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US-12616677-B2 - Injectable pharmaceutical compositions and uses thereof

US12616677B2US 12616677 B2US12616677 B2US 12616677B2US-12616677-B2

Abstract

An injectable pharmaceutical composition comprising an isoxazoline compound of Formula (I), or a salt or N-oxide and moxidectin microspheres and a method of preventing or treating a parasite infestation using the same.

Inventors

  • Brenda L. Valle Colon
  • Keith A. Freehauf
  • Frank Guerino
  • Christopher D. Kulczar
  • Brian Carrillo

Assignees

  • INTERVET INC.

Dates

Publication Date
20260505
Application Date
20200501

Claims (19)

  1. 1 . An injectable veterinary composition comprising a) moxidectin microspheres comprising from about 50% to about 99% by weight of a fat, wax or mixture thereof, and 0.01-10% by weight of an anti-oxidant; and b) particles of an isoxazoline compound wherein the isoxazoline compound is fluralaner wherein the moxidectin microspheres and isoxazoline compound particles are suspended in an aqueous carrier comprising one or more suspending agents selected from sodium carboxymethylcellulose, polyvinylpyrrolidone and methylcellulose, one or more wetting agents comprising a poloxamer, and water and optionally one or more preservatives.
  2. 2 . The injectable veterinary composition of claim 1 wherein the fat, wax or mixture thereof has a melting point of higher than about 40° C.
  3. 3 . The injectable veterinary composition of claim 1 wherein the moxidectin microspheres comprise from about 75% to about 95% by weight of the fat, wax or mixture thereof.
  4. 4 . The injectable veterinary composition according to claim 1 wherein said fat, wax or mixture thereof comprises a fatty acid ester.
  5. 5 . The injectable veterinary composition according to claim 4 wherein said fatty acid ester is glyceryl tristearate.
  6. 6 . The injectable veterinary composition according to claim 1 in which the moxidectin microspheres and/or isoxazoline compound particles have a volume weighted particle size distribution D50 as measured by a static light scattering instrument of from about 25 μm to about 250 μm.
  7. 7 . The injectable veterinary composition according to claim 6 wherein the moxidectin microspheres or isoxazoline compound particles size distribution D50 is from about 75 μm to about 150 μm.
  8. 8 . The injectable veterinary composition according to claim 1 in which the isoxazoline compound particles have a thickness of greater than 10 μm but less than 100 μm, as measured by scanning electron microscopy.
  9. 9 . The injectable veterinary composition according to claim 8 wherein the isooxazoline compound particles have a thickness of greater than 30 μm but less than 80 μm.
  10. 10 . The injectable veterinary composition of claim 1 , wherein the D10 of the volume weighted particle size of the moxidectin microspheres or the isoxazoline compound particles as measured by a static light scattering instrument is about 20 to 35 μm, the D50 of the particle size is about 90 to 105 μm and the D90 of the particle size is about 155 to 175 μm.
  11. 11 . The injectable veterinary composition of claim 1 , wherein the wetting agent is a poloxamer.
  12. 12 . A kit, wherein the kit comprises: a) a first container comprising a solid mixture of particles of isoxazoline compound wherein the isoxazoline compound is fluralaner and moxidectin microspheres comprising from about 50% to about 99% by weight of a fat, wax or mixture thereof, and 0.01-10% by weight of an anti-oxidant and; b) a second container with an aqueous carrier comprising one or more suspending agents wherein the suspending agent is selected from sodium carboxymethylcellulose, polyvinylpyrrolidone and methylcellulose, one or more wetting agents comprising poloxamer, and water and optionally preservatives; and c) instructions for reconstituting moxidectin microspheres and isoxazoline compound particles with the aqueous carrier prior to subcutaneous or intramuscular injection to the animal.
  13. 13 . The kit according to claim 12 , wherein the first container comprises an effective amount of moxidectin and of the isoxazoline compound that is sufficient for treating or preventing a parasite infestation of an animal.
  14. 14 . The kit according to claim 12 , wherein the kit further comprises an apparatus for reconstituting and parenterally administering a mixture of the composition from the first and second container to an animal.
  15. 15 . The kit according to claim 14 , wherein the apparatus comprises a syringe.
  16. 16 . The kit according to claim 12 wherein in the first container the isoxazoline compound and/or the moxidectin microspheres have a volume weighted particle size distribution D50 of about 25 microns to about 250 microns as measured by a static light scattering instrument.
  17. 17 . The kit according to claim 12 wherein in the first container the D10 of the particle size of the isoxazoline compound is about 20 to 35 μm, the D50 of the particle size is about 90 to 105 μm and the D90 of the particle size is about 155 to 175 μm.
  18. 18 . A method of treating or preventing a parasite infestation in an animal comprising administering to the animal in need thereof the injectable veterinary composition of claim 1 .
  19. 19 . A method of producing the injectable veterinary composition according to claim 1 comprising the steps of: a) Preparing isoxazolines particles; b) Preparing the moxidectin microspheres by melting the fat, wax or mixture thereof and adding the moxidectin and optionally an antioxidant and preparing the microspheres through spinning disk atomization and sieving; c) filling the moxidectin microspheres obtained by step b) together with the isoxazoline particles obtained by step a) in a first container; d) preparing the aqueous carrier by dissolving the excipients including the suspending agents, wetting agents and/or preservatives in water and filling into a second container; e) reconstituting the solids by transferring the aqueous carrier from the second container d) to the first container c) and shake to form a ready-to-use suspension.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage entry under 35 U.S.C. § 371 of PCT/EP2020/062181 filed May 1, 2020, which claims priority under 35 U.S.C. § 119(e) of provisional application U.S. Ser. No. 62/842,709 filed May 3, 2019, the contents of which are hereby incorporated by reference in their entireties. BACKGROUND Isoxazoline compounds are known in the art and these compounds and their use as antiparasitic are described, for example, in US patent application US 2007/0066617, and International Patent applications WO 2005/085216, WO 2007/079162, WO 2009/002809, WO 2009/024541, WO 2009/003075, WO 2010/070068 and WO 2010/079077, the disclosures of which, as well as the references cited herein, are incorporated by reference. This class of compounds is known to possess excellent activity against ectoparasitic arthropods. WO2015/048371 discloses long acting injectable compositions comprising spirocyclic isoxazoline compounds, one biopolymer and at least one carrier, solvent or excipient. WO2016/138339 discloses long acting injectable formulations for comprising at least one isoxazoline active agent, a poloxamer and a co-solvent. WO2016/164487 discloses extended release injectable veterinary formulations comprising at least one isoxazoline active agent, a pharmaceutically acceptable polymer and a solvent for use against parasites. U.S. Pat. No. 9,609,869 discloses insecticidal compounds based on isoxazoline derivatives for use in controlling pest associated with agriculture, horticulture, animal husbandry and companion animals. US Patent Application Publication No. 2017/0239218 discloses long acting injectable compositions for combating parasites comprising at least one isoxazoline active agent, a liquid PEG and/or a neutral oil. Recently another ectoparasitic compound has been described: 2-Chloro-N-(1-cyanocyclopropyl)-5-[1′-methyl-3′-(1,1,2,2,2-pentafluoroethyl)-4′-(trifluoromethyl)[1,5′-bi-1H-pyrazol]-4-yl]benzamide; Tigolaner (CAS RN 1621436-41-6) that was disclosed in WO 2019/012377. Moxidectin is an active ingredient that is useful for the prevention and treatment of infections and infestations caused by helminths, nematodes, acarids and endo- and ectoparasitic arthropods especially when parenterally administered to animals. Moxidectin has been disclosed in U.S. Pat. No. 4,916,154. EP0525307 and EP1197207 disclose moxidectin microspheres and injectable compositions and their preparation and use. An advantageous injectable pharmaceutical composition for veterinary application would be one, that enables a single injection to provide efficacious concentration levels of both active compounds (moxidectin and an isoxazoline compound) in blood plasma of the treated animals over an extended period. Besides the duration of release for such compositions the technical features of the injectable veterinary formulation, e.g. easiness of application (syringeability and re-suspendability), and the absence of side effects (local injection site reaction and systemic side effects following administration) and the possibility to sterilize the formulation are important features. It would therefore be desirable to have a technically feasible injectable formulation available that allows the effective and safe release of an effective amount of an isoxazoline compound as described above and moxidectin in a combined formulation over a prolonged time. This would allow the use of these modern compounds under conditions, were separate injections and a repeated administration is not desirable. The composition should also ensure that the excipients do not interfere with the moxidectin microspheres and provide a stable moxidectin content. Thus, a need exists for an injectable pharmaceutical composition for prolonged release of an isoxazoline compound and moxidectin that overcomes one or more of the limitations of the prior art. SUMMARY OF THE INVENTION Accordingly, the present invention provides injectable compositions comprising isoxazoline compounds and moxidectin microspheres with long term efficacy against parasites, safety, physical and chemical stability and reduced risk of injection site irritation. An embodiment of the invention is an injectable veterinary composition comprising a) moxidectin microspheres comprising from about 50% to about 99% by weight of a fat, wax or mixture thereof, and 0.01-10% by weight of an anti-oxidant; andb) particles of an isoxazoline compound of Formula (I) whereinR1=halogen, CF3, OCF3, CN,n=integer from 0 to 3, preferably 1, 2 or 3,R2=C1-C3-haloalkyl, preferably CF3 or CF2Cl,T=5 to 12 membered mono- or bicyclic ring system, which is optionally substituted by one or more radicals Y,Y=methyl, halomethyl, halogen, CN, NO2, NH2—C═S, or two adjacent radicals Y form together a chain, especially a three or four membered chain;Q=X—NR3R4 or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals;X=CH2, CH(CH3), CH(CN), CO, CS,R3=hydrogen, met