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(12) United States Patent (10) Patent No.: US 8,623,419 B2 Malakhov Et Al

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(12) United States Patent (10) Patent No.: US 8,623,419 B2 Malakhov Et Al USOO8623419B2 (12) United States Patent (10) Patent No.: US 8,623,419 B2 Malakhov et al. (45) Date of Patent: Jan. 7, 2014 (54) TECHNOLOGY FOR PREPARATION OF WO 2004/047735 6, 2004 MACROMOLECULAR MICROSPHERES WO WO2005/035088 4/2005 WO 2006/031291 3, 2006 (75) Inventors: Michael P. Malakhov, San Francisco, CA (US); Fang Fang, Rancho Santa Fe, OTHER PUBLICATIONS CA (US) US 5,849,884, 11/09/99, Woiszwillo et al (withdrawn). Agrawal et al., “Basis of rise in intracellular sodium in airway hyper (73) Assignee: Ansun Biopharma, Inc., San Diego, CA responsiveness and asthma.” Lung, 183:375-387. (2005). (US) Alcock, R., et al., “Modifying the release of leuprolide from spray dried OED microparticles,” Journal of Control Release, 82(2-3):429 (*) Notice: Subject to any disclaimer, the term of this 440, (2002). patent is extended or adjusted under 35 Barbey-Morel, C.L., et al., “Role of respiratory tract proteases in U.S.C. 154(b) by 0 days. infectivity of influenza A virus,” Journal of Infectious Diseases, 155:667-672, (1987). (21) Appl. No.: 13/289,644 Bot A.I. et al., “Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract.” Phar (22) Filed: Nov. 4, 2011 maceutical Research, 17(3):275-283, (2000). (65) Prior Publication Data Cryan S.A., "Carrier-based strategies for targeting protein and peptide drugs to the lungs.” American Association of Pharmaceutical US 2012/O116062 A1 May 10, 2012 Scientists PharmSci AAPS electronic resource), 7(1): E20-E41, (2005). Edwards D.A. et al., "Large porous particles for pulmonary drug Related U.S. Application Data delivery.” Science, 276(5320): 1868-1871, (1997). Garcia-Contreras, L., et al., “Evaluation of novel particles as pulmo (63) Continuation of application No. 12/633,773, filed on nary delivery systems for insulin in rats.” American Association of Dec. 8, 2009, now abandoned, which is a continuation Pharmaceutical Scientists PharmSci AAPS electronic resource, of application No. 1 1/657,812, filed on Jan. 24, 2007, 5(2): E9, (2003). now abandoned. Goger, B., et al., “Different affinities of glycosaminoglycan oligosac charides for monomeric and dimeric interleukin-8: a model for (60) Provisional application No. 60/762.002, filed on Jan. chemokine regulation at inflammatory sites. Biochemistry, 24, 2006. 41: 1640-1646, (2002). Grenha A. et al., “Microencapsulated chitosan nanoparticles for lung (51) Int. Cl. protein delivery.” European Journal of Pharmaceutical Sciences, A6 IK38/43 (2006.01) 25(4-5):427-437, (2005). A6 IK 9/14 (2006.01) Huntington, J.A., et al., “Structure of a serpin-protease complex A 6LX 9/19 (2006.01) shows inhibition by deformation.” Nature, 407:923-926, (2000). (52) U.S. Cl. Ito, T., “Interspecies transmission and receptor recognition of influ USPC .......................... 424/499: 424/94.1: 514/21.2 enza A viruses.” Microbiology and Immunology, 44:423-430, (58) Field of Classification Search (2000). None Laube, B.L., “The expanding role of aerosols in Systemic drug deliv See application file for complete search history. ery, gene therapy, and vaccination. Respiratory Care, 50(9): 1161 1176, (2005). (56) References Cited Le Calvez, H., et al., “Biochemical prevention and treatment of viral infections—a new paradigm in medicine for infectious diseases.” U.S. PATENT DOCUMENTS Virology Journal. 1:12, (2004). LeBlond, J., et al., “The Serpin proteinase inhibitor 8: an endogenous 3,439,089 A 4, 1969 Cherkas et al. ............... 514f159 furin inhibitor released from human platelets.” Thrombosis and 5,033,252 A 7/1991 Carter ............................. 53.425 Haemostasis, 95:243-252, (2006). 5,052,558 A 10, 1991 Carter ...... ... 206,439 5,145,702 A 9, 1992 Stark et al. ... ... 426,531 (Continued) 5,323,907 A 6/1994 Kalvelage ....... ... 206,531 5,981,719 A 11/1999 WoiSZwillo et al. ... 530,410 6,051,256 A 4/2000 Platz et al. .................... 424/489 Primary Examiner — Marianne P Allen 6,063,910 A 5, 2000 Debenedetti et al. 6,090,925 A 7/2000 WoiSZwillo et al. .......... 530/410 (74) Attorney, Agent, or Firm — Fish & Richardson P.C. 2002fO142985 A1 10, 2002 Dwek et al. 2005, 0004020 A1 1/2005 Yu et al. .......................... 514/12 2005/O112751 A1 5/2005 Fang et al. ... 435,206 (57) ABSTRACT 2005/02341 14 A1 10, 2005 Lee ............................... 514,365 2007/0207210 A1 9, 2007 Brown et al. Microspheres are produced by contacting an aqueous solu tion of a protein or other macromolecule with an organic FOREIGN PATENT DOCUMENTS Solvent and a counterion, and chilling the solution. The CN 1729013 2, 2006 microspheres are useful for preparing pharmaceuticals of EP O542314 5, 1993 defined dimensions. WO WO9420856 9, 1994 WO 98.06.279 2, 1998 WO O1,28524 4/2001 11 Claims, No Drawings US 8,623.419 B2 Page 2 (56) References Cited Sellers, S.P. et al., “Drypowders of stable protein formulations from aqueous solutions prepared using Supercritical CO(2)-assisted OTHER PUBLICATIONS aerosolization.” Journal of Pharmaceutical Sciences, 90(6):785-797. (2001). Lee, M.K. and A.D. Lander, "Analysis of affinity and structural Shak, S., et al., “Recombinant human DNase I reduces the viscosity Selectivity in the binding of proteins to glycosaminoglycans: devel of cystic fibrosis sputum.” Proceedings of the National Academy of opment of a sensitive electrophoretic approach.” Proceedings of the Sciences of the United States of America, 87.9 188-9192 (1990). National Academy of Sciences of the United States of America, Sinha, V.R., etal, "Biodegradable microspheres for protein delivery.” 88:2768-2772, (1991). Journal of Controlled Release, 90(3):261-280, (2003). LiCalsi, C., et al., “A powder formulation of measles vaccine for Smyth, H. and A.J. Hickey, "Carriers in drug powder delivery. Impli aerosol delivery.” Vaccine, 19(17-19):2629-2636, (2001). 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Gumbleton, "Aerosols for Macromolecule Deliv Agents and Chemotherapy, 1470-1479, (2006). ery: Design Challenges and Solutions.” American Journal of Drug McKenna, B.J., et al., “Micrometer-sized spherical assemblies of Delivery, 2(3): 143-155, (2004). polypeptides and Small molecules by acid-base chemistry.” Vanbever, R. et al., “Formulation and physical characterization of Angewandte Chemie, 43(42):5652-5655, (2004). large porous particles for inhalation. Pharmaceutical Research, NexBio Featured by NIHNews Article. New Drugs Against Flu Seal 16(11): 1735-1742, (1999). of (articlecanbefoundat: www3.iniaid.nih.gov/news/focuson/flu? re Varki, A., “Selectins and other mammalian sialic acid-binding search/treatment?chen newdrugs.htm) (accessed on Jun. 12, 2007) lectins.” Current Opinion in Cell Biology, 4:257-266, (1992). (2004). Weisgraber, K.H., et al., “Human apolipoprotein E. Determination of Oh, M. and C.A. Mirkin, M. "Chemically tailorable colloidal par the heparin binding sites of apolipoprotein E3,” Journal of Biological ticles from infinite coordination polymers.” Nature, 438(7068):651 Chemistry, 261:2068-2076, (1986). 654, (2005). Witt, D.P. and A.D. Lander, “Differential binding of chemokines to Pages THER-1 to THER-28 of The Merck Index, 12th Edition, glycosaminoglycan Subpopulations. Current Biology, 4:394-400, Merck & Co. Rahway, N.J. (1996). (1994). Pfutzner, A., et al., “Pilot study with technosphere/PTH(1-34)—a Zhirnov, O.P. et al., “Cleavage of Influenza A Virus Hemagglutinin in new approach for effective pulmonary delivery of parathyroid hor Human Respiratory Epithelium Is Cell Associated and Sensitive to mone (1-34).” Hormone and Metabolic Research, 35(5):319-323, Exogenous Antiproteases,” Journal of Virology, 76:8682-8689, (2003). (2002). Potier, M., et al., “Fluorometric assay of neuraminidase with a Zhirnov, O.P. et al., “Protective effect of protease inhibitors in influ sodium (4-methylumbelliferyl-alpha-D-N-acetylneuraminate) Sub enza virus infected animals.” Archives of Virology, 73:263-272, strate.” Analytical Biochemistry, 94:287-296, (1979). (1982). US 8,623,419 B2 1. 2 TECHNOLOGY FOR PREPARATION OF temperature and that do not contain a significant amount of MACROMOLECULAR MICROSPHERES denatured protein. There also is a need for a method of pro ducing microparticles of proteins and other macromolecules RELATED APPLICATIONS wherein substantially all of the protein or macromolecule in the starting material is recovered in the microparticle formu This application is a continuation of U.S. application Ser. lation, with minimal loss. There also is a need for micropar No. 12/633,773, filed Dec. 8, 2009, now abandoned, which ticles of proteins or other macromolecules containing these claims priority to U.S. application Ser. No. 1 1/657,812, filed properties for administration, for example, as a therapeutic or Jan. 24, 2007, now abandoned, which claims priority to U.S. nutritional Supplement. provisional application No. 60/762.002, filed Jan. 24, 2006. 10 The prior applications are hereby incorporated by reference SUMMARY in their entireties. This application also is related to International PCT appli Provided herein are methods for producing protein and cation Application Serial No.
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