Claims
- 1. A process for preparing submicron sized particles comprising the steps of:
providing a crude dispersion of a multiphase system having an organic phase and an aqueous phase, the organic phase having a pharmaceutically active compound therein; providing energy to the crude dispersion to form a fine dispersion; freezing the fine dispersion; and lyophilizing the frozen dispersion to obtain particles having a mean particle size of less than 500 nm.
- 2. The process of claim 1 wherein the particles have a mean particle size of less than 200 nm.
- 3. The process of claim 1 wherein the particles are substantially free of the organic phase.
- 4. The process of claim 1 wherein the crude dispersion or the fine dispersion includes solid particles in one or more phases in the multiphase system.
- 5. The process of claim 1 wherein the water solubility of the pharmaceutical active compound is less than 10 mg/ml.
- 6. The process of claim 1 wherein the water solubility of the pharmaceutical active compound is less than 8 mg/ml.
- 7. The process of claim 1 wherein the multiphase system is an oil in water (O/W) emulsion.
- 8. The process of claim 1 wherein the multiphase system is a water in oil (W/O) emulsion.
- 9. The process of claim 1 wherein the multiphase system is a water in oil in water (W/O/W) emulsion.
- 10. The process of claim 1 wherein the multiphase system is an oil in water in oil (O/W/O) emulsion.
- 11. The process of claim 1 wherein the ratio by weights of the organic phase to the aqueous phase is from about 1:99 to about 99:1.
- 12. The process of claim 1 wherein the ratio by weights of the organic phase to the aqueous phase is from about 1:99 to about 40:60.
- 13. The process of claim 1 wherein the ratio by weights of the organic phase to the aqueous phase is from about 2:98 to about 30:70.
- 14. The process of claim 1 wherein the compound is present in an amount by weight of the organic phase from less than about 1% to about 40%.
- 15. The process of claim 1 wherein the compound is present in an amount by weight of the organic phase from less than about 1% to about 25%.
- 16. The process of claim 1 wherein the compound is present in an amount by weight of the organic phase from less than about 1% to about 10%.
- 17. The process of claim 1 wherein the method of providing the crude dispersion is selected from the group consisting of: shaking, agitating, vortexing, mixing, and stirring.
- 18. The process of claim 1 wherein the step of providing energy to the crude dispersion comprises the steps of:
providing a sonication device having a transducer for emitting sonic energy; and exposing the system to said sonic energy sufficient to allow for cavitation to occur.
- 19. The process of claim 18 wherein the sonication device is operating at a frequency of from about 1 kHz to about 90 kHz.
- 20. The process of claim 18 wherein the sonication device is operating at a frequency of from about 20 kHz to about 40 kHz.
- 21. The process of claim 1 wherein the step of providing energy to the crude dispersion is by homogenization.
- 22. The process of claim 21 wherein the crude dispersion is homogenized at about 5,000 to 30,000 psi.
- 23. The process of claim 21 wherein the crude dispersion is homogenized at about 10,000 to 15,000 psi.
- 24. The process of claim 21 wherein the crude dispersion is homogenized at about 15,000 to 20,000 psi.
- 25. The process of claim 1 further comprises the step of adding a surface active compound to the multiphase system.
- 26. The process of claim 25 wherein the surface active compound is added to the organic phase.
- 27. The process of claim 25 wherein the surface active compound is added to the aqueous phase.
- 28. The process of claim 25 wherein the surface active compound is added to both the organic phase and the aqueous phase.
- 29. The process of claim 25 wherein the surface active compound is selected from the group consisting of anionic surfactants, cationic surfactants, zwitterionic surfactants and biological surface active molecules.
- 30. The process of claim 29 wherein the nonionic surfactant is selected from the group consisting of: polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters, glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, polaxamines, methylcellulose, hydroxycellulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose, polyvinyl alcohol, polyvinylpyrrolidone, albumin, heparin, and hirudin.
- 31. The process of claim 29 wherein the anionic surfactant is selected from the group consisting of: potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidyl inositol, phosphatidylserine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, bile acids and their salts, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, and calcium carboxymethylcellulose.
- 32. The process of claim 29 wherein the cationic surfactant is selected from the group consisting of quaternary ammonium compounds, benzalkonium chloride, cetyltrimethylammonium bromide, chitosans and lauryldimethylbenzylammonium chloride.
- 33. The process of claim 29 wherein the surface active compound is albumin.
- 34. The process of claim 1 further comprises the step of adding an excipient to the multiphase system.
- 35. The process of claim 34 wherein the excipient is selected from the group consisting of proteins, saccharides, diaccharides, and sugar alcohols.
- 36. The process of claim 35 wherein the disaccharide is sucrose.
- 37. The process of claim 35 wherein the sugar alcohol is mannitol.
- 38. The process of claim 25 wherein the surface active compound is present in an amount by weight of the aqueous phase or the organic phase from less than about 1% to about 30%.
- 39. The process of claim 25 wherein the surface active compound is present in an amount by weight of the aqueous phase or the organic phase from less than about 1% to about 20%.
- 40. The process of claim 1 wherein the organic phase comprises a water immiscible solvent.
- 41. The process of claim 40 wherein the water immiscible solvent is selected from the group consisting of: linear, branched or cyclic alkanes with carbon number of 5 or higher, linear, branched or cyclic alkenes with carbon number of 5 or higher, linear, branched or cyclic alkynes with carbon number of 5 or higher; aromatic hydrocarbons completely or partially halogenated hydrocarbons, ethers, esters, ketones, mono-, di- or tri-glycerides, native oils, alcohols, aldehydes, acids, amines, linear or cyclic silicones, hexamethyldisiloxane, or any combination of these solvent.
- 42. The process of claim 34 wherein the water immiscible solvent has a vapor pressure higher than water at room temperature.
- 43. The process of claim 1 wherein the organic phase comprises a partially water miscible solvent.
- 44. The process of claim 43 wherein the partially water miscible solvent is selected from the group consisting of: fluorinated solvents, tetrahydrofuran, propylene carbonate, benzyl alcohol, and ethyl acetate.
- 45. The process of claim 1 wherein the organic phase further includes a co-solvent.
- 46. The process of claim 45 wherein the co-solvent is a water miscible organic solvent.
- 47. The process of claim 1 wherein the compound is selected from the group consisting of: antihyperlipidemics, anesthetics, antiasthamatics, antimicrobials, antifungals, antineoplastics, non-steroidal anti-inflammatory drugs, antihypercholesteremic agents, analgesics, steroidal compounds, antipyretics, antidepressants, antiarrhthmics, antianxiety drugs, antimanics, antiarthritics, antihistamines, anti-infectives, water insoluble vitamins, antipsychotics, sedatives, antihypertensive agents, diagnostic agents, anticonvulsants and immunosuppresants.
- 48. The process of claim 1 further comprises the step of sterile filtering the fine dispersion prior to freezing and lyophilizing to produce the particles.
- 49. The process of claim 1 further comprising the step of redispersing the lyophilized particles in an aqueous medium.
- 50. The process of claim 49 wherein the redispersed nanoparticles are suitable for in vivo delivery by parenteral administration.
- 51. A process for preparing submicron sized particles comprising the steps of:
providing an organic phase of a pharmacologically active compound dissolved in a water immiscible solvent; providing an aqueous phase with a surface active compound; combining the organic phase with the aqueous phase to form a crude dispersion; and providing energy to the crude dispersion to form a fine dispersion; freezing the fine dispersion; lyophilizing the frozen dispersion to obtain particles having a mean particle size of less than 500 nm.
- 52. The process of claim 51 wherein the particles have a mean particle size of less than 200 nm.
- 53. The process of claim 51 wherein the surface active compound is albumin.
- 54. The process of claim 51 wherein the particles are substantially free of the organic phase.
- 55. The process of claim 51 wherein the method of forming the crude dispersion is selected from the group consisting of: shaking, agitating, vortexing, mixing, and stirring.
- 56. The process of claim 51 wherein the method of providing energy to the crude dispersion to form the dispersion is selected from the group consisting of sonication and homogenization.
- 57. The process of claim 51 further comprises the step of sterile filtering the fine dispersion prior to freezing and lyophilizing to obtain the particles.
- 58. The process of claim 51 further comprises the step of redispersing the particles in an aqueous medium.
- 59. The process of claim 58 wherein the redispersed particles are suitable for in vivo delivery by parenteral administration.
- 60. A process for preparing an aqueous suspension of submicron sized particles comprising the steps of:
providing an organic phase of a pharmacologically active compound dissolved in a water immiscible solvent; providing an aqueous phase with a surface active compound; combining the organic phase with the aqueous phase to form a crude dispersion; providing energy to the crude dispersion to form a fine dispersion; sterile filtering the fine dispersion; freezing the sterile filtered dispersion; lyophilizing the frozen dispersion to obtain particles having a mean particle size of less than 500 nm; and redispersing the particles in an aqueous medium.
- 61. The process of claim 60 wherein the particles have a mean particle size of less than 200 nm.
- 62. The process of claim 60 wherein the particles are substantially free of the organic phase.
- 63. The process of claim 60 wherein the surface active compound is albumin.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 09/964,273, filed Sep. 26, 2001.
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
09964273 |
Sep 2001 |
US |
Child |
10183035 |
Jun 2002 |
US |