Claims for Patent: 7,887,845

Summary for Patent: 7,887,845

Title:	Antiviral compositions
Abstract:	The present invention is concerned with pharmaceutical compositions of antiviral compounds which can be administered to a mammal, in particular a human, suffering from a viral infection. These compositions comprise particles obtainable by melt-extruding a mixture comprising one or more antiviral compounds and one or more appropriate water-soluble polymers and subsequently milling said melt-extruded mixture.
Inventor(s):	Verreck; Geert (Malle, BE), Baert; Lieven (Brugge 2, BE)
Assignee:	Janssen Pharmaceutica NV (BE)
Application Number:	11/347,071
Patent Claims:	1. A particle comprising a solid dispersion comprising (a) 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile, a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof and (b) one or more pharmaceutically acceptable water-soluble polymers. 2. The particle according to claim 1 wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 5000 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v). 3. The particle according to claim 1 wherein the water-soluble polymer is selected from the group consisting of: alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- or polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids, the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and -copolymers of ethylene oxide and propylene oxide. 4. The particle according to claim 3 wherein the water-soluble polymer is selected from the group consisting of methylcellulose; hydroxymethylcellulose; hydroxyethylcellulose; hydroxypropylcellulose; hydroxybutylcellulose; hydroxyethyl methylcellulose; hydroxypropyl methylcellulose; carboxymethylcellulose; sodium carboxymethylcellulose; carboxymethylethylcellulose; sodium carboxymethylamylopectine; chitosan; trehalose; cyclodextrins; alginic acid, alkali metal and ammonium salts thereof; carrageenans; galactomannans; tragacanth; agar-agar; gummi arabicum; guar gummi; xanthan gummi; polyethylene oxide; polypropylene oxide; and copolymers of ethylene oxide and propylene oxide. 5. The particle according to claim 3 wherein the water-soluble polymer is selected from poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (1:2:1) and hydroxypropyl methylcellulose. 6. The particle according to claim 3 wherein the water-soluble polymer is poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) (1:2:1). 7. The particle according to claim 3 wherein the water-soluble polymer is hydroxypropyl methylcellulose. 8. The particle according to claim 7 wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 1 to about 100 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v). 9. The particle according to claim 8 wherein the hydroxypropyl methylcellulose has an apparent viscosity from about 3 to about 15 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v). 10. The particle according to claim 9 wherein the hydroxypropyl methylcellulose has an apparent viscosity of about 5 mPas when dissolved at 20.degree. C. in an aqueous solution at 2% (w/v). 11. The particle according to claim 10 wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose HPMC 2910 5 mPas. 12. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:899. 13. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:100. 14. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of 1:1 to 1:5. 15. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of from about 1:1 to about 1:3. 16. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:3 to about 1:5. 17. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:1.5. 18. The particle according to claim 1 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1.5 to about 1:3. 19. The particle according to claim 1 wherein 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof, is in a non-crystalline phase. 20. The particle as claimed in claim 1 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b). 21. The particle as claimed in claim 1 having a particle size of less than 1500 .mu.m. 22. The particle as claimed in claim 1 having a particle size of less than 250 .mu.m. 23. The particle as claimed in claim 1 having a particle size of less than 125 .mu.m. 24. The particle as claimed in claim 1 further comprising one or more pharmaceutically acceptable excipients. 25. A solid dispersion comprising (a) 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; and (b) one or more pharmaceutically acceptable water-soluble polymers. 26. The solid dispersion according to claim 25 wherein the water soluble polymer is selected from the group consisting of: alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, di-, oligo- or polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids, the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and -copolymers of ethylene oxide and propylene oxide. 27. The solid dispersion according to claim 25 wherein the weight-by-weight ratio of components (a):(b) in the range of 1:1 to 1:899. 28. The solid dispersion according to claim 25 which is in the form of a solid solution comprising (a) and (b). 29. The solid dispersion according to claim 25 wherein the solid dispersion is in the form of a solid solution comprising (a) and (b), or in the form of a dispersion wherein amorphous or microcrystalline (a) or amorphous or microcrystalline (b) is dispersed more or less evenly in a solid solution comprising (a) and (b). 30. A pharmaceutical dosage form comprising a therapeutically effective amount of particles as claimed in claim 1. 31. The dosage form according to claim 30 which is a tablet. 32. The dosage form according to claim 31 for immediate release of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; upon oral ingestion wherein said particles are homogeneously distributed throughout a mixture of a diluent and a disintegrant. 33. A dosage form according to claim 30 surrounded by a film-coat comprising a film-forming polymer, a plasticizer and optionally a pigment. 34. The dosage form according to claim 32 wherein the diluent is a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75:25), and the disintegrant is crospovidone or croscarmellose. 35. The dosage form according to claim 30 wherein the weight of said particles is at least 40% of the total weight of the dosage form. 36. The dosage form according to claim 30 containing from 200 to 400 mg of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]am- ino]-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; per unit dosage form. 37. The dosage form according to claim 30 containing from 5 to 200 mg of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]-benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; per unit dosage form. 38. A process of preparing a particle according to claim 1 characterized by spray-drying of a solution of the components (a) and (b). 39. A particle according to claim 1 consisting of a solid solution comprising two parts by weight of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; and three parts by weight of hydroxypropyl methylcellulose HPMC 2910 5 mPas, obtainable by blending said components, extruding the blend at a temperature in the range of 20.degree. C.-300.degree. C., grinding the extrudate, and optionally sieving the thus obtained particles. 40. A process of preparing a solid dispersion according to claim 25 characterized by (a) spray-drying of a solution of the components (a) and (b); (b) preparing a solution of the components (a) and (b), pouring said solution onto a large surface so as to form a thin film, and evaporating the solvent therefrom; or (c) melt-extruding the components (a) and (b). 41. A pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; as claimed in claim 30, and associated with said package written matter. 42. The particle according to claim 7 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:3. 43. The particle according to claim 11 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:3. 44. The particle according to claim 7 wherein the weight-by-weight ratio of (a):(b) is about 1:3. 45. The particle according to claim 11 wherein the weight-by-weight ratio of (a):(b) is about 1:3. 46. A solid dispersion according to claim 25 wherein the water-soluble polymer is hydroxypropyl methylcellulose. 47. A solid dispersion according to claim 25 wherein the water-soluble polymer is HPMC 2910 mPas. 48. A solid dispersion according to claim 46 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:3. 49. A solid dispersion according to claim 47 wherein the weight-by-weight ratio of (a):(b) is in the range of about 1:1 to about 1:3. 50. A solid dispersion according to claim 46 wherein the weight-by-weight ratio of (a):(b) is about 1:3. 51. A solid dispersion according to claim 47 wherein the weight-by-weight ratio of (a):(b) is about 1:3. 52. The dosage form according to claim 30 containing 200 mg of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt, or a quaternary amine thereof; per unit dosage form. 53. The particle according to claim 7 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 54. The particle according to claim 11 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 55. The particle according to claim 44 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 56. The particle according to claim 45 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 57. The solid dispersion according to claim 46 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 58. The solid dispersion according to claim 47 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 59. The solid dispersion according to claim 50 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 60. The solid dispersion according to claim 51 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 61. The dosage form according to claim 52 containing 200 mg of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile per unit dosage form. 62. The particle according to claim 1 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 63. The particle according to claim 24 wherein (a) is 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino- ]benzonitrile. 64. The particle according to claim 63 wherein the water-soluble polymer is hydroxypropyl methylcellulose. 65. The particle according to claim 64 wherein the water-soluble polymer is HPMC 2910 mPas. 66. The particle according to claim 65 wherein the weight-by-weight ratio of (a):(b) is about 1:3.