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Wo 2009/015286 A2 (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 29 January 2009 (29.01.2009) WO 2009/015286 A2 (51) International Patent Classification: Not classified AO, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, (21) International Application Number: EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, PCT/US2008/071055 IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, (22) International Filing Date: 24 July 2008 (24.07.2008) MX, MY,MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY,TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 60/961,872 24 July 2007 (24.07.2007) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (71) Applicant (for all designated States except US): NEXBIO, European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, INC. [US/US]; 10665 Sorrento Valley Road, San Diego, California 92121 (US). FR, GB, GR, HR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, (72) Inventors; and CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): MALAKHOV, Michael [RU/US]; 3717 Nobel Drive, #1319, San Diego, Declaration under Rule 4.17: California 92122 (US). FANG, Fang [US/US]; 11124 — as to applicant's entitlement to apply for and be granted a Corte Pleno Verano, San Diego, California 92130 (US). patent (Rule 4.17(U)) (74) Agent: MEIKLEJOHN, Anita, L.; Fish & Richardson Published: RC, P.O. Box 1022, Minneapolis, Minnesota 55440-1022 — without international search report and to be republished (US). upon receipt of that report — with sequence listing part of description published sep a (81) Designated States (unless otherwise indicated, for every rately in electronic form and available upon request from kind of national protection available): AE, AG, AL, AM, the International Bureau (54) Title: TECHNOLOGY FOR THE PREPARATION OF MICROPARTICLES (57) Abstract: Microspheres are produced by contacting a solution of a macromolecule or small molecule in a solvent with an antisolvent and a counterion, and chilling the solution. The microspheres are useful for preparing pharmaceuticals, nutraceuticals, cosmetic products and the like of defined dimensions. Technology for the Preparation of Microparticles RELATED APPLICATIONS Priority is claimed herein to U.S. provisional patent application Serial No. 60/961 ,872, entitled "TECHNOLOGY FOR THE PREPARATION OF MICROPARTICLES" to Fang et al. filed July 24, 2007. The subject matter of the provisional application is incorporated by reference herein. This application is related to U.S. Application No. (Attorney Dkt. No. 2 1865- 005001/6505) filed on the same day herewith. The subject matter of the U.S. application is incorporated by reference herein. This application also is related to International PCT Application Serial No. (Attorney Docket No. 2 1865-004WO1/6504PC, filed January 24, 2007), and to U.S. Application Serial No. 11/657,81 2 , filed January 24, 2007 (Attorney Docket No. 21865-004001/6504). This application also is related to published U.S. applications Serial Nos. US20050004020 A 1 and US200501 12751 A 1. Each of these applications is incorporated by reference herein in its entirety. INCORPORATION BY REFERENCE OF SEQUENCE LISTING FILED ELECTRONICALLY An electronic version of the Sequence Listing is filed herewith, the contents of which are incorporated by reference in their entirety. The computer-readable file is 46 kilobytes in size and titled 6505SEQ.WO1 .txt. BACKGROUND The preparation and delivery of compounds of interest in powder or particle form is an area of concentrated research and development activity in a variety of industries, including the pharmaceutical, nutraceutical and cosmetic industries. For optimal efficacy, it is desirable to have a uniform formulation of the compound, whether it is a small molecule, such as a steroid hormone or penicillin antibiotic, or a macromolecule, such as a protein or nucleic acid. For example, for pulmonary administration of a compound, such as a therapeutic protein, antibiotic or chemotherapeutic agent, the compound ideally should be 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 microparticles to have as high a content of the compound as possible, in a form that maintains its activity for concentrated delivery and therapeutic efficacy. Previous methods of producing microparticles or nanoparticles of compounds 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 such methods include processing steps, such as heating, that inactivate the compounds and compromise their activity (e.g., denaturation of a protein). In addition, some methods do not provide a quantitative recovery of the compound from solution into the solid microparticle formulation. Other methods, such as directly precipitating a compound out of solution by adding an antisolvent, can generate microparticles in an uncontrolled manner that results in uneven-sized and/or aggregated microparticles. Accordingly, there is a need for a method for producing protein and other macromolecular microparticles, and small-molecule microparticles, which 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 of a compound that contain high concentrations of the compound relative to other components of the microparticles, 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 inactive compound. There also is a need for a method of producing microparticles of compounds where substantially all of the compound present in the starting material (e.g., a solution of the compound) is recovered in the microparticle formulation, with minimal loss. There also is a need for microparticles containing these properties for administration, for example, as a therapeutic or nutritional supplement, or in a cosmetic product. SUMMARY The methods of making a microparticle, the microparticles 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 for producing microparticles of a compound, which do not require complex or specialized equipment and that produce uniform-sized microparticles for delivery. Also provided herein are methods of producing microparticles of a compound that contain high concentrations of the compound relative to other components of the microparticles, 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 inactive compound. Also provided are methods of producing microparticles of compounds where substantially all of the compound present in the starting material is recovered in the microparticle formulation, with minimal loss. Also provided are methods of producing microparticle containing a carrier that facilitates the formation of microspheres containing the molecule that is the active agent or therapeutic agent of interest, or promotes stability of the resulting microspheres, or facilitates transportation of the resulting microsphere to the target (cells, tissues, etc.) of interest. In some embodiments, the carrier can be a material, such as gelatin or dextran, which is capable of forming a hydrogel. Further, provided herein are microparticles containing these properties for administration, for example, as a therapeutic or nutritional supplement, as a diagnostic or in a cosmetic product. The methods of making the microparticles of the compounds, including macromolecular microparticles and small-molecule microparticles, the 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. The methods provided herein can include the steps of: a) adding a counterion to a solution containing the compound in a solvent; b) adding an antisolvent to the solution; and c) gradually cooling the solution to a temperature below about 25 °C, whereby a composition containing microparticles of the compound is formed, In the method, steps a), b) and c) can be performed simultaneously, sequentially, intermittently, or in any order. In some examples, the counterion is not a polymer. In further examples, the antisolvent is not a polymer. The temperature at which the steps are performed also can be altered. In some embodiments, the compound is dissolved in the solvent at a temperature of about or at 30 °C or below prior to step a). In other embodiments, the compound is dissolved in the solvent at a temperature of about or at 25 °C or below.
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