Patent EA-001219-B1 (EA)
Title: Antifungal compositions with improved bioactivity
Inventor: BAERT LIEVEN ELVIRE COLETT
IPC: A61K9/14
Filed: 1997-05-12
Abstract: 1. A particle consisting of a solid dispersion comprising  (a) itraconazole, or one of its stereoisomers, or a mixture of two or three or four of its  stereoisomers, and  (b) one or more pharmaceutically acceptable water-soluble polymers. 2. A particle according to claim 1 having a particle size of less than 600 μm. 3. A particle according to claim 1 or 2 wherein the itraconazole is in a non-crystalline phase. 4. A particle according to claim 3 wherein the solid dispersion is in the form o f 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). 5. A particle according to the preceding claims wherein the water-soluble polymer is a polymer that has an apparent viscosity of 1 to 100 mPa.s (mn.sec/m<2>) when dissolved in a 2 % aqueous solution at 20 degree C solution. 6. A particle according to claim 5 wherein the water-soluble polymer is selected from the group comprising  - alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxymethylcellulose,  hydroxyethylcellulose,  - hydroxypropylcellulose and hydroxybutylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, - carboxyalkylcelluloses such as carboxymethylcellulose,  - alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose,  carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,  - carboxyalkylcellulose esters,  - starches,  - pectines such as sodium carboxymethylamylopectine,  - chitin derivates such as chitosan,  - polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, traganth, agar-agar, gummiarabicum, guar gummi and xanthan gummi,  - polyacrylic acids and the salts thereof,  - polymethacrylic acids and the salts thereof, methacrylate copolymers,  - polyvinylalcohol,  - polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate  - polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide. 7. A particle according to claim 6 wherein the water-soluble polymer is hydroxypropyl  methylcellulose HPM 2910 with a viscosity of 5 mPa.s (mn.sec/m<2>). 8. A particle according to claim 7 wherein the weight-by-weight ratio of (a): (b ) is in  the range of 1: 1 to 1: 17. 9. A particle according to any one of the preceding claims obtainable by melt-extrusion  of the components and grinding, and optionally sieving. 10. A particle according to any one of the previous claims consisting of a solid solution comprising two parts by weight of itraconazole and three parts by weight of hydroxypropyl methylcellulose HPMC 2910 5 with a viscisity of 5 mPa.s (mn.sec/m<2>). 11. A particle according to the preceding claims further comprising one or more pharmaceutically acceptable excipients. 12. A pharmaceutical dosage form comprising a therapeutically effective amount of particles as claimed in any one of the preceding claims. 13. A dosage form according to claim 12 adapted for oral administration shaped as a tablet. 14. A dosage form according to claim 12 for immediate release of itraconazole up on oral ingestion wherein said particles are homogeneously distributed throughout a mixture of a diluent and a disintegrant. 15. A dosage form according to claim 13 or 14 surrounded by a film-coat comprising a film-forming polymer, a plasticizer and optionally a pigment. 16. A dosage form according to claim 14 wherein the diluent is a spray-dried mixture of lactose monohydrate and microcrystalline cellulose (75 : 25), and the disintegrant is crospovidone or croscarmellose. 17. A dosage form according to any one of claims 12 to 16 wherein the weight of said particles is at least 40 % of the total weight of the dosage form. 18. A dosage form according to claim 12 comprising by weight based on the total weight of the dosage form: 21.65 % itraconazole (200 mg) 32.48 % HPMC 2910 with a viscosity of 5 mPa.s (mn.sec/m<2>) (300 mg) 30.57 % spray-dried lactose monohydrate microcrystalline cellulose (75: 25) mixture (282.4 mg) 8.49 % crospovidonc (78.4 mg)  2.79 % talc (25.8 mg) 0.93 % hydrogenated vegetable oil Type I (8.6 mg) 0.28 % colloidal anhydrous silica (2.6 mg) 0.24 % magnesium stearate (2.2 mg), yielding  97.43 % tablet core, and  1.47 % HPMC 2910 5 mPa.s (mn.sec/m<2>) (13.57) 0.37 % propyleneglycol (3.39 mg) 0.29 % talc (2.71 mg) 0.44 % titanium dioxide (4.07 mg), yielding  2.57 % film-coat.  19. A dosage form according to any one of claims 12 to 18 from which at least 85 % of the available itraconazole dissolves within 60 minutes when a dosage form equivalent to 200 mg itraconazole is tested as set forth in USP test <711> in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 ml phosphate buffer, pH 6.0, 37 degree C with paddles turning at 100 rpm. 20. A process of preparing particles as claimed in any one of claims 1 to 11 characterized by blending the components, extruding said blend at a temperature in the range of 120-300  degree C, grinding the extrudate, and optionally sieving the particles. 21. A solid dispersion obtainable by melt-extrusion of  (a) itraconazole or one of its stereoisomers or a mixture of two or three of its stereoisomers, and  (b) one or more pharmaceutically acceptable water-soluble polymers. 22. A process of preparing a pharmaceutical dosage form as claimed in any one of claims 12 to 19 characterized by blending a therapeutically effective amount of particles as claimed in any one of claims 1 to 11 with pharmaceutically acceptable excipients and compressing said blend into tablets. 23. Particles according to any one of claims 1 to 11 for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a fungal infection, wherein a single such dosage form can be administered once daily to said mammal. 24. Particles according to any one of claims 1 to 11 for use in preparing a pharmaceutical dosage form for oral administration to a mammal suffering from a fungal infection, wherein said dosage form can be administered at any time of the day independently of the food taken in by said mammal. 25. A pharmaceutical package comprising a container , an oral dosage form of itraconazole as claimed in any one of claims 12 to 19, and associated with said package written matter non-limited as to hether the dosage form can be taken with or without food.