Search

EP-4153133-B2 - INJECTABLE PHARMACEUTICAL COMPOSITIONS AND USES THEREOF

EP4153133B2EP 4153133 B2EP4153133 B2EP 4153133B2EP-4153133-B2

Inventors

  • VALLE COLON, Brenda, L
  • FREEHAUF, KEITH
  • KULCZAR, Christopher, D
  • GUERINO, FRANK

Dates

Publication Date
20260506
Application Date
20210519

Claims (15)

  1. An injectable veterinary pharmaceutical composition comprising (a) microspheres comprising (a1) about 1% to about 40% w/w, based on the weight of the microspheres, of one or more physiologically active macrocyclic lactone(s), and (a2) about 60% to about 99% w/w, based on the weight of the microspheres, of polycaprolactone (PCL), and (b) particles of an isoxazoline compound of Formula (I) wherein R 1 = halogen, CF 3 , OCF 3 , CN, n = integer from 0 to 3, preferably 1, 2 or 3, R 2 = C 1 -C 3 -haloalkyl, preferably CF 3 or CF 2 Cl, 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, NO 2 , NH 2 -C=S, or two adjacent radicals Y form together a chain, especially a three or four-membered chain; Q = X-NR 3 R 4 ora 5-membered N-heteroaryl ring which is optionally substituted by one or more radicals; X = CH 2 , CH(CH 3 ), CH(CN), CO, CS, R 3 = hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, wherein Z A = hydrogen, halogen, cyano, halomethyl (CF 3 ); R 4 = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; or R 3 and R 4 together form a substituent selected from the group consisting of: and c) an aqueous carrier; wherein the microspheres (a) and the particles of compound (b) are suspended in the aqueous carrier (c).
  2. The injectable veterinary composition according to claim 1, wherein the macrocyclic lactone is moxidectin.
  3. The injectable veterinary composition according to any one of claims 1 to 2, wherein the D50 of the volume weighted particle size distribution of the microspheres (a) is from about 8 µm to about 250 µm, more preferably from about 20 µm to about 200 µm, even more preferably from about 40 µm to about 80 µm, in particular from about 50 µm to about 70 µm.
  4. The injectable veterinary composition according to any one of claims 1 to 3, wherein the isoxazoline compound according to Formula (I) is selected from the group consisting of fluralaner, afoxolaner, sarolaner, and lotilaner.
  5. The injectable veterinary composition according to any one of claims 1 to 4, wherein the aqueous carrier comprises a suspending agent and the suspending agent is selected from sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose and mixtures thereof.
  6. The injectable veterinary composition according to any one of claims 1 to 5, wherein the aqueous carrier comprises a wetting agent and the wetting agent is a poloxamer.
  7. A method of preparing the injectable veterinary composition according to any one of claims 1 to 6 comprising the steps of: i) preparing microspheres (a) of a macrocyclic lactone by solvent evaporation, spinning disk atomization or spray drying, and optionally sieving the resulting product, ii) preparing particles (b) of the isoxazoline compound of Formula (I), iii) preparing the aqueous carrier by dissolving one or more suspending agents and/or one or more wetting agents in water, and iv) mixing the particles obtained from step i) and the microspheres obtained from step ii) with the aqueous carrier obtained in step iii).
  8. The method according to claim 7 wherein the macrocyclic lactone is moxidectin and the isoxazoline compound according to Formula (I) is selected from the group consisting of fluralaner, afoxolaner, sarolaner, and lotilaner.
  9. The method according to claim 7 or 8, wherein the wetting agent is a poloxamer and the suspending agent is selected from sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose and mixtures thereof
  10. A kit, wherein the kit comprises: (A) a first container comprising a mixture of microspheres and particles of an isoxazoline compound of Formula (I) as defined in any one of claim 1 to 6, (B) a second container with an aqueous carrier as defined in any one of claim 1 to 6; and (C) instructions for reconstituting the microspheres and the particles in the aqueous carrier prior to an injection to an animal.
  11. The injectable veterinary composition of claims 1 to 6 for use in treating and/or preventing a parasite infestation in an animal.
  12. The injectable veterinary composition for use according to claim 11, wherein the injectable veterinary composition is administered by a subcutaneous or intramuscular injection to the animal.
  13. The injectable veterinary composition for use according to claim 11 or 12, wherein the dosage regime of the injectable veterinary composition is once every six months or once every twelve months.
  14. The injectable veterinary composition for use according to any one of claims 11 to 13, wherein the animal is a pet.
  15. The injectable veterinary composition for use according to claim 14, wherein the animal is a dog.

Description

The present invention relates to injectable veterinary pharmaceutical compositions comprising the combination of an isoxazoline compound and a physiologically active macrocyclic lactone. Background of the Invention A number of parasites can infest or infect domestic animals, especially companion animals such as cats and dogs. These parasites are of great nuisance to both the animals and their owners. Isoxazoline compounds are known in the art and the preparation of these compounds and their use as an 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 2009/080250, WO 2010/070068, WO 2010/079077 and WO 2011/124998. Injectable formulations of isoxazoline compounds have been described. WO 2015/048371 discloses long acting injectable compositions comprising spirocyclic isoxazoline compounds, one biopolymer and at least one carrier, solvent or excipient. WO 2016/138339 discloses long acting injectable formulations for comprising at least one isoxazoline active agent, a poloxamer and a co-solvent. WO 2016/164487 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. patent 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. Further, physiologically active macrocyclic lactones are known for controlling parasite infestations. For example, moxidectin is useful for the prevention and treatment of infections and infestations caused by helminths, nematodes, and ectoparasitic arthropods. Moxidectin was disclosed in U.S. patent number 4,916,154 and EP 0 525 307 and EP 1 197 207 disclose moxidectin microspheres and injectable compositions and their preparation and their use. Summary of the invention In one aspect the subject of the present invention is directed to an injectable veterinary pharmaceutical composition comprising (a) microspheres comprising (a1) about 1% to about 40% w/w based on the weight of the microspheres, of one or more physiologically active macrocyclic lactone(s), and(a2) about 60% to about 99% w/w, based on the weight of the microspheres, of polycaprolactone (PCL), and(b) particles of an isoxazoline compound of Formula (I) wherein R1 = 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 ora 5-membered N-heteroaryl ring which is optionally substituted by one or more radicals;X = CH2, CH(CH3), CH(CN), CO, CS,R3 = hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, wherein ZA = hydrogen, halogen, cyano, halomethyl (CF3);R4 = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; orR3 and R4 together form a substituent selected from the group consisting of: andc) an aqueous carrier; wherein the microspheres (a) and the particles of compound (b) are suspended in the aqueous carrier (c). In another aspect the subject of the present invention is directed to a method of preparing such injectable veterinary composition comprising the steps of: i) preparing microspheres (a) of a macrocyclic lactone by solvent evaporation, spinning disk atomization or spray drying, and optionally sieving the resulting product,ii) preparing particles (b) of the isoxazoline compound of Formula (I),iii) preparing the aqueous carrier by dissolving one or more suspending agents and/or one or more wetting agents in water, andiv) mixing the particles obtained from s