AU2006203347C1

AU2006203347C1 - Stabilised formulation

Info

Publication number: AU2006203347C1
Application number: AU2006203347A
Authority: AU
Inventors: Michael John Gliddon
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2006-05-15
Filing date: 2006-08-04
Publication date: 2009-11-05
Anticipated expiration: 2026-08-04
Also published as: AU2006203347A1; AU2006203347B2; AU2006100657C4; NZ548931A; AU2006100657A4; AU2006100657B4

Description

P/0010 1 1 AUST ALIARegulation 3.2 A USTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Stabilised formulation The following statement is a full description of this invention, including the best method of performing it known to us: 2 Stabilised formulation Field of the invention The present invention relates to stabilised macrolide compositions, and the use of such compositions for treating, controlling, preventing and protecting animals from infestation 5 and infection by internal and external parasites. Background of the invention Macrolide antibiotics such as the avermectin, milbemycin or LL-F28249 family of compounds tend to be unstable under normal conditions of preparation, use and storage. Such compounds have antibiotic, anti-endoparasitic, anti-ectoparasitic, 10 nematicidal and acaricidal activity and are of special interest for use in agriculture, horticulture and animal and human health. They are also useful as intermediates in the preparation of other active compounds. EP329460 discloses that the stability of said compounds may be enhanced when they are in the presence of certain antioxidants. In particular, EP329460 discloses the stabilisation of a group of compounds designated 15 LL-F28249a-, which are isolates from the fermentation broth of the microorganism Streptomyces cyaneogriseus subspecies noncyanogenus (deposited in the NRRL under deposit accession No. 15773), and to derivatives thereof, in particular to 23[E] methoxyimino-LL-F28249a, also known as moxidectin. The antioxidants described in EP329460 as useful for stabilisation are: a C-12 alkyl gallate; C 1

.

6 alkyl 20 hydroxybenzoate or a salt thereof; benzyl hydroxybenzoate or a salt thereof; butylated hydroxyanisole (BHA); butylated hydroxytoluene (BHT); a quinone or a salt thereof; nordihydroguaiaretic acid; and a tocopherol such as a-tocopherol. Summary of the invention It has now been determined that the above described antibiotic compounds may be 25 stabilised by a further range of stabilising agents. The present invention provides an oral drench composition including moxidectin and a stabilising agent selected from the group consisting of: ascorbic acid or a salt thereof; 3 dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylenediamine tetra-acetic acid or a salt thereof; potassium bisulfate; sodium metabisulfite; sodium 5 bisulfite; thiosorbitol; fumaric acid; malic acid; and a mixture thereof. Also provided are stabilised veterinary oral drench formulations containing moxidectin as an active ingredient. The present invention also provides a method for the treatment, prevention or control of helminth, acarid or arthropod endo- or ectoparasitic infection or infestation in an animal 10 including administering to said animal an efficacious amount of a composition or veterinary formulation according to the invention. The present invention will now be described with reference to particular embodiments and examples. Nothing in the following discussion is intended to limit the scope of the invention as claimed. 15 Detailed description of the embodiments Macrolide antibiotic compounds, including avermectin and milbemycin compounds, such as moxidectin, tend to be unstable under normal conditions of preparation, use and storage. Enhanced stability of said compounds can minimise any loss due to instability, during the preparative process. Similarly, enhanced stability increases the 20 shelf-life of said compounds, thereby allowing for preparation of said compounds well in advance of their intended use. Moreover, enhanced stability offers increased protection against photodegradation and against thermal instability, thus allowing for transportation and ready storagability of said compounds. Accordingly, the present invention provides an oral drench composition including 25 moxidectin and a stabilising agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene diamine tetra-acetic acid or a 4 salt thereof; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and a mixture thereof. In one embodiment, the composition of the invention is in the form of a technical material or technical concentrate suitable for use in formulating a final dosage form. 5 The stabilising agent may be present in the composition of the invention in an amount of about 0.005-5.0% by weight of the total composition (w/w), preferably about 0.005-1.0% w/w, and more preferably about 0.02-0.3% w/w. The composition of the invention may be prepared by mixing or blending the moxidectin and the stabilising agent in a conventional manner to produce a stabilised technical 10 material or technical concentrate. Advantageously, the present invention also provides a method of stabilizing an oral drench veterinary composition including moxidectin as an active ingredient including adding to said composition an effective amount of a stabilizing agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; 15 sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene diamine tetra-acetic acid or a salt thereof; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and a mixture thereof. In one embodiment of the method of the invention, the veterinary composition also 20 includes a second active ingredient such as praziquantel, triclabendazole, closantel, levamisole, albendazole, or the like, preferably praziquantel or triclabendazole. Veterinary compositions suitable for use in the method of the invention include, but are not limited to, oral compositions such as an oral drench, a gavage, a feed additive or the like; topical compositions such as a pour-on, spray, dip, spot-on, or the like; injectable 25 compositions; and the like, preferably oral drench or pour-on compositions.

5 Effective amounts of the stabilizing agent suitable for use in the method of the invention include amounts of about 0.05-5.0% w/w, preferably 0.1-5.0% w/w, and more preferably 0.2-1.0% w/w. Accordingly, the present invention further provides a stabilised oral drench veterinary 5 composition including moxidectin as an active ingredient; optionally a second active ingredient; and an effective amount of a stabilising agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene 0 diamine tetra-acetic acid or a salt thereof; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and a mixture thereof. The stabilising agent may be present in said veterinary composition in an amount of about 0.05% to 5.0% by weight of the total composition. In a preferred embodiment the stabilising agent is present in said veterinary composition in an amount in the range of 5 about 0.075% to 1.0% w/w. It is known that compounds such as citric or phosphoric acid can act as synergists for some stabilising agents. Accordingly, in one embodiment, the stabilised veterinary composition of the present invention further includes citric or phosphoric acid. Preferably, said veterinary composition includes about 0.1-1.5% of citric acid by weight 20 per total volume of the composition (w/v). Stabilised veterinary compositions of the invention include oral compositions such as an oral drench, a gavage, a feed additive or the like; topical compositions such as a pour on, spray, dip, spot-on, or the like; injectable compositions; and the like, preferably oral drench or pour-on compositions. 25 In one embodiment, the veterinary composition of the invention may further include 0 15% w/v surfactant. Suitable surfactants include, but are not limited to, one or more of the following: C 8

-C

10 alkylphenol ethoxylates (e.g. Teric N9, Teric N20, Teric N100); C 9 - C17 alcohol ethoxylates (e.g. Teric 9A2, Teric 16A16); C8-C20 alkyl amine ethoxylates 6 (e.g Teric 13M15, Teric 18M20); castor oil ethoxylates (e.g. Cremophor EL, Acconon CA-5, Teric 380); lanolin alcohol ethoxylates (e.g. Polycol 5, Polycol 40); sorbitan fatty acid ethoxylates (e.g. Polysorbate 20, Polysorbate 60, Polysorbate 80); sorbitan fatty acid esters (e.g. sorbitan monoisostearate, sorbitan monostearate, Hodag SML and 5 Span 25); polyoxyethylenated alkyl ethers; polyethylene glycol stearate; polyglycerol esters; polyoxyethylenated fatty alcohols; polyoxyethylenated fatty acids, copolymers of ethylene oxide, copolymers of propylene oxide; or the like; preferably, Polysorbate 80. Excipients such as dyes, antimicrobial agents, antifoam agents or mixtures thereof may be included in the veterinary composition of the present invention. The amounts of said 10 excipients suitable for use in the invention range from about 0.0005% to 2.0% w/v. Dyes suitable for use in the veterinary composition of the present invention include anthroquinone dyes, azo dyes and the like. Examples of antimicrobial agents useful in the veterinary composition of the present invention are benzoic acid, benzoic acid derivatives, methylparaben, propylparaben, sodium edetate, or combinations thereof. 15 The stabilised veterinary composition may include additional components known in the formulation art including, but not limited to: carriers; buffering agents; preservatives and solvents. The efficacious amounts of moxidectin may vary according to the presence of a second active ingredient, the method of application, the host animal, the target parasite, the 20 degree of infestation, or the like. In general, amounts of about 0.01-5.0% w/v, preferably 0.05-2.0 % w/v, of moxidectin may be suitable. As used herein, the term "w/w" designates weight/weight, the term "w/v" designates weight/volume, and the term "mg/kg" designates milligrams per kilogram of body weight. The stabilised veterinary composition of the invention may be prepared by mixing or 25 blending the ingredients in a conventional manner. Beneficially, the stabilised moxidectin and stabilised veterinary compositions of the invention are highly effective for protecting or treating farm and companion animals, 7 such as cattle, sheep, deer, horses, swine, goats, dogs, cats or the like, against infection and infestation by helminths, nematodes, acarids and endo- and ectoparasites. Accordingly, the present invention further provides a method for the treatment, prevention or control of helminth, acarid or arthropod endo- or ectoparasitic infection or 5 infestation in an animal which includes administering to said animal an efficacious amount of a stabilised moxidectin composition or a stabilised veterinary composition as described herein above. Examples of administrations suitable for use in the method of the invention include oral administration such as by an oral drench, a gavage, a feed additive or the like; topical 10 administration such as by a pour-on, spray, dip, spot-on, or the like; or parenteral administration such as by an injectable. Administrations preferred for use in the method of the invention are oral administration by oral drench application or topical administration by pour-on application. Homeothermic animals suitable for treatment in the method of the invention include: 15 swine, cattle, sheep, horses, goats, camels, water buffalos, donkeys, fallow deer, reindeer, or the like, preferably swine, cattle, horses or sheep. Infections and infestations that may be treated, prevented or controlled by the method of the invention include, but are not limited to, Helminthiases caused by helminths such as Ostertagia circumcincta, Haemonchus contortus, Trichostrongylus colubn'formis, or the 20 like; nematode infections caused by, for example Haemonchus, Ostertagia, Cooperia, Oesphagostomum, Nematodirus, or the like; acarid infestations such as biting lice, i.e. Damalinia ovis, Damalinia bovis, or the like; chorioptic, sarcoptic or demodectic mange caused by Chorioptes bovis Sarcoptes scabiei and Demodex, respectively, Psoroptic mange caused by Psoroptes ovis; arthropod endo- parasites such as cattle grubs; and 25 the like. In actual practice, the composition of the invention may be administered in dose rates of mg of active ingredient per kg of body weight of the host animal. Dose rates suitable for use in the method of the invention will vary depending upon the mode of administration, the species and health of the host animal, the target parasite, the degree of infection or 8 infestation, the breeding habitat, the potency of the active ingredient, or the like. In general, amounts sufficient to provide about 0.1-5.0 mg/kg of active ingredient are suitable. In order to facilitate a further understanding of the invention, the following examples are 5 presented primarily for the purpose of illustrating more specific details thereof. EXAMPLE 1 Preparation of a Stabilised Veterinary Oral Drench Composition Component Description w/v/ moxidectin 0.117 Antifoam 9020 0.07 Polysorbate 80 10.0 Disodium EDTA 0.20 Polyethylene glycol 6000 3.0 Propylene Glycol 10.0 Polyoxyethylene 40 stearate 2.50 Xanthan Gum 0.25 Sodium Phosphate 1.57 Benzyl alcohol 1.22 isoascorbic acid 0.25 Purified Water q.s.* *quantity sufficient to obtain a total of 100% w/v Method of Preparation 10 To approximately 70% of the water needed for the batch size, at 700 C, is added polyethylene glycol 6000, polyoxyethylene 40 stearate and isoascorbic acid. The resultant mixture is stirred, treated with disodium EDTA and sodium phosphate, stirred' until homogeneous, treated with polysorbate 80 and the antifoam and stirred. The 9 resultant mixture is treated with a solution of the triclabendazole in propylene glycol and stirred. The moxidectin is dissolved in benzyl alcohol in a separate vessel. The mixture is cooled to 400 C, treated with the moxidectin solution and stirred. The resultant mixture is cooled to 250 C, treated with the remaining purified water and stirred until 5 homogeneous. EXAMPLE 2 Preparation of a Stabilised Veterinary Pour-On Composition Component Description w/v% Moxidectin 0.5% Aromatic Solvent mixture 15.0% PPG2 Myristyl Ether Propionate 10.0% Polybutene polymer 10.0 Tocopherol 0.075% Capric/caprylic glyceryl triester qs* *quantity sufficient to obtain a total of 100% w/v Method of Preparation 10 A solution of 16% w/v polybutene polymer in the capric/caprylic glyceryl triester, at 40* C, is treated with a solution of moxidectin in the aromatic solvent and stirred. The resultant mixture is treated with the PPG2 myristyl ether propionate and the tocopherol and stirred until homogeneous. It will be understood that the invention disclosed and defined in this specification 15 extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Reference to any prior art in this specification is not, and should not be taken as, an acknowledgement, or any form of suggestion, that this prior art forms part of the 10 common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be ascertained, understood and regarded as relevant by a person skilled in the art.

Claims

1. An oral drench composition including moxidectin and a stabilising agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium 5 metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene diamine tetra-acetic acid; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; and a mixture thereof, with the proviso that when the composition contains two active ingredients, the second active ingredient is not 10 praziquantel.

2. A composition according to claim I wherein said stabilising agent is present in an amount of about 0.005-1.0% w/w. 15

3. A composition according to claim I or 2 wherein said stabilising agent is present at an amount of about 0.02-0.3% w/w.

4. A method for stabilising an oral drench veterinary composition including moxidectin as an active ingredient including adding to said composition an effective 20 amount of a stabilising agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene diarnine tetra-acetic acid; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; fumaric acid; malic acid; 25 and a mixture thereof, with the proviso that when the composition contains two active ingredients, the second active ingredient is not praziquantel.

5. A method according to claim 4 wherein the effective amount of the stabilising agent is about 0.1-5.0% w/w. 30 P OPER\MJC2006201147 a ded claims doc-26/2(X9 - 12

6. A method according to claims 4 or 5 wherein the effective amount of the stabilising agent is about 0.2-1.0% w/w.

7. A stabilised oral drench veterinary composition including moxidectin as an active 5 ingredient; optionally a second active ingredient; and a stabilising agent selected from the group consisting of: dilauryl thiodipropionate; monothioglycerol; potassium metabisulfite; sodium formaldehyde sulfoxylate; sodium thiosulfate; thioglycolic acid; thiourea; ascorbyl palmitate; cysteine or a salt thereof; ethoxyquin; isoascorbic acid; ethylene diamine tetra acetic acid; potassium bisulfate; sodium metabisulfite; sodium bisulfite; thiosorbitol; 10 fumaric acid; malic acid; and a mixture thereof, with the proviso that when the composition contains two active ingredients, the second active ingredient is not praziquantel.

8. A stabilised veterinary composition according to claim 7 wherein the stabilising 15 agent is present in an amount of about 0.05-5.0% w/w.

9. A stabilised veterinary composition according to claim 7 or 8 wherein the stabilising agent is present in an amount of about 0.075-1.0% w/w. 20

10. A stabilised veterinary composition according to any one of claims 7 to 9 wherein the second active ingredient is selected from the group consisting of: praziquantel; triclabendazole; closantel; levamisole; and albendazole.

11. A stabilised veterinary composition according to any one of claims 7 to 10 wherein 25 the second active ingredient is praziquantel or triclabendazole.

12. A stabilised veterinary composition according to any one of claims 7 to 9 wherein moxidectin is the sole active ingredient. 30

13. A stabilised veterinary composition according to any one of claims 7 to 12 further including citric acid or phosphoric acid. P:\OPER\MIC\2006203147 amended claims doc2/06/20)9 -13

14. A stabilised veterinary composition according to claim 13 wherein said citric acid is present in an amount of about 0.1-1.5% w/v. 5

15. A method for the treatment, prevention or control of helminth, acarid or arthropod endo- or ectoparasitic infection or infestation in an animal including administering to said animal an efficacious amount of a composition according to any one of claims I to 3.

16. A method for the treatment, prevention or control of helminth, acarid or arthropod 10 endo- or ectoparasitic infection or infestation in an animal including administering to said animal an efficacious amount of a stabilized veterinary composition according to any one of claims 7 to 14.

17. An oral drench composition according to claim 1, substantially as described herein 15 with reference to any one of the examples.

18. A method for stabilizing an oral drench veterinary composition according to claim 4, substantially as described herein with reference to any one of the examples. 20

19. A stabilized oral drench veterinary composition according to claim 7, substantially as described herein with reference to any one of the examples.