Claims
- 1. A method for preparing a pharmaceutical composition of submicron particles of paclitaxel or its derivative compounds, the solubility of which is greater in a water-miscible first solvent than in a second solvent that is aqueous, the method comprising the steps of:
(i) mixing into the water-miscible first solvent or the second solvent or both the water-miscible first solvent and the second solvent a first surface modifier comprising a phospholipid conjugated with a water-soluble or hydrophilic polymer; (ii) dissolving paclitaxel or its derivative compounds in the water-miscible first solvent to form a solution; (iii) mixing the solution with the second solvent to define a pre-suspension of particles; and (iv) homogenizing the pre-suspension to form a suspension of small particles having an average effective particle size of less than about 1000 nm.
- 2. The method of claim 1, wherein the phospholipid is natural or synthetic.
- 3. The method of claim 1, wherein the phospholipid is phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof.
- 4. The method of claim 3, wherein the diacyl-glycero-phosphethanolamine is selected from the group consisting of: dimyristoyl-glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine (DPPE), distearoyl-glycero-phosphoethanolamine (DSPE), and dioleolyl-glycero-phosphoethanolamine (DOPE).
- 5. The method of claim 1, wherein the soluble or hydrophilic polymer conjugating with the phospholipid is polyethylene glycol (PEG).
- 6. The method of claim 5, wherein the PEG is selected from the group consisting of PEG 350, PEG 550, PEG 750, PEG 1000, PEG 2000, PEG 3000, and PEG 5000.
- 7. The method of claim 1, wherein the soluble or hydrophilic polymer conjugating with the phospholipid is selected from the group consisting of: dextran, hydroxypropyl methacrylate (HPMA) and polyglutamate
- 8. The method of claim 1 further comprising mixing into the water-miscible first solvent or the second solvent or both the water-miscible first solvent and the second solvent a second surface modifier selected from the group consisting of: anionic surfactant, cationic surfactant,: anionic surfactants, cationic surfactants, nonionic surfactants and surface active biological modifiers.
- 9. The method of claim 8, wherein the second surface modifier is a copolymer of oxyethylene and oxypropylene.
- 10. The method of claim 9, wherein the copolymer of oxyethylene and oxypropylene is copolymer of oxyethylene and oxypropylene is a block copolymer.
- 11. The method of claim 8, wherein the surface modifier is poloxamer.
- 12. The method of claim 1, wherein the water-miscible first solvent is N-methyl-2-pyrrolidinone.
- 13. The method of claim 1, wherein the homogenization is carried out at about 30° C. or greater.
- 14. The method of claim 1, wherein the small particles have an average effective particle size of less than about 400 nm.
- 15. The method of claim 1, wherein the small particles have an average effective particle size of less than about 200 nm.
- 16. The method of claim 1, wherein the small particles have an average effective particle size of less than 150 nm.
- 17. The method of claim 1 further comprising sterilizing the composition.
- 18. The method of claim 17, wherein the sterilizing of the composition comprises sterile filtering the solution and the second solvent before mixing and carrying out the subsequent steps under aseptic conditions.
- 19. The method of claim 17, wherein the sterilizing of the composition comprises sterile filtering the particles.
- 20. The method of claim 17, wherein the sterilizing comprises heat sterilization.
- 21. The method of claim 20, wherein the heat sterilization is effected by the heat within the homogenizer in which the homogenizer serves as a heating and pressurization source for sterilization.
- 22. The method of claim 17, wherein sterilizing comprises gamma irradiation.
- 23. The method of claim 1 further comprising removing the water-miscible first solvent from the suspension.
- 24. The method of claim 23, wherein the removing of the water-miscible first solvent is by the removal of the first solvent is by filtration.
- 25. The method of claim 24, wherein the filtration is cross-flow ultrafiltration.
- 26. The method of claim 23, wherein the removing of the water miscible first solvent is simultaneous with the homogenization.
- 27. The method of claim 1 further comprising removing the liquid phase of the suspension to form a dry powder of the particles.
- 28. The method of claim 27, wherein the removing of the liquid phase is selected from the group consisting of: evaporation, rotary evaporation, lyophilization, freeze-drying, diafiltration, centrifugation, force-field fractionation, high-pressure filtration, and reverse osmosis.
- 29. The method of claim 27 further comprising adding a diluent to the dry powder.
- 30. The method of claim 29, wherein the diluent is suitable for parenteral administration of the particles.
- 31. The method of claim 1, wherein the composition is formulated for administration by a route selected from the group consisting of: parenteral, oral, pulmonary, topical, ophthalmic, nasal, buccal, rectal, vaginal, and transdermal.
- 32. The method of claim 1, wherein the particles are not soluble.
- 33. The method of claim 1, wherein the particles do not aggregate under stressed conditions or upon storage.
- 34. A pharmaceutical composition of submicron particles of paclitaxel or its derivative compounds prepared by the method of claim 1.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of application Ser. No. 10/390,333 filed on Mar. 17, 2003, which is a continuation-in-part of application Ser. No. 10/246,802 filed on Sep. 17, 2002, which is a continuation-in-part of application Ser. No. 10/035,821 filed on Oct. 19, 2001, which is a continuation-in-part of application Ser. No. 09/953,979 filed Sep. 17, 2001 which is a continuation-in-part of application Ser. No. 09/874,637 filed on Jun. 5, 2001, which claims priority from provisional application Ser. No. 60/258,160 filed Dec. 22, 2000. All of the above-mentioned applications are incorporated herein by reference and made a part hereof.
Provisional Applications (1)
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Number |
Date |
Country |
|
60258160 |
Dec 2000 |
US |
Continuation in Parts (5)
|
Number |
Date |
Country |
Parent |
10390333 |
Mar 2003 |
US |
Child |
10703395 |
Nov 2003 |
US |
Parent |
10246802 |
Sep 2002 |
US |
Child |
10390333 |
Mar 2003 |
US |
Parent |
10035821 |
Oct 2001 |
US |
Child |
10246802 |
Sep 2002 |
US |
Parent |
09953979 |
Sep 2001 |
US |
Child |
10035821 |
Oct 2001 |
US |
Parent |
09874637 |
Jun 2001 |
US |
Child |
09953979 |
Sep 2001 |
US |