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WO 2007/114881 Al (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 11 October 2007 (11.10.2007) WO 2007/114881 Al (51) International Patent Classification: AT,AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, A61K9/16 (2006.01) A61K 38/48 (2006.01) CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, A61K 38/16 (2006.01) GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, (21) International Application Number: LT, LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, PCT/US2007/001914 MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, (22) International Filing Date: 24 January 2007 (24.01.2007) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (AT,BE, CH, CY, CZ, DE, DK, EE, FI, (30) Priority Data: European BG, ES, 60/762,002 24 January 2006 (24.01.2006) US FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (71) Applicant (for all designated States except US): NEXBIO, INC. [US/US]; 10665 Sorrento Valley Road, San Diego, Declarations under Rule 4.17: CA 92121 (US). — as to applicant's entitlement to apply for and be granted a patent (Rule 4.17(U)) (72) Inventors; and — as to the applicant's entitlement to claim the priority of the (75) Inventors/Applicants (for US only): MALAKHOV, earlier application (Rule 4.17(Ui)) Michael, P. [RU/US]; 11530 Caminito La Bar #124, San Diego, CA 92126 (US). FANG, Fang [US/US]; 11124 Published: Corte Pleno Verano, San Diego, CA 92130 (US). — with international search report — with sequence listing part of description published sep a (74) Agent: SEIDMAN, Stephanie L.; Fish & Richardson rately in electronic form and available upon request from RC, 12390 El Camino Real, San Diego, California 92130 the International Bureau (US). For two-letter codes and other abbreviations, refer to the "G uid (81) Designated States (unless otherwise indicated, for every ance Notes on Codes and Abbreviations" appearing at the beg in kind of national protection available): AE, AG, AL, AM, ning of each regular issue of the PCT Gazette. (54) Title: TECHNOLOGY FOR PREPARATION OF MACROMOLECULAR MICROSPHERES (57) Abstract: Microspheres are produced by contacting an aqueous solution of a protein or other macromoiecule with an organic solvent and a counterion, and chilling the solution. The microspheres are useful for preparing pharmaceuticals of defined dimensions. Technology for Preparation of Macromolecular Microspheres RELATED APPLICATIONS Benefit of priority is claimed to U.S. Provisional Application No. 60/762,002, filed 24 January 2006, entitled "Technology for Preparation of Macromolecular Microspheres." Where permitted, this application is incorporated by reference in its entirety. This application also is related to U.S. Application Serial No.1 1/657,812 (Attorney Docket No. 21865-004001/6504, filed 24 January 2007). This application also is related to U.S. Publication Nos. US20050004020 A 1 and US200501 12751 A 1. Where permitted, each of these applications is incorporated by reference in its entirety. BACKGROUND The administration of proteins to animals, including humans, in nutritional supplements or as therapeutics has been known for some time. Proteins for therapeutic or nutritional administration generally are available either as ( 1) concentrates or powders that are administered directly or are reconstituted in a liquid of choice prior to use; or (2) liquid formulations. The preparation and delivery of therapeutic proteins of interest in powder or particle form is an area of concentrated research and development activity in the pharmaceutical industry. For therapeutic efficacy, it is desirable to have a uniform formulation. For example, for pulmonary administration, the protein ideally is prepared in the form of discrete microspheres, which are solid or semi-solid particles having a diameter of between 0.5 and 5.0 microns. It also is desirable for the particles to have a protein content that is as high as possible and that maintains its activity for concentrated delivery and therapeutic efficacy. Previous methods of producing protein microparticles or nanoparticles have involved complex steps, such as blending with organic polymers and/or forming a lattice array with polymers; spray drying, spray freeze-drying or supercritical fluid antisolvent techniques that use specialized and complex equipment; or lyophilization followed by pulverization or milling that often results in non-uniform particles that must further be sorted. Often previous methods of producing solid protein formulations involve processing steps, such as heating, that denature the protein and compromise its activity. In addition, some methods do not provide high recovery from solution into the solid formulation. Accordingly, there is a need for a method for producing protein and other macromolecular microparticles that does not require complex or specialized equipment and that produces uniform-sized microparticles for delivery. There further is a need for a method of producing microparticles that contain high concentrations of the protein or macromolecule relative to other components, that are stable and maintain their activity for long periods of time when stored at ambient temperature and that do not contain a significant amount of denatured protein. There also is a need for a method of producing microparticles of proteins and other macromolecules wherein substantially all of the protein or macromolecule in the starting material is recovered in the microparticle formulation, with minimal loss. There also is a need for microparticles of proteins or other macromolecules containing these properties for administration, for example, as a therapeutic or nutritional supplement. SUMMARY Provided herein are methods for producing protein and other macromolecular microparticles that do not require complex or specialized equipment and that produces uniform-sized microparticles for delivery; methods for producing microparticles that contain high concentrations of protein or macromolecule relative to other components, that are stable and maintain their activity for long periods of time when stored at ambient temperature and that do not contain a significant amount of denatured protein. Also provide are methods for producing microparticles of proteins and other macromolecules where substantially all of the protein or macromolecule in the starting material is recovered in the microparticle formulation, with minimal loss. Also provided are microparticles of proteins and other macromolecules containing these properties for administration, for example, as a therapeutic or nutritional supplement. The methods of making a protein-based composition, the protein- based compositions themselves, combinations and articles of manufacture provided below are characterized by a variety of component ingredients, steps of preparation, and biophysical, physical, biochemical and chemical parameters. As would be apparent to one of skill in the art, the compositions and methods provided herein include any and all permutations and combinations of the ingredients, steps and/or parameters described below. Provided herein are methods of making a protein-based composition. The method provided herein can be used to make compositions from other macromolecules besides proteins, including DNA, RNA, PNA, lipids, oligosaccharides and combinations thereof. The methods provided herein can include the steps of : a) adding a counterion to a solution containing the protein in an aqueous solvent; b) adding an organic solvent to the solution; and c) gradually cooling the solution to a temperature below about 25 0C, whereby a composition containing microparticles comprising the protein is formed, wherein steps a), b) and c) are performed simultaneously, sequentially, intermittently, or in any order. In one embodiment, the steps are performed sequentially a), b) and then c). In another embodiment, the method of making a protein-based composition includes performing steps a) and b) simultaneously or sequentially in any order, followed by step c). The resulting microparticles can be obtained by precipitation, by phase separation or by colloid formation. In some aspects, the methods provided herein further comprise separating the microparticles from the solution to remove components other than the microparticles. This separation step can be performed following the above-mentioned step c). The separation can be effected by, for example, sedimentation, filtration and/or freeze-drying. The methods provided herein include the addition of an organic solvent to an aqueous solvent containing the protein. In certain embodiments, the organic solvent is miscible or partially miscible with the aqueous solvent. In further embodiments of the methods provided herein, the organic solvent is selected from among aliphatic alcohols, aromatic alcohols, chloroform, dimethyl chloride, polyhydric sugar alcohols, aromatic hydrocarbons, aldehydes, ketones, esters, ethers, dioxanes, alkanes, alkenes, conjugated dienes, dichloromethane, acetonitrile, ethyl acetate, polyols, polyimides, polyesters, polyaldehydes and mixtures thereof. For example, where the organic solvent is an aliphatic alcohol, the organic solvent can be isopropanol. The amount of organic solvent added can vary in the methods provided herein. For example, the amount of organic solvent added can be from about 0.1 % or 0.1 % to about 50% or 50% v/v. In other embodiments, the amount of organic solvent added is from about 1% or 1% to about 30% or 30% v/v, from about 5% or 5% to about 30% or 30% v/v, from about 10% or 10% to about 30% or 30% v/v or from about 15% or 15% to about 20% or 20% v/v.
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