Claims for Patent: 8,075,919

Summary for Patent: 8,075,919

Title:	Methods for fabrication, uses and compositions of small spherical particles prepared by controlled phase separation
Abstract:	The present invention is related to a method for preparing small spherical particles of an active agent by providing a solution in a single liquid phase. The single liquid phase comprises an active agent, a phase separation enhancing agent, and a first solvent. A phase change is induced at a controlled rate in the solution to cause a liquid-solid phase separation of the active agent and to form a solid phase and a liquid phase. The solid phase comprises solid small spherical particles of the active agent. The liquid phase comprises the phase separation enhancing agent and the solvent. The small spherical particles are substantially spherical and having a size from about 0.01 .mu.m to about 200 .mu.m.
Inventor(s):	Brown; Larry (Newton, MA), McGeehan; John K. (Woodbury, NJ), Rashba-Step; Julia (Newton, MA), Scott; Terrence L. (Winchester, MA)
Assignee:	Baxter International Inc. (Deerfield, IL) Baxter Healthcare S.A. (Wallisellen, CH)
Application Number:	10/894,430
Patent Claims:	1. A method for preparing small spherical particles of an active agent comprising: providing a solution in a single liquid phase and comprising the active agent, a phase separation enhancing agent and a first solvent; and cooling the solution to thereby form a suspension comprising solid small spherical particles of the active agent in a liquid phase comprising the phase separation enhancing agent and the solvent, the small spherical particles being substantially spherical, wherein said cooling is performed at a controlled rate from about 8.6.degree. C./minute to about 26.5.degree. C./minute, wherein said active agent is a macromolecule, and wherein the particles have an average particle size of from about 0.5 .mu.m to about 10 .mu.m. 2. The method of claim 1, further comprising a step selected from the group consisting of: adjusting the concentration of the active agent, adjusting the concentration of the phase-separation enhancing agent, adjusting the ionic strength of the solution, adjusting the pH, and adjusting the osmolality of the solution before or during the cooling step. 3. The method of claim 1 further comprising changing the concentration of the active agent. 4. The method of claim 1 further comprising changing the concentration of the phase separation enhancing agent. 5. The method of claim 1, wherein the solution has a phase transition temperature, a first temperature and a second temperature and the solution is cooled from the first temperature to the second temperature wherein the first temperature is above the phase transition temperature of the solution and the second temperature is below the phase transition temperature of the solution. 6. The method of claim 5, wherein the second temperature is above the freezing point of the solution. 7. The method of claim 5, wherein the second temperature is below the freezing point of the solution. 8. The method of claim 1, wherein the step of providing the solution comprises: dissolving the phase-separation enhancing agent in the first solvent to form a mixture; and adding the active agent to the mixture to form the solution. 9. The method of claim 8 further comprising the step of dissolving the active agent in the first solvent or a second solvent which is miscible with the first solvent before adding the active agent to the mixture. 10. The method of claim 6, wherein the solution further comprises a freezing point depression agent to lower the freezing point of the solution. 11. The method of claim 10, wherein the freezing point depression agent is selected from the group of polyethylene glycol and propylene glycol. 12. The method of claim 1, wherein the phase-separation enhancing agent is an aqueous soluble or aqueous miscible agent. 13. The method of claim 1, wherein the phase-separation enhancing agent is selected from the group consisting of linear or branched polymers, carbohydrate-based polymers, polyaliphatic alcohols, poly(vinyl) polymers, polyacrylic acids, polyorganic acids, polyamino acids, co-polymers and block co-polymers, tert-polymers, polyethers, naturally occurring polymers, polyimides, surfactants, polyesters, branched and cyclo-polymers, polyaldehydes, starches, substituted starches, polyethylene glycol, polyvinylpyrrolidone, poloxamers, ethanol, acetone, and isopropanol. 14. The method of claim 1, wherein the phase separation enhancing agent is polyethylene glycol (PEG). 15. The method of claim 1, wherein the small spherical particles further comprises an excipient to enhance the stability of the small spherical particles, to provide controlled release of the active agent from the small spherical particles, or to enhance permeation of the active agent through biological tissues. 16. The method of claim 15, wherein the excipient is selected from the group consisting of: carbohydrates, cations, anions, amino acids, lipids, fatty acids, surfactants, triglycerides, bile acids or their salts, fatty acid esters, and polymers. 17. The method of claim 16, wherein the cation is selected from group consisting of Zn.sup.2+, Mg.sup.2+, and Ca.sup.2+. 18. The method of claim 16, wherein the bile acid is cholate or its salt. 19. The method of claim 1, further comprising the step of harvesting the small spherical particles. 20. The method of claim 19, wherein the step of harvesting the small spherical particles is by washing the particles with a liquid medium at a temperature at which the active agent is not soluble in the liquid medium and the phase-separation enhancing agent is soluble in the liquid medium. 21. The method of claim 20, wherein the step of washing is by diafiltration or centrifugation. 22. The method of claim 20, wherein the liquid medium is aqueous or organic. 23. The method of claim 20, wherein the liquid medium is a supercritical fluid or a mixture of a supercritical fluid and a supercritical fluid miscible solvent. 24. The method of claim 22, wherein the organic liquid medium is selected from the group consisting of: methylene chloride, chloroform, acetonitrate, ethylacetate, ethanol, and pentane. 25. The method of claim 20, wherein the liquid medium further comprises an agent which reduces the solubility of the active agent in the liquid medium. 26. The method of claim 25, wherein the agent to reduce the solubility of the active agent in the liquid medium comprises a complexing ion. 27. The method of claim 26, wherein the complexing ion is selected from the group consisting of: Zn.sup.2+, Ca.sup.2+, Fe.sup.2+, Mg.sup.2+, Mn.sup.2+, Na.sup.+, and NH.sub.4.sup.+. 28. The method of claim 20, further comprises the step of removing the liquid medium. 29. The method of claim 28, wherein the step of removing the liquid medium is by lyophilization, drying or evaporation. 30. The method of claim 20, wherein the liquid medium further comprises an excipient. 31. The method of claim 30, wherein the excipient enhances the stability of the small spherical particles, provides controlled release of the active agent from the small spherical particles, or enhances permeation of the active agent through biological tissues. 32. The method of claim 31, wherein the excipient is selected from the group consisting of: carbohydrates, cations, anions, amino acids, lipids, fatty acids, surfactants, triglycerides, bile acids or their salts, fatty acid esters, and polymers. 33. The method of claim 32, wherein the cation is selected from group consisting of Zn.sup.2+, Mg.sup.2+, and Ca.sup.2+. 34. The method of claim 32, wherein the excipient is cholate or its salt. 35. The method of claim 1, wherein the phase separation enhancing agent is selected from the group consisting of poloxamers, polyethylene glycols, and mixtures thereof. 36. The method of claim 1, wherein the solution comprises an aqueous or aqueous-miscible solvent. 37. The method of claim 36, wherein the aqueous-miscible solvent is selected from the group consisting of: N-methyl-2-pyrrolidinone (N-methyl-2-pyrrolidone), 2-pyrrolidinone (2-pyrrolidone), 1,3-dimethyl-2-imidazolidinone (DMI), dimethylsulfoxide, dimethylacetamide, acetic acid, lactic acid, methanol, ethanol, isopropanol, 3-pentanol, n-propanol, benzyl alcohol, glycerol, polyethylene glycol (PEG), PEG-4, PEG-8, PEG-9, PEG-12, PEG-14, PEG-16, PEG-120, PEG-75, PEG-150, polyethylene glycol esters, PEG-4 dilaurate, PEG-20 dilaurate, PEG-6 isostearate, PEG-8 palmitostearate, PEG-150 palmitostearate, polyethylene glycol sorbitans, PEG-20 sorbitan isostearate, polyethylene glycol monoalkyl ethers, PEG-3 dimethyl ether, PEG-4 dimethyl ether, polypropylene glycol (PPG), polypropylene alginate, PPG-10 butanediol, PPG-10 methyl glucose ether, PPG-20 methyl glucose ether, PPG-15 stearyl ether, propylene glycol dicaprylate/dicaprate, propylene glycol laurate, and glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether), or a combination thereof. 38. The method of claim 1, wherein the macromolecule is selected from the group consisting of proteins, polypeptides, carbohydrates, polynucleotides, viruses and nucleic acids. 39. The method of claim 38, wherein the protein is selected from the group consisting of: a protein of the blood clotting cascade, Factor VII, Factor VIII, Factor IX, subtilisin, ovalbumin, alpha-1-antitrypsin, DNAse, superoxide dismutase, lysozyme, ribonuclease, hyaluronidase, collagenase, growth hormone, erythropoetin, insulin-like growth factors or their analogs, interferons, glatiramer, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, antibodies, monoclonal antibodies, polyclonal antibodies, Fab fragments, single-chain antibodies, PEGylated proteins, glycosylated or hyperglycosylated proteins, desmopressin, LHRH agonists such as: leuprolide, goserelin, nafarelin, buserelin, LHRH antagonists, vasopressin, cyclosporine, calcitonin, parathyroid hormone, parathyroid hormone peptides and insulin. 40. The method of claim 1, wherein the particles are suitable for in vivo delivery to a subject in need of the active agent. 41. The method of claim 40, wherein the in vivo delivery is selected from the group consisting of injectable, inhalable, parenteral, topical, oral, rectal, nasal, pulmonary, vaginal, buccal, sublingual, transdermal, transmucosal, otic, ocular, intraocular and ophthalmic. 42. The method of claim 41, wherein the in vivo delivery is by pulmonary delivery. 43. The method of claim 42, wherein the particles are suitable for deposition in the central or peripheral area of the lung of the subject. 44. The method of claim 42, wherein the particles are delivered by a device selected from the group consisting of dry powder inhaler, a metered dose inhaler, and a nebulizer. 45. The method of claim 40, wherein the particles are delivered as a stable liquid suspension. 46. The method of claim 1, wherein the particles have substantially the same particle size. 47. The method of claim 1, wherein the active agent is from about 0.1% to about 100% by weight of the particle. 48. The method of claim 1, wherein the active agent is from about 75% to about 100% by weight of the particle. 49. The method of claim 1, wherein the active agent is equal to or greater than 90% by weight of the particle. 50. The method of claim 1 wherein the small spherical particles have a narrow size distribution. 51. The method of claim 50 wherein the ratio of a volume diameter of the 90.sup.th percentile of the small spherical particles to the volume diameter of the 10.sup.th percentile is less than or equal to about 5. 52. The method of claim 1 wherein the active agent in the small spherical particles is semi-crystalline or non-crystalline. 53. A method for preparing small spherical particles of an active agent, the method comprising the steps of: dissolving the active agent and a phase-separation enhancing agent in an aqueous or aqueous-miscible solvent to form a solution of a single continuous phase, and cooling the solution to thereby form a suspension comprising solid, small spherical particles of the active agent in a liquid phase comprising the phase-separation enhancing agent, wherein said cooling is performed at a controlled rate from about 8.6.degree. C./minute to about 26.5.degree. C./minute, wherein said active agent is a macromolecule, and wherein the particles have an average particle size of from about 0.5 .mu.m to about 10 .mu.m. 54. The method of claim 53, wherein the solution has a phase transition temperature, a first temperature and a second temperature and the solution is cooled from the first temperature to the second temperature wherein the first temperature is above the phase transition temperature of the solution and the second temperature is below the phase transition temperature of the solution. 55. The method of claim 1 wherein said solution is cooled at a controlled rate to a temperature above the freezing point of said solution. 56. The method of claim 1, wherein the first solvent is water. 57. The method of claim 1, wherein a percentage conversion of the active agent from the starting solution into the particles is at least 90%. 58. The method of claim 1, wherein the active agent released from the particles retains the bioactivity of the active agent in the starting solution, as determined by specific activity. 59. The method of claim 1, wherein the active agent released from the particles retains the structural integrity of the active agent in the starting solution, as determined by circular dichroism spectroscopy. 60. The method of claim 1, wherein the small spherical particles have a geometric standard deviation of less than 2.5. 61. The method of claim 60, wherein the geometric standard deviation is less than 1.8, and a ratio of a volume diameter of the 90.sup.th percentile of the particles to a volume diameter of the 10.sup.th percentile of the particles is less than 3. 62. A method for preparing solid, small spherical particles of active agent comprising: providing an aqueous solution in a single liquid phase and comprising the active agent and a phase separation enhancing agent; cooling the aqueous solution; thereby forming a suspension comprising solid, small spherical particles of active agent suspended in a liquid phase comprising the phase separation enhancing agent and water, the solid, small spherical particles being substantially spherical, wherein said cooling is performed at a controlled rate from about 8.6.degree. C./minute to about 26.5.degree. C./minute, wherein said active agent is a macromolecule, and wherein the particles have an average particle size of from about 0.5 .mu.m to about 10 .mu.m. 63. The method of claim 62, wherein the cooling the aqueous solution is carried out at a constant or linear rate, a non-linear rate, an intermittent rate, or a programmed rate. 64. The method of claim 62, wherein the cooling the aqueous solution involves cooling the solution to a temperature below the phase transition temperature of the active agent. 65. The method of claim 62, wherein the aqueous solution further comprises a freezing point depressing agent. 66. The method of claim 62, wherein the cooling the aqueous solution includes cooling the solution to a temperature above the freezing point of the solution. 67. The method of claim 65, wherein the freezing point depressing agent comprises polyethylene glycol. 68. The method of claim 1, wherein the active agent comprises insulin. 69. The method of claim 53, wherein the active agent comprises insulin. 70. The method of claim 62, wherein the active agent comprises insulin.

Details for Patent 8,075,919

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	05/05/2004		2023-07-18
Bausch & Lomb Incorporated	VITRASE	hyaluronidase	Injection	021640	12/02/2004		2023-07-18
Amphastar Pharmaceuticals, Inc.	AMPHADASE	hyaluronidase	Injection	021665	10/26/2004		2023-07-18