Claims for Patent: 8,323,615

Summary for Patent: 8,323,615

Title:	Methods of processing multi-phasic dispersions
Abstract:	A method for processing multi-phasic dispersions is provided. The method comprises providing a multi-phasic dispersion, the dispersion including dispersed and continuous phases, the dispersion comprising solid microparticles, providing a non-solvent, combining the multi-phasic dispersion and the non-solvent, and selectively effecting migration of the dispersed phase into or through the non-solvent such that the microparticles are separated from the dispersion.
Inventor(s):	Piran; Uri (Sharon, MA)
Assignee:	Baxter International Inc. (Deerfield, IL) Baxter Healthcare S. A. (Glattpark (Opfikon), CH)
Application Number:	12/195,149
Patent Claims:	1. A method of processing multi-phasic dispersions comprising: providing a multi-phasic dispersion including dispersed and continuous phases, the dispersion comprising solid microparticles and at least a first non-volatile material; providing a non-solvent, combining the multi-phasic dispersion and the non-solvent; and selectively effecting migration of the microparticles into or through the non-solvent such that a majority of the microparticles is separated from the dispersion, wherein the continuous phase is either aqueous or aqueous-miscible, the first non-volatile material comprises a non-ionic aqueous-soluble polymer or a non-ionic aqueous-miscible polymer, the microparticles arc substantially insoluble in the non-solvent and the non-solvent has either a density which is greater than that of the continuous phase or a viscosity which is greater than that of the continuous phase, wherein providing the non-solvent comprises introducing the non-solvent into a centrifugation apparatus, thereby forming a non-solvent layer therein, combining the multi-phasic dispersion and the non-solvent comprises layering the multi-phasic dispersion on a top surface of the non-solvent layer, thereby forming a layered composition; and selectively effecting migration of the microparticles into or through the non-solvent comprises centrifuging the layered composition. 2. The method of claim 1, further comprising freezing the non-solvent prior to adding the multi-phasic dispersion to the non-solvent. 3. The method of claim 1, wherein the centrifugation apparatus comprises a centrifuge tube. 4. The method of claim 1, wherein the centrifugation apparatus comprises a continuous-flow centrifuge. 5. The method of claim 1, further comprising collecting the microparticles separated from the dispersion. 6. The method of claim 1, wherein the non-solvent comprises a second non-volatile material. 7. The method of claim 6, further comprising collecting the microparticles separated from the dispersion, and exposing the collected microparticles to a supercritical fluid to remove at least a portion of the second non-volatile material while retaining at least the solid microparticles. 8. The method of claim 1, wherein the non-solvent is a pharmaceutically acceptable diluent. 9. The method of claim 1, wherein the microparticles have a density D.sub.p, the continuous phase has a density D.sub.c, and the non-solvent is homogeneous having a density D.sub.n, such that D.sub.p.gtoreq.D.sub.n.gtoreq.D.sub.c. 10. The method of claim 9, wherein D.sub.n, is greater than 1 g/cm.sup.3. 11. The method of claim 1, wherein the non-solvent comprises a density gradient. 12. The method of claim 1, wherein the non-solvent comprises one or more components selected from the group consisting of aqueous liquids, organic liquids, halogenated liquids, non-volatile materials, and combinations thereof. 13. The method of claim 6, wherein the second non-volatile material is water-soluble, a liquid at ambient temperature, or both. 14. The method of claim 6, wherein the concentration of the second non-volatile material in the non-solvent is greater than the concentration of the first non-volatile material in the dispersion. 15. The method of claim 14, wherein the second non-volatile material is different from and has a lower molecular weight than the first non-volatile material. 16. The method of claim 14, wherein the first and second non-volatile materials are the same. 17. The method of claim 6, wherein the second non-volatile material is selected from liquid polyethylene glycols, liquid poloxamers, and combinations of thereof. 18. The method of claim 6, wherein the first and second non-volatile materials comprise non-ionic polymers independently selected from the group consisting of nonionic polyethers, nonionic copolyethers, nonionic polyesters, nonionic copolyesters, nonionic polyether-polyester copolymers, non-ionic vinyl polymers, non-ionic pyrrolidone-containing polymers, non-ionic polymeric carbohydrates, derivatives and salts of the foregoing materials, and combinations thereof. 19. The method of claim 1, wherein the non-solvent further comprises one or more solutes selected from the group consisting of stabilizers, salts, antioxidants, and combinations thereof. 20. The method of claim 1, wherein the non-solvent is soluble in or miscible with the continuous phase. 21. The method of claim 1, wherein each microparticle comprises at least one bioactive macromolecule that is present at least on an outer surface of the microparticle. 22. The method of claim 21, wherein the at least one bioactive macromolecule is selected from the group consisting of carbohydrates, peptides, proteins, vectors, nucleic acids, complexes thereof, conjugates thereof, and combinations thereof. 23. The method of claim 1, wherein the microparticles are amorphous, spherical, solid, or a combination of two or more thereof. 24. The method of claim 1, wherein the solid microparticles comprise at least one active agent. 25. The method of claim 24, wherein the active agent is selected from the group consisting of bioactive agents, pharmaceutical agents, diagnostic agents, nutritional supplements, and cosmetic agents. 26. The method of claim 24, wherein the active agent is a bioactive agent comprising at least one bioactive macromolecule selected from the group consisting of carbohydrates, peptides, proteins, vectors, nucleic acids, complexes thereof, conjugates thereof, and combinations thereof. 27. The method of claim 24, wherein the active agent is a pharmaceutical agent selected from the group consisting of adjuvants, adrenergic agents, adrenergic blocking agents, adrenocorticoids, adrenolytics, adrenomimetics, alkaloids, alkylating agents, allosteric inhibitors, anabolic steroids, analeptics, analgesics, anesthetics, anorexiants, antacids, anti-allergic agents, antiangiogenesis agents, anti-arrhythmic agents, anti-bacterial agents, antibiotics, antibodies, anticancer agents, anticholinergic agents, anticholinesterases, anticoagulants, anticonvulsants, antidementia agents, antidepressants, antidiabetic agents, antidiarrheals, antidotes, antiepileptics, antifolics, antifungals, antigens, antihelmintics, antihistamines, antihyperlipidemics, antihypertensive agents, anti-infective agents, anti-inflammatory agents, antimalarials, antimetabolites, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antiosteoporosis agents, antipathogen agents, antiprotozoal agents, adhesion molecules, antipyretics, antirheumatic agents, antiseptics, antithyroid agents, antiulcer agents, antiviral agents, anxiolytic sedatives, astringents, beta-adrenoceptor blocking agents, biocides, blood clotting factors, calcitonin, cardiotonics, chemotherapeutics, cholesterol lowering agents, cofactors, corticosteroids, cough suppressants, cytokines, diuretics, dopaminergics, estrogen receptor modulators, enzymes and cofactors thereof, enzyme inhibitors, growth differentiation factors, growth factors, hematological agents, hematopoietics, hemoglobin modifiers, hemostatics, hormones and hormone analogs, hypnotics, hypotensive diuretics, immunological agents, immunostimulants, immunosuppressants, inhibitors, ligands, lipid regulating agents, lymphokines, muscarinics, muscle relaxants, neural blocking agents, neurotropic agents, paclitaxel and derivative compounds, parasympathomimetics, parathyroid hormone, promoters, prostaglandins, psychotherapeutic agents, psychotropic agents, radio-pharmaceuticals, receptors, sedatives, sex hormones, sterilants, stimulants, thrombopoietics, trophic factors, sympathomimetics, thyroid agents, vaccines, vasodilators, vitamins, xanthines, as well as conjugates, complexes, precursors, metabolites, and mixtures thereof. 28. The method of claim 1, wherein the microparticles comprise a carrier macromolecule. 29. A method of processing multi-phasic dispersions comprising: providing a multi-phasic dispersion including dispersed and continuous phases, the dispersion comprising solid microparticles and a first non-volatile material at a first concentration, the continuous phase is either aqueous or aqueous-miscible, the first non-volatile material comprises a non-ionic aqueous-soluble polymer or a non-ionic aqueous-miscible polymer; providing a non-solvent comprising a second non-volatile material at a second concentration that is greater than the first concentration, wherein the microparticles are substantially insoluble in the non-solvent; combining the multi-phasic dispersion and the non-solvent; and selectively effecting migration of the microparticles into or through the non-solvent such that a majority of the microparticles is separated from the dispersion, wherein providing the non-solvent comprises introducing the non-solvent into a centrifugation apparatus, thereby forming a non-solvent layer therein, combining the multi-phasic dispersion and the non-solvent comprises layering the multi-phasic dispersion on a top surface of the non-solvent layer, thereby forming a layered composition; and selectively effecting migration of the microparticles into or through the non-solvent comprises centrifuging the layered composition. 30. The method of claim 29, wherein the microparticles comprise an active agent. 31. The method of claim 29, wherein the microparticles comprise a macromolecule selected from the group consisting of carrier macromolecules, bioactive macromolecules, and combinations thereof. 32. The method of claim 31, wherein the macromolecule comprises at least one bioactive macromolecule selected from the group consisting of carbohydrates, peptides, proteins, vectors, nucleic acids, complexes thereof, conjugates thereof, and combinations thereof. 33. The method of claim 29, wherein the first and second non-volatile materials are different in their chemical structure and/or molecular weight. 34. The method of claim 29, wherein the first and second non-volatile materials are the same.

Details for Patent 8,323,615

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2039-02-26