazole.un micronised forn. Preferably the imidazothiazole is levamisole. In a further embodiment there is provided a substantially anhydrous anthelmintic Composition composing: " levamisole, " at least one non-water-soluble benzimidazole, " a substantially anhydrous veterinarily acceptable carrier, and wherein the composition is applied tratsdermally. In a further embodiment there is provided a substantially anhydrous anthelmintic Composition, as a transdermal pour-on, comprising: about 1 to about 0% w/v of levatmsole, - about .1 to about 40% w/v of at least one non-water-soluble benzindazole, and " a substantially anhydrous veterinarily acceptable carrier, and wherein the composition is applied transdermally. In one cinbodiment the imidazcirhiazole (c.g. levamisole) is present at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40% w/v, and useful ranges may be selected between amy of these values (for example, about 1 to about 5, about 1 to about 10, about 1 to about 15, about 1 to about 26, about I to about 25, about I to about 30, about I to about 35, about I to about 40, about 1 to about 45, about I to about 50, about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 5 to about 35, about 5 to about 40, about 5 to about 15, about 5 to about 50, about 1 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 10 tO about 35, about 10 to about 40, about 10 to about 45, about 10 to about 50, 15 to about 20, about 15 to about 25, about 15 to about 30, about 15 to about 35, about 15 to about 40, about 15 to about 45, about 15 to about 50, about 20 to about 25, about 20 to about 30, about 20 to about 35, about 20 to about 40, about 20 to about 45, about 20 to about 50, about 25 to about 30, about 25 to about 35, about 25 to about 9 4D, about 25 to about 45, about 25 to about 50, about 30 to about 35, about 30 to about 40, about 30 to about 45, about 30 to about 50, about 35 to about 40, about 35 to about 45, about 35 to about 50, about 40 to about 45, about 40 to about 50, about or 45 to about 50% w/v). In one embodiment the non-water-solubile active (e.g benzimidazole) is present at 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40% w/v, and useful ranges may be selected between any of these values (for example, about 0.1 to about 0.5, about 0.1 to about 1, about 0.1 to about 5, about 0.1 to about 5, about 0.1 to about 10, about 0.1 to about 15, about 0.1 to about 20, about 0.1 to about 25, about 0,1 to about 30, about 0.1 to about 35, about 0.1 to about 40, about 0.1 to about 45, about 0.1 to about 50, about 0.5 to about 1 ,0.5 to about 5, about 0.5 to about 10, about 0.5 to about 15, about 0.5 to about 20, about 0.5 to about 25, about 0.5 to about 30, about 0.5 to about 35, about 0.5 to about 40, about 0.5 to about 45, about 0.5 to about 50, about I to about 5, about 1 to about 10, about I to about 15, about I to about 20, aout I to about 25, about 1 to about 30, about 1 to about 35, about I to about 40, about t to about 45, about 1 to about 50, about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 5 to about 35, about 5 to about 40, about 5 to about 45, about 5 to about 50, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 10 to about 35, about 10 to about 40, about 10 to about 45, about 10 to about 50. 15 to about 20, about 15 to about 25, about 15 to about 30, about 15 to about 35, about 15 to about 40, about 15 to about 45, about 15 to about 50, about 20 to about 25, about 20 to about 30, about 20 to about 35, about 20 to about 40, about 20 to about 45, about 20 to about 50, about 25 to about 30, about 25 to about 35, about 25 to about 40, about 25 to about 45, about 25 to about 50, about 30 to about 35, about 30 to about 40, about 30 to about 45, about 30 to about 50, about 35 to about 40, about 35 to about 45, about 35 to about 50, about 40 to about 45, about 4C to abOut 50, about or 45 to about 50% w/v). Transdernally applied anhhhninties have a numrnber of specific characteristics. For example, the composition has to be able to penetrate through the skin quickly. Failure to do this may mean that the composition is removed from the skin before it can have its desired effect. For example, the composition could be washed off by rain, or licked off by other animals. In onc embodiment the composition includes a permcatiton enhancer. The permeation enhancer can be present at 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 10 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30% w/v, and useful ranges may be selected between any of these values (for example, about 1 to about 5, about 1 to about 10, about I to about 1 5, about 1 To about 20, about I to about 25, about 1 to about 30, about 3 to about 5, about 3 to about 10, about 3 to about 15, about 3 to about 20, about 3 to about 25, about 3 to about 30, about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 8 to about 10, about 8 to about 15, about 8 to about 20, about 8 to about 25, about 8 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 13 to about 15, about 13 to about 20, about 13 to about 25, about 13 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 18 to about 20, about 18 to about 25, about 18 to about 30, about 20 to about 25, about 20 to about 30, about 22 to about 25, about 22 to about 30, about 25 to about 30 or 28 to about 39% v/w), Examples of permeation enhancer include dimethyl isosorbide and ethoxy diglycul (Transcutol CG). It should be appreciated that the permeation enhancer facilitates the movement of the composition through the skin so that the composition can get to the site of action quicdy. iis is important, as certain anthehnintic actives, such as oxfendazole, have to be carried through the skin quickly to ensure good efficacy. A dditionally, the compyiosition has to have a pH-l and formulation that will not burn the anima High 1y acdic or h.1y : a ine composmons are not suitable for transdermal tiplicati on. Anthelmintic compositions also have to be able to be stored for long periods of time, vet remain suitable for use. The advantage of the preseit coimposition is that it remains stable for a long period tf time prior to use. Prior to use the composition can be shaken to re suspend any actives. Te composition of the present invention can remain stable for up to about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 or about 48 months from manufacture. In one emibodimenit there is provided a method of formulating a stable non-aqueous anthelmintic composition of the kind having: " levanisole, " at least a second active or actives that is not readily soluble in an anhydrous " optionally an anti-caking agent, " optionally at least one aerosol, and - a substantially anhydrous veterinarily acceptable carrier, said method comprising the steps of: 1. providing a mix of said first active with said catrier, 2. nictonising said second activc and adding to the mix of said active and said solvent, 3. mixing to form an suspension. The active tihal is noL readily soluble in an anhydrous carrier is preferably a benzamidazole, and more preferably oxfendazole. A benzimidazole for use with the present invention could be any one or more of the following benziimadizoies such as mnebendazole, fenbendazole, flubendazole, oxfendazole, oxienda, zole, thiophanate, febantel, netobinijnc, triclabendazoe, netobinine, triclabendazole, parbendazole, carbendazole, or fenbantel. The imidazothiazole could include any one or more of levamisole, pyrantel pamontc, butamisole, and tetramisol, Preferably the inidazothiazole is levamisole. Other active can also be used in conjunction with the composition including , for example, salicylanilides or macrocyclic lactones. A macrocyclic kactone for use with the present invention could be any one or mote of the following nacrocyclic lactone such as avermectin, ivernectin, eprimomectin, moxidectin, selamecrin, doramecrin, milbemycin, abamectin, or cydectin. A salicylanilide for use with the present invention could be any one or more of the following salicylanilide such as brotianide, clioxanide, closantel, niclosamide, oxyclozanide, rafoxanide, bithionole, disophenole, hexachlorophene, nitroxynile, diam fenetide, diamphenethide, niclofolan, or menichlophol. A imidazothiazole for use with the present invention could be any one or more of the following imidazothiazole such as levamisole, pyrantel pamoate, butamrisole, or terramisoL. It should be appreciated that other actives may also be used with the said composition of the present invention such as anti-virals, tetrahydropyrimidines, or organophosphates. 12 In one embodiment the veterinadly acceptable anhydrous carrier is for mammals. Preferable the veterir acceptable anhydrous carrier is for sheep, cattle, deer, pigs, horse. To produce a stable emulsion the active that is insoluble (or at least practically insoluble) in the carrier has a paricle size of about 5 to about 30 microns. More preferably the particle size is less than about 10 miCrons, This results in a cotmposition that can be used as a transdernal pour-on. In one embodiment the anhydrous carrier is an organic solvent, Preferably said organic solvents is glycol or an alcohol diglycol. In one embodiment the non-aqueous solvent is a glycol. More preferably the solvent is butyl diglycol. In one embodiment of the present invention said organic solvents is glycol or an alcohol diglycol. In one embodiment of the present invention buty) diglycol is present at about 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 12, 43, 41, d5, 16, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or about 60% w/v. Preferably said glycol or alcohol diglycol is present between about 40 to about 65' w/w More preferably said glycol or alcohol diglycol is present at about 40% w /w. Preferably said diglycol is preseml t at about 51%5 w/v. In one embodiment the composition includes an emollient. A preferable emollient is crodamol CAP. In onc embodiment said composition includes any one or more of the following: m anti cakes) " aerosol(s) ' anthelmintic(s), " anti-freeze(s), thickening agent(s), " ant-focculant(s}. In one embodiment said emulsifying agent is Tween 80 and/or 'lrra 380. In one embodiment said aerosol is silicon dioxide. 13 In one embodiment said ant-caking agent is present at between about 1 to about 5% w/w. lore preferably it is present at about 2% w/w. Preferably said anti-caking agent is Peak 6000. Preferred forns of the present invention may also comprise such additives as: antifocculants a minerals/vitamins " thickening agents " anti-freezes - an antimicrobial * pH stabiliser Preferably the active that is in the nicronised form is micronised using the pneumatic jet mill process, however, it should be appreciated that any micronisation techniepie known to a person skilled in the art could be used. Preferably the micronised active has a particle size of about 5, 10, 15, 20. 25 or about 30 microns. More preferably the particle size is at Icas less than about 10 microns. As shown in Table I is a summary of solubility information for various activ es as derailed in the Merck Index. Any number of these active can be combined in any combination through the processes described. Briefly stated, by providing an anhydrous carrier such as glycol, various actives that are soluble in this can be incorporated. Other actives that may be insoluble, or sparingly soluble, at required concentration in an anhydrous earlier can he present in a micronised form. This reduces settling velocity and allows the composition to be present in a substantially "solubilised" fomn. Table 2. Table summarising solubility information for various actives as detailed in the MERCK index. Anthelmintic Solubility Benzimadizoles albendazole - soluble in HCL fenbendazole . insoluble in water - soluble in DMSO Mebendazole - practically soluble in water - practically insoluble in chloroform - practically_ insoluble in methanol netobimine, - soluble in water - soluble in acetone - soluble in DMSO 14 Anthelmintic Solubility - insoluble in ether - soluble in methanol parlbendazole - actically insoluble in water thiahenlazole, soluble in DMSO - slightly soluble in alcohols, esters, chlorinated hy drocarbons triclabendazole, - soluble in absolute ethanol and methanol Macrocyclic lactone abamectin - solubility in water of 10 at 21 'C - solubility in acetone of 100 at 21 "C solubility in ethanol and methanol of 2D at 21 'C> * solubility in toluene of 350 at 21 "C solubility in isopropanol of 70 at 21 "C avermectin soluble in water of less than 5 jig/mil - soluble in organic solvents vermeetin - soluble in ketone, propylene gycol - insoluble in clohexane milbemycin - very slightly soluble in water - soluble in acetone - soluble in n-hexane - soluble in chloroform soluble in ethanol and methanol sclamectin a very water soluble Salicylanilide bithionole - solubility in water of 0 - solubility in polysorbate 80 of 19 - solubility in 70'% ethanol of 0.3 - solubility in dimethyl/acetainide of 72.5 - solubility in acetone of 15 closantel - soluble in DMF clisophenole - sparingly soluble in water - alcohol soluble exachlorophee -c insoluble in water niclosamide - sparingly soluble in water - sparingly soluble in chloroform - sparingly soluble in ethanol nitroxynile . readily soluble in water - moderately soluble in organic solvents oxyclozanide slightly soluble in water - soluble in acetone rafoxanide - practically insoluble in water - moderately soluble in acetone Imidazothiazole pyrantel pamoate - insoluble in water levamisole - insoluble in water - Miscellaneous clorsulon -slightly soluble in water 15 Anthehnintic Solubility diethylcarbanazine = very soluble in water insoluble in acetone soluble in chlorocorm csiprantel - spaying y water soluble nitroscanate insoluble in waver - soluble in organic solvents piperazine freely soluble in water praziquantel solubility of 0.04 in water solubility of 56.7 in chloroform - solubility of 9.7 in ethanol plzitaantel - poor solubility in water tetrahy dropyrimidines - insoluble in water Additional excipients that may be included are shown below in Table 3. Table 3. Other excipients that may he included. Ingredient Purpose Dinmethyl isosorbide Peuncailo eibauicr Ethoxy diglycol (Tr anscutol CC) Permeation enhancer nzyl alcoholic Buitlated 1ydrmy toluenc Preservatire But diglvcol Solvent , ' .0C .... ........ ................ .... . . Isopvopanel Sol.ent Diptopylene Glycol Nlononmthyl 1Fther (IOw anol DP yl) Poiyoxvethylcnesorbitan AvIonooleare (Poly sorbar 80) Cctearyl lErbylhexanoate and Isopropyl 211 Ist3 1 (Q1 aml CAP) Isopropyl paliniate Emollicent EXAMPLES As shona in table 4, a number of different compositions were designed. Each of the examples below comprises levam-sole tha,,t forms a solution with butyl di glycol. A\s albenidazole is insoluble in hutyl cliglycol, it was nu-1cronise"d to all1ow the nu-1crop.artieles to form a suspension Ina butyl d&gly col, 16 Table 4. Table showing the formulations of the present invention. Ingredient Comp. A Comtp. B Comp. C Albendazole 15 15 15 Levamisole Base 10 10 I0 Butyl diglycol 51 59 40 Crodamol CAp 10 15 10 Tween 80 1 2 Transcutol CG 15 Isopropyl palmitate - - DPM 25 Specification Comp. A Comp. B Comp. C pI 7.98-8.83 8.15-9 Specific Gravity 0.962-1.064 0.9535- .0573 Spdl.2@10 rpm 152-168 cps 152-168 cpsa- Various aspects of the invention will now be illustrated in non-limiting ways by reference to the following examples. Trial 1 - Efficacy Study ITis study was conducted from 15 Feb 2008 to 10 March 2008 with the aim of studying and evaluating, under field conditions, the efficacy of a treatment formulation when administered to catle. On Day -7 of the trial, faccal egg counts were obtained from all cattle in the trial mob. On Day -3 of the trial, cattle that met the inclusion criteria were identified and tagged with uniquely numbered eartags and weighed. Incision criteria for the trial included: Friesian X steers aged 4-18 months - a facial egg count of 200 epg - a history of having not been treated with a pour on or incetablc anthehnintic for at least six weeks or an oral drench for at least 4 weeks prior to the trial. 17 ihe catle were then randomly allocated to either a control group or the treatment group as shown in Table 5 to ensure a similar arithmetic group mean fecal egg count. Table 5. Treatment table Treatment Fonnulation n Group I Untreated control 10 2 'Treatment 10 formulation On Day 0 of the trial, each cattle was treated with Iml/kg treatment via pour-on administration. The treatment formulation as used in this trial is shown in Table 6. The formulation had an oxfendazole content of between 142.5-157.6 g/L and a levamisole content of 95.0-105.0 g/L Table 6. Treatment formulation Ingredient %7o wt/wt Oxfendazole 15 Levamisole 1( Butyl dioxitol 57 crodanol 15 Tween 80 2 A erosil 200/Rcosil/Cabosil 1 Faccal egg samples were obtained from both groups on days 7, 14, 21 and 28, and analysed. The raw facca] egg counts are shown An Table 7. 18 Table 7. Raw data - Faecal egg count Day -3 Day 0 Day 7 Day 14 Day 21 Day 28 Weight FEC FEC FEC FEC FEC FEC Group 1 148.5 400 :50 200 100 100 200 148.5 350 50 150 100 100 150 143 3C0 50 50 125 125 250 163 250 100 100 /O 150 148 200 50 50 150 150 150 1,56 20 '150 l00 00 100 4006 158 200 200 125 100 100 200 135.5 200 100 100 50 50 200 156 200 100 150 255 167 150 150 50 100 100 50 138.5 300 300 0 0 0 50 145 300 150 0 0 0 0 150 250 00 0 157 230 100 0 0 0 0 1591200 150 0 0 0 0 142.5 200 200 0 0 0 0 134 200 500 0 00 0 .Pb~ io.. ...... ..... .. . . . . .2 149 200 250 0 0 0 25 126.5 15O 150 0 0 0 0 Table B shows the percentage efficacy of the treatment formulation in reducing faccal egg counts at days 7, 14 antd 21 Table 8. Overall percentage efficacy of the treatment formulation calculated using geometric group mean faecal egg counts. Day %o efficacy 7 >99.9 14 >99.9 21 >99.9 28 98.7 These results demonstrate that pour-on administration of the treatment formulation is highly effective in reducing faeCcal egg couLLts in cattle at 7, 14, and 21 days post treanment. 19 Trial 2 - Slaughter Efficacy Study This study was conducted from 29 iMay 2008 to 18 JLily 2008 with the aim of confirming the findings of Trial I and to evaluate The efficacy of the same novel treatment formrulation for decreasing adult Worm loading In the gastrointestinal tract. On Day -7 of the trial, faccal egg counts were obtained from all cattle in the trial mob. On Day -2 of the trial, cattle that met the inclusion criteria were identified and tagged with uniquely numbered eartags and weighed. Inclusion criteria for the cattle in the trial included: Friesian X steers aged 4-18 months - a faccal egg count of 200 epg " a history of having not been treated with a pour on or injectable anthelmintic for at least six weeks or an orai drench for at least 4 weeks prior to the trial. The cattle were then randomly allocated to either a control group or the treatment group as shown in Tabie 9 to ensure a similar arithmetic group mean fecal egg count. Table 9. Treatment table Treatment Formulation p Group 1 Untreated control 16 2 Treatment 16 formulation On Day 0 of the trial, each cattle was treated with I mL./kg treatment via pour-ton administration. The treatment formulation as used in this trial is shown in Table 10. T'he formulation had an oxfendazole content of between 142.5-157.6 g/L. and a levamisole base content of 95.0-105.0 g/L. 20 Table 10. Treatment formulation Ingredient % wt/wt Oxfendazole 15 Levam11isole 10 Butyl dlioxitol 57 crodarnol 115 Teen 80 2 Aerosil 200/Rcosil/Cahosil 1 Fecal egg samples were obtained from both groups on days 7 and 10, On Day 10 of the trial, 6 cattle from each group were slaughtered. Worm load within three regions (abomasums, small intestine and large intestine) of the gastrointestinal tract was calculated and the percentage efficacy of treatment formulation was analysed. The overall percentage efficacy data are shown in Table 11. Table 11. Overall percentage efficacy of the treatment formulation AM = arithmetic nean Abomasum Small intestine Large Intestine GM = Ccomctric mean % efficacy % efficacy % efficacy AM GM N AM GM AM GM 5th Stage Haenionchus L4 E,4 5th Stage 94.5* 99.8* Ostertagia IL %.J* 79* EA 87.0* 99.4* 5th Stage >999* >99.9* >99.9* >99.9* Triehostrongylus 1A 9 >9. >999 >99.9* >99.9*-l' E,4 5th Stage 99.8*", 99.9* Cooperia L4 98.0* 98.0* -174 -__ _ -__ _ ------ 9Y __ _ _ __ _ _ Oesophagostomum _>99.9* >99.9* Faccal egg samples were obtained from the remaining 10 cattle in both groups on days 7, 28, 33 and 42, and analysed. The raw facial egg counts are shown in Table 12. 21 Table 12. Raw data - Faccal egg count Day -2 Day 0 Day 7 Day 28 Day 35 Day 42 FEC FEC FEC FEC FEC FEC Group 1 150 150 0 0 0 0 100 JOO 0 50 0 150 150 0 0 0 0 200 200 0 0 100 100 l6< 0 0 f 0 100 100 100 0 0 0 150 150 0 0 0 50 . 150 150 0 C 1 0 0 250 250 0 0 0 1.5c 150 0 0 0 0 Group 2 100 100 .00 150 150 200 200 200 100 200 200 200 150 150 400 200 550 400 50 50 150 15) 150 150 100 100 150 250 300 100 150 150 200 100 600 150 , 100 100 10 200 250 250 300 300 250 200 200 150 150 250 300 '100 100 250 200 '150 1 50 Table 13 shows the percI.entage effiicc of the ireitment formulaition in reducing fecal egg counts at days 7, 14 and 21. Table 13. Overall percentage efficacy of the treatment formulation calculated using arithmetic group mean faccal egg counts. Day %/ efficacy 28 99.4 35 99.4 42 98.0 These results reconfirm the findings of Trial 1 and demonstrate that pour-on administration of the treatment formulation is highly effective at reducing worm load in the gastroilntestinl tract, and reducing facial egg counts in cattle, for up to 42 days post treatment. 22 Wher'c in the foregoing description reference has been made to elements or integers having known equivalents, then such ecquivalen ts are included as if they were individually set forth. Although the invention has been described by way of example and with reference to particular embodiments, it is to be understood that modifications and/or improvements may be made without departing from the scope or spirit of the invention. 23

Claims (46)

1. A substantially anhydrous anthelinintic composition comprising (a) a lipophilic imidazothiazole (b) a non-water-soluble active, (c) an anhydrous veterinarily acceptable carrier, and wherein the composition is applied transdermally.

2. A composition of claim 1 wherein the non-water-soluble active is suspended in the anthelmintic composition without a requirement to be held m an aqueous carner at any stage.

3. A composition of claim I or 2 wherein the non-water-soluble active is a benzimidazole.

4. A\ composition of any one of claims I to 3 wherein the non-water-soluble benzimidazole is present at about 0.1 to about 40% w/v.

5. A composition of any one of claims 1 to 4 wherein the imidazothiazole is present at about to aoui 40A w/v.

6. A composition of any one of claims 1 to 5 that comprises about 3 to about 20% w/v of an imidazothiazie, and about 2 to about 30% w/v of a benziniidazole in a mnicronised fort.

7. A composition of any one of claims 1 to 6 wherein the inidazotiazole is levaiisole,

8. A composition of claim 7 wherein the levamisole is levamisole base.

9. A composition of any one of claims 1 to 8 wherein the non-water-soluble beizirnidazole has a particle size of less than about 30 pim.

10. A\ composition of any one of claims 1 to 9 wherein the anhydrous carrier is present from about 20 to about 75% w/v.

11. A composition of any one of claims 1 to 10 wherein the anhydrous carrier is an organic solvent.

12. A composition of claim 11 wherein the organic solvent is glycol or an alcohol diglycol, isopropanol, dipropylene glycol monomethyl ether.

13. A composition of claim 12 wherein the butyl diglycol is present at between about 30 to about 60% w/v. 24

14. A composition of any one of claims 3 to 13 wherein the benzimidazole is selected from one or more of albendazole, oxfendazole, mebendazolc, fenbendazole and trichlabendazole.

15. A composition of any one of claims 1 to 14 wherein the composition also includes an active selected from the macrocyclic lactole frnmily of anthelmintics.

16. A composition of any onc of claims 1 to 15 wherein the composition also includes an active selected frorn the salicylanilide family of anthelmintics.

17. A composition of any one of claims 1 to 16 wherein the composition includes a further active selected from one or more of a tetrahydropyrimidines, an organophosphate, piperazine, diethylcarbamazine, praziquantel, epsiprantel, clorsulon, bunamidine, or mitroscanate.

18. A composition of any one of claims I to 17 wherein the composition includes a permeation enhancer.

19. A composition of claim 18 wherein the perneation enhancer is present a bout 1 to about 30%/o w/v.

20. A composition of claim 18 or 19 wherein the perimeation enhancer is transcutol C.

21. A composition of any one of claims I to 20 wherein the composition includes an anti calnog agCet.

22. A composition of claim 21 wherein the anti-caking agent is present at between about 1 to about 5% w/v.

23. A composition of claim 21 or 22 wherein the anti-caking agent is silicon dioxide,

24. A composition of any one of claims 1 to 23 wherein the composition includes an aerosol.

25. A composition of claim 24 whercin the aerosol is silicon dioxide.

26. A composition of any one of claims 1 to 25 wherein the composition includes an emollient.

27. A composition of claim 26 wherein the emollient is selected from crodamol CAP, isopropyl palmitate, and caprylic/capric triglyceride. 25

28. A conposition of any one of clairns I to 27 wherein the composition includes a Ienneation enhancer.

29. A composition of claim 28 wherein the permeation enhancer is dimethyl isosorbide orthoxy diglycol.

30. A conposition of any one of claims 1 to 29 wherein the composition includes an emulsifier.

31. A composition of claim 30 wherein the emulsifying agent is Tween 80,

32. A stable mix of two or moe immiscible anthelmintics present in a ioin-aqucous solvent, wherein one of the anthelminrics is levamisole, and the anthelmintic composition forms' stable suspension for transderrnal application.

33. A method of making an anthelmintic composition for transdermal application, the method comprising the steps of: (a) providing a nix of an imidazothiazole with a carter, (b) micronising a second active and adding to the mix of said active and said solvent (c) mixing to form a suspension.

34. A method of claim 33 wherein the second active is suspended in the alithelntic composition without a requiremen( to be held in an aqueous carrier at any stage.

35. A method of claim 33 or 34 wherein the second active is a benzimidaztile.

36. A method o; any one of claims 33 to 35 wherein the second active is present at about 0.i to about 40%: w/v.

37, A method of Alyi one of claims 33 to 36 wherein the imidazothiazole is present at about I to about 40% w/v.

38. A method of any one of claims 33 to 37 that comprises about 3 to about 20% w/v of an tmidazothiazole, and about 2 to about 30% w/v of a benirnidazole in a micronised form.

39. A method of any one of claims 33 to 38 wherein the imidazothiazole is levamisole.

40. A method of claim 7 wherein the levamisole is levamisole base.

41 A method of any one of claims 33 to 39 wherein the second active has a particle size of less than about 30 pam. 26

42. A method of any one of claims 33 to 40 wherein the anhydrous catrier is present from about 20 to about 75% w/v.

43. A method of any one of claims 33 to 41 wherein the anhydrous carrier is an organic solvent.

44. A method of claim 42 wherein the organic solveat is glycol or an alcohol diglycol, isopropianol, dipropylene glycol monomethyl ether .

45. A method of claim 43 wherein the butyl diglycol is present at between about 30 to about 60% w/v,

46. The use of an Anthelmintic composition of any one of claims I to 32. 27