Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/00
A01N-025/00
A61F-013/00
출원번호
US-0047902
(2002-01-14)
발명자
/ 주소
Gao,Ping
Morozowich,Walter
출원인 / 주소
Pharmacia &
Upjohn Company
대리인 / 주소
Harness, Dickey &
인용정보
피인용 횟수 :
15인용 특허 :
26
초록▼
Pharmaceutical compositions suitable for oral administration comprising paclitaxel, a solvent, a surfactant, a substituted cellulosic polymer, and optionally but preferably a P-glycoprotein inhibitor. The composition may further comprise a diglyceride or mixture of diglyceride and monoglyceride. The
Pharmaceutical compositions suitable for oral administration comprising paclitaxel, a solvent, a surfactant, a substituted cellulosic polymer, and optionally but preferably a P-glycoprotein inhibitor. The composition may further comprise a diglyceride or mixture of diglyceride and monoglyceride. The composition generates a supersaturated paclitaxel microemulsion upon contact with water resulting in improved oral bioavailability of paclitaxel.
대표청구항▼
What is claimed is: 1. A composition for administering paclitaxel, wherein: the composition is self-emulsifying; the composition comprises: (a) a paclitaxel or an analog thereof; (b) a pharmaceutically acceptable surfactant; (c) a pharmaceutically acceptable solvent; and (d) a substituted cellu
What is claimed is: 1. A composition for administering paclitaxel, wherein: the composition is self-emulsifying; the composition comprises: (a) a paclitaxel or an analog thereof; (b) a pharmaceutically acceptable surfactant; (c) a pharmaceutically acceptable solvent; and (d) a substituted cellulosic polymer; the paclitaxel and surfactant are present in a ratio of from about 1:3 to about 1:20 by weight; and the substituted cellulosic polymer and paclitaxel are present in a ratio of from about 50:1 to about 0.1:1 by weight. 2. The composition of claim 1 which is for oral administration. 3. The composition of claim 1 wherein said surfactant is selected from the group consisting of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, poloxamers, VE-TPGS 1000, polyoxyethylene alkyl ethers, Solutol HS-15, Tagat TO, Peglicol 6-oleate, polyoxyethylene sterates, and saturated polyglycolyzed glycerides. 4. The composition of claim 3 wherein said surfactant is selected from the group consisting of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 hydrogenated castor oil, polyoxyl sorbitan fatty acid esters, poloxamers, and VE-TPGS 1000. 5. The composition of claim 4 wherein said surfactant is a polyoxyl 40 hydrogenated castor oil or polyoxyl 35 hydrogenated castor oil. 6. The composition of claim 1 wherein the weight ratio of paclitaxel to the surfactant (paclitaxel:surfactant) is from about 1:5 to about 1:10. 7. The composition of claim 1 wherein said solvent is selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, glycerol, triacetin, glycofurol, propylene carbonate, dimethyl acetamide; dimethyl isosorbide, N-methyl pyrrolidinone, and a mixture thereof. 8. The composition of claim 7 wherein said solvent is selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, and a mixture thereof. 9. The composition of claim 8 wherein said solvent is a mixture of ethanol and a polyethylene glycol consisting of polyethylene glycol 400. 10. The composition of claim 1 wherein the said substituted cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethylcellulose, methylcellulose, maltodextrin, and povidones. 11. The composition of claim 10 wherein the said substituted cellulosic polymer is selected from the group consisting hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, and methylcellulose. 12. The composition of claim 11 wherein said substituted cellulosic polymer is hydroxypropyl methylcellulose. 13. The composition of claim 1 wherein said substituted cellulosic polymer and paclitaxel are present in a ratio of about 10:1 to about 0.1:1 by weight. 14. The composition of claim 13 wherein said substituted cellulosic polymer and paclitaxel are present in a ratio of about 5:1 to about 0.5:1 weight. 15. The composition of claim 1 wherein said substituted cellulosic polymer is substantially water-soluble. 16. The composition of claim 12 wherein the hydroxypropyl methylcellulose has about 15% to about 35% methoxyl substitution and about 4% to about 15% hydroxypropyl substitution. 17. The composition of claim 16 wherein the hydroxypropyl methylcellulose has about 19% to about 24% methoxyl substitution and about 7% to about 12% hydroxypropyl substitution. 18. The composition of claim 2 which is contained in a water-soluble capsule. 19. The composition of claim 18 wherein the substituted cellulosic polymer is present in the capsule wall. 20. The composition of claim 19 wherein the substituted cellulosic polymer constitutes from about 5% to 100% by weight of the capsule wall. 21. The composition of claim 20 wherein the substituted cellulosic polymer constitutes from about 5% to 100% by weight of the capsule wall. 22. The composition of claim 1 which further comprises a diglyceride. 23. The composition of claim 22 wherein the diglyceride contains fatty acids of a carbon chain having 8 to 22 carbons with 0 to 3 double bonds. 24. The composition of claim 23 wherein the diglyceride contains fatty acids of a carbon chain having 16 to 18 carbons with 1-2 double bonds. 25. The composition of claim 22 wherein the diglyceride is selected from the group consisting of diolein, dilinoleate, and a mixture thereof. 26. The composition of claim 22 which further comprises a monoglyceride. 27. The composition of claim 26 wherein the monoglyceride contains fatty acids of a carbon chain having 8 to 22 carbons with 0 to 3 double bonds. 28. The composition of claim 26 wherein the monoglycerides contains fatty acids of a carbon chain having 16 to 18 carbons with 1-2 double bonds. 29. The composition of claim 26 wherein the monoglyceride is selected from the group consisting of monoolein, monolinoleate, and a mixture thereof. 30. The composition of claim 26 wherein the ratio of diglyceride to monoglyceride (diglyceride:monoglyceride) by weight is from about 9:1 to about 6:4. 31. The composition of claim 1 wherein the paclitaxel is present in an amount of up to about 100 mg/gm. 32. The composition of claim 31 wherein the paclitaxel is present in an amount of from about 10 to about 80 mg/gm. 33. The composition of claim 32 wherein the paclitaxel is present in an amount of from about 30 to 70 mg/gm. 34. The composition of claim 33 wherein the paclitaxel is present in an amount of from about 40 mg/gm to about 65 mg/gm. 35. The composition of claim 1 wherein said surfactant is present in an amount from about 100 to about 700 mg/g. 36. The composition of claim 1 wherein said solvent is present in an amount from about 100 to about 700 mg/g. 37. The composition of claim 2 further comprising a P-glycoprotein inhibitor. 38. The composition of claim 37 wherein said P-glycoprotein inhibitor is selected from the group consisting of alginates, xanthan, gellan gum, CRK-1605, cyclosporin A, verapamil, tamoxifen, quinidine, valspodar, SDZ PSC 833, GF120918 (GG918, GW0918), ketocomazole, Psoralens, sucroster-15, R101933, OC144-093, Erythromycin, azithromycin, RS-33295-198, MS-209, XR9576, and phenothiazine. 39. The composition of claim 38 wherein said P-glycoprotein inhibitor is cyclosporin A. 40. The composition of claim 39 wherein said cyclosporin A in the composition is in an amount of from about 0.1 to about 20 mg/kg patient body weight. 41. The composition of claim 1 wherein the surfactant is selected from the group consisting of polyoxyl 40 hydrogenated castor oil, polyoxyl 35 hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, poloxamers, vitamin E-TPGS 1000, polyoxyethylene alkyl ethers, Solutol HS-15, Tagat TO, Peglicol 6-oleate, polyoxyethylene sterates, and saturated polyglycolyzed glycerides; and wherein the substituted cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethylcellulose, methylcellulose, maltodextrin, and povidones. 42. The composition of claim 41 wherein the surfactant is selected from the group consisting of a polyoxyl 40 hydrogenated castor oil and a polyoxyl 35 hydrogenated castor oil; wherein the solvent is selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, and a mixture thereof; and wherein the substituted cellulosic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, and methylcellulose. 43. The composition of claim 42 wherein the surfactant is a polyoxyl 35 hydrogenated castor oil; wherein the solvent is a mixture of polyethylene glycol ethanol; and wherein the substituted cellulosic polymer is hydroxypropyl methylcellulose. 44. The composition of claim 42 further comprising a diglyceride. 45. The composition of claim 44 wherein the diglyceride is glyceryl dioleate. 46. A method of treating a patient suffering from cancer and in need of treatment, wherein: the method comprises administering a self-emulsifying composition to the patient; the composition comprises: a) a chemotherapeutically effective amount of paclitaxel, b) a pharmaceutically acceptable surfactant, c) a pharmaceutically acceptable solvent, and d) a substituted cellulosic polymer; the paclitaxel and surfactant are present in a ratio of from about 1:3 to about 1:20 by weight; and the substituted cellulosic polymer and paclitaxel are present in a ratio of from about 50:1 to about 0.1:1 by weight. 47. The method of claim 46 wherein the amount of said paclitaxel in the composition is from about 10 to about 80 mg/g. 48. The method of claim 47 wherein the amount of said paclitaxel in the composition is from about 30 to about 70 mg/g. 49. The method of claim 48 wherein the amount of said paclitaxel in the composition is from about 40 to about 65 mg/g. 50. The method of claim 46 wherein said composition further comprises a diglyceride. 51. The method of claim 50 wherein said composition further comprises a monoglyceride. 52. The method of claim 51 wherein the ratio of the diglyceride to monoglyceride, by weight, in the composition is from about 9:1 to about 6:4. 53. The method of claim 50 wherein the composition is administered orally. 54. The method of claim 53 wherein the composition further comprises a P-glycoprotein inhibitor. 55. The method of claim 54 wherein said P-glycoprotein inhibitor is selected from the group consisting of cyclosporin A, verapamil, tamoxifen, quinidine, phenothiazine, and mixtures thereof or related P-glycoprotein inhibitors. 56. The method of claim 54 wherein the amount of said P-glycoprotein inhibitor in the composition is from about 0.1 to about 20 mg/kg patient body weight. 57. The composition of claim 12 wherein the hydroxypropyl methylcellulose has a viscosity range of about 1 to 1 about 100,000 cps. 58. The composition of claim 57 wherein the hydroxypropyl methylcellulose has a viscosity range of about 1 to about 4,000 cps. 59. The composition of claim 12 wherein the hydroxypropyl methylcellulose is type 2208 or 2910. 60. The composition of claim 18 wherein the substituted cellulosic polymer is present in the fill liquid composition of the water-soluble capsule. 61. The composition of claim 1 which generates a supersaturated state upon dilution with water.
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