초록 ▼

Paclitaxel is provided in a porous matrix form, which allows the drug to be formulated without Cremophor and administered as a bolus. The paclitaxel matrices preferably are made using a process that includes (i) dissolving paclitaxel in a volatile solvent to form a paclitaxel solution, (ii) combini

Paclitaxel is provided in a porous matrix form, which allows the drug to be formulated without Cremophor and administered as a bolus. The paclitaxel matrices preferably are made using a process that includes (i) dissolving paclitaxel in a volatile solvent to form a paclitaxel solution, (ii) combining at least one pore forming agent with the paclitaxel solution to form an emulsion, suspension, or second solution, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of paclitaxel. The pore forming agent can be either a volatile liquid that is immiscible with the paclitaxel solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. In a preferred embodiment, microparticles of the porous paclitaxel matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

대표청구항 ▼

We claim: 1. A pharmaceutical composition comprising a porous matrix formed of a hydrophilic excipient, a wetting agent and nanoparticles and microparticles of a taxane, wherein the nanoparticles and microparticles have a mean diameter between about 0.01 and 5 μm and a total surface area great

We claim: 1. A pharmaceutical composition comprising a porous matrix formed of a hydrophilic excipient, a wetting agent and nanoparticles and microparticles of a taxane, wherein the nanoparticles and microparticles have a mean diameter between about 0.01 and 5 μm and a total surface area greater than about id="DEL-S-00001" date="20080909" 0.5 m2id="DEL-S-00001" id="INS-S-00003" date="20080909" 0.5 m2/mLid="INS-S-00003" , wherein the porous matrix is in a dry powder form, and wherein upon exposure to an aqueous medium, the matrix dissolves to leave the taxane nanoparticles and microparticles, wherein the dissolution rate of the taxane nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed taxane. 2. The composition of claim 1, wherein the matrix is made by a process comprising (a) dissolving a taxane in a volatile solvent to form a taxane solution, (b) combining at least one pore forming agent, a wetting agent, and a hydrophilic excipient with the taxane solution to form an emulsion, suspension, or second solution, and (c) removing the volatile solvent and the pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix. 3. The composition of claim 2 wherein the pore forming agent is a volatile salt. 4. The composition of claim 1 wherein the porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL. 5. The composition of claim 1, wherein the matrix comprises at least one excipient selected from the group consisting of hydrophilic polymers, sugars, tonicity agents, pegylated excipients, and combination thereof. 6. The composition of claim 1 wherein the mean diameter of the taxane microparticles is between about 0.50 and 5 μm. 7. A taxane suspension comprising the composition of claim 1 added to an aqueous solution suitable for parenteral administration. 8. The composition of claim 1 wherein the matrix is processed into tablets or capsules suitable for oral administration. 9. The composition of claim 1 wherein the matrix is formed into suppositories suitable for vaginal or rectal administration. 10. The composition of claim 1 wherein the matrix is in a dry powder form suitable for pulmonary administration. 11. A method for making a porous matrix of a taxane comprising (a) dissolving a taxane in a volatile solvent to form a taxane solution, (b) combining at least one pore forming agent, a wetting agent, and a hydrophilic excipient with the taxane solution to form an emulsion, suspension, or second solution, and (c) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix comprising nanoparticles and microparticles of taxane, wherein the dissolution rate of the taxane nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed taxane. 12. The method of claim 11 wherein the wetting agent is a polyoxyethylene sorbitan fatty acid ester. 13. The method of claim 11 wherein step (c) is conducted using a process selected from spray drying, evaporation, fluid bed drying, lyophilization, vacuum drying, or a combination thereof. 14. The method of claim 11 wherein the taxane solution or pore forming agent comprises excipients selected from the group consisting of hydrophilic excipients, pegylated excipients, and tonicity agents. 15. The method of claim 11 wherein the pore forming agent is a volatile salt. 16. The method of claim 15 wherein the volatile salt is selected from the group consisting of ammonium bicarbonate, ammonium acetate, ammonium chloride, ammonium benzoate, and mixtures thereof. 17. A method of treating a patient with a taxane, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a taxane id="INS-S-00004" date="20080909" to provide anticancer or antitumor activity id="INS-S-00004" in a formulation comprising a porous matrix formed of a hydrophilic excipient, a wetting agent and nanoparticles and microparticles of a taxane, wherein the nanoparticles and microparticles have a mean diameter between about 0.01 and 5 μm and a total surface area greater than about 0.5 m2/mL, and wherein the porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL wherein upon exposure to an aqueous medium, the matrix dissolves to leave the taxane nanoparticles and microparticles wherein the dissolution id="DEL-S-00002" date="20080909" rareid="DEL-S-00002" id="INS-S-00005" date="20080909" rate id="INS-S-00005" of the taxane nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed taxane. 18. The method of claim 17 wherein the formulation is suitable for administration by a route selected from the group consisting of parenteral, mucosal, oral, and topical administration. 19. The method of claim 18 wherein the parenteral route is selected from the group consisting of intravenous, intraarterial, intracardiac, intrathecal, intraosseous, intraarticular, intrasynovial, intracutaneous, subcutaneous, and intramuscular administration. 20. The method of claim 18 wherein the mucosal route is selected from the group consisting of pulmonary, buccal, sublingual, intranasal, rectal, and vaginal administration. 21. The method of claim 18 wherein the formulation is suitable for intraocular or conjunctival administration. 22. The method of claim 18 wherein the formulation is suitable for intracranial, intralesional, or intratumoral administration. 23. The method of claim 18 wherein the formulation is in an aqueous solution suitable for parenteral administration. 24. The method of claim 18 wherein the formulation is in a tablet or capsule suitable for oral administration. 25. The method of claim 18 wherein the formulation is in a suppository suitable for vaginal or rectal administration. 26. The method of claim 18 wherein the formulation is a dry powder suitable for pulmonary administration. 27. The composition of claim 1 wherein the taxane is paclitaxel. 28. The method of claim 11 wherein the taxane is paclitaxel. 29. The method of claim 17 wherein the taxane is paclitaxel. 30. The composition of claim 1 wherein the hydrophilic excipient is selected from the group consisting of water soluble polymers and sugars, and the wetting agent is a surfactant. 31. The method of claim 11 wherein the hydrophilic excipient is selected from the group consisting of water soluble polymers and sugars, and the wetting agent is a surfactant. 32. The method of claim 17 wherein the hydrophilic excipient is selected from the group consisting of water soluble polymers and sugars, and the wetting agent is a surfactant. id="INS-S-00006" date="20080909" 33. A method for making a porous matrix comprising nanoparticles and microparticles of paclitaxel, the method comprising (a) dissolving paclitaxel in a volatile solvent to form a paclitaxel solution, (b) combining at least one pore forming agent including ammonium bicarbonate, a polyoxyethylene sorbitan fatty acid ester, and polyvinylpyrrolidone with the paclitaxel solution to form an emulsion, suspension, or second solution, and (c) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix comprising nanoparticles and microparticles of paclitaxel, wherein the dissolution rate of the paclitaxel nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed paclitaxel.id="INS-S-00006" id="INS-S-00007" date="20080909" 34. The method of claim 33, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.id="INS-S-00007" id="INS-S-00008" date="20080909" 35. The method of claim 33, wherein step (b) further comprises adding a sugar to the paclitaxel solution.id="INS-S-00008" id="INS-S-00009" date="20080909" 36. The method of claim 35, wherein the sugar is mannitol.id="INS-S-00009" id="INS-S-00010" date="20080909" 37. A pharmaceutical composition comprising a porous matrix formed of polyvinylpyrrolidone, a polyoxyethylene sorbitan fatty acid ester and nanoparticles and microparticles of paclitaxel, wherein the nanoparticles and microparticles have a mean diameter between about 0.01 and 5 μm and a total surface area greater than about 0.5 m2/mL, wherein the porous matrix is in a dry powder form, and wherein upon exposure to an aqueous medium, the matrix dissolves to leave the paclitaxel nanoparticles and microparticles, wherein the dissolution rate of the paclitaxel nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed paclitaxel.id="INS-S-00010" id="INS-S-00011" date="20080909" 38. The composition of claim 37, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.id="INS-S-00011" id="INS-S-00012" date="20080909" 39. The composition of claim 37, further comprising a sugar.id="INS-S-00012" id="INS-S-00013" date="20080909" 40. The composition of claim 39, wherein the sugar is mannitol.id="INS-S-00013" id="INS-S-00014" date="20080909" 41. A method of treating a patient with a paclitaxel formulation, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of paclitaxel to provide anticancer or antitumor activity in a formulation comprising a porous matrix formed of polyvinylpyrrolidone, a polyoxyethylene sorbitan fatty acid ester and nanoparticles and microparticles of paclitaxel, wherein the nanoparticles and microparticles have a mean diameter between about 0.01 and 5 μm and a total surface area greater than about 0.5 m2/mL, and wherein the porous matrix is in a dry powder form having a TAP density less than or equal to 1.0 g/mL, wherein upon exposure to an aqueous medium, the matrix dissolves to leave the paclitaxel nanoparticles and microparticles wherein the dissolution rate of the paclitaxel nanoparticles and microparticles in an aqueous solution is increased relative to unprocessed taxane.id="INS-S-00014" id="INS-S-00015" date="20080909" 42. The method of claim 41, wherein the polyoxyethylene sorbitan fatty acid ester is polysorbate 80.id="INS-S-00015" id="INS-S-00016" date="20080909" 43. The method of claim 41, wherein the formulation further comprises a sugar.id="INS-S-00016" id="INS-S-00017" date="20080909" 44. The method of claim 43, wherein the sugar is mannitol.id="INS-S-00017" id="INS-S-00018" date="20080909" 45. The composition of claim 1, wherein the hydrophilic excipient is the wetting agent.id="INS-S-00018" id="INS-S-00019" date="20080909" 46. The method of claim 11, wherein the hydrophilic excipient is the wetting agent.id="INS-S-00019" id="INS-S-00020" date="20080909" 47. The method of claim 17 wherein the hydrophilic excipient is the wetting agent.id="INS-S-00020"