(12) Patent Application Publication (10) Pub. No.: US 2009/0098207 A1 Malakhov Et Al
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US 20090098207A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0098207 A1 Malakhov et al. (43) Pub. Date: Apr. 16, 2009 (54) TECHNOLOGY FOR THE PREPARATION OF Related U.S. Application Data MCROPARTICLES (60) Provisional application No. 60/961,872, filed on Jul. 24, 2007. (75) Inventors: Michael Malakhov, San Diego, CA s (US); Fang Fang, San Diego, CA Publication Classification (US) (51) Int. Cl. A6IR 9/14 (2006.01) Correspondence Address: A6IR 8/02 (2006.01) FISH & RICHARDSON, PC (52) U.S. Cl. ........................................................ 424/489 P.O. BOX 1022 MINNEAPOLIS, MN 55440-1022 (US) (57) ABSTRACT Microspheres are produced by contacting a solution of a (73) Assignee: NexBio, Inc., San Diego, CA (US) macromolecule or Small molecule in a solvent with an anti Solvent and a counterion, and chilling the solution. The (21) Appl. No.: 12/179,520 microspheres are useful for preparing pharmaceuticals, nutraceuticals, cosmetic products and the like of defined (22) Filed: Jul. 24, 2008 dimensions. US 2009/00982O7 A1 Apr. 16, 2009 TECHNOLOGY FOR THE PREPARATION OF an antisolvent, can generate microparticles in an uncontrolled MICROPARTICLES manner that results in uneven-sized and/or aggregated micro particles. RELATED APPLICATIONS 0006. Accordingly, there is a need for a method for pro 0001. This application claims priority under 35 U.S.C. ducing protein and other macromolecular microparticles, and S119(e) to U.S. provisional application Ser. No. 60/961,872, Small-molecule microparticles, which does not require com entitled TECHNOLOGY FOR THE PREPARATION OF plex or specialized equipment and that produces uniform MICROPARTICLES” to Fang et al. filed Jul. 24, 2007. The sized microparticles for delivery. There further is a need for a Subject matter of the provisional application is incorporated method of producing microparticles of a compound that con in its entirety by reference herein. This application also is tain high concentrations of the compound relative to other related to International PCT Application No. (Attorney Dkt. components of the microparticles, that are stable and main No. 21865-005WO1/6505PC) filed on the same day here tain their activity for long periods of time when stored at with. The subject matter of the PCT application is incorpo ambient temperature, and that do not contain a significant rated by reference herein. amount of inactive compound. There also is a need for a 0002 This application is related to International PCT method of producing microparticles of compounds where Application Serial No. (Attorney Docket No. 21865 Substantially all of the compound present in the starting mate 004WO1/6504PC, filed Jan. 24, 2007), and to U.S. applica rial (e.g., a solution of the compound) is recovered in the tion Ser. No. 1 1/657,812, filed Jan. 24, 2007 (Attorney microparticle formulation, with minimal loss. There also is a Docket No. 21865-004001/6504). This application also is need for microparticles containing these properties for related to published U.S. applications Serial Nos. administration, for example, as a therapeutic or nutritional US2005.0004020A1 and US2005O112751 A1. Each of these Supplement, or in a cosmetic product. applications is incorporated by reference herein in its entirety. SUMMARY INCORPORATION BY REFERENCE OF 0007. The methods of making a microparticle, the micro SEQUENCE LISTING FILED particles themselves, combinations, and articles of manufac ELECTRONICALLY ture provided below are characterized by a variety of compo nent ingredients, steps of preparation, and biophysical, 0003. An electronic version of the Sequence Listing is physical, biochemical and chemical parameters. As would be filed herewith, the contents of which are incorporated by apparent to one of skill in the art, the compositions and reference in their entirety. The computer-readable file, cre methods provided herein include any and all permutations ated on Jul. 24, 2008, is 46 kilobytes in size and titled and combinations of the ingredients, steps and/or parameters 21865.005001 SeqList.txt. described below. 0008 Provided herein are methods for producing micro BACKGROUND particles of a compound, which do not require complex or 0004. The preparation and delivery of compounds of inter specialized equipment and that produce uniform-sized micro est in powder or particle form is an area of concentrated particles for delivery. Also provided herein are methods of research and development activity in a variety of industries, producing microparticles of a compound that contain high including the pharmaceutical, nutraceutical and cosmetic concentrations of the compound relative to other components industries. For optimal efficacy, it is desirable to have a uni of the microparticles, that are stable and maintain their activ form formulation of the compound, whether it is a small ity for long periods of time when stored at ambient tempera molecule. Such as a steroid hormone or penicillin antibiotic, ture, and that do not contain a significant amount of inactive or a macromolecule. Such as a protein or nucleic acid. For compound. Also provided are methods of producing micro example, for pulmonary administration of a compound. Such particles of compounds where substantially all of the com as atherapeutic protein, antibiotic or chemotherapeutic agent, pound present in the starting material is recovered in the the compound ideally should be prepared in the form of microparticle formulation, with minimal loss. Also provided discrete microspheres, which are solid or semi-solid particles are methods of producing microparticle containing a carrier having a diameter of between 0.5 and 5.0 microns. It also is that facilitates the formation of microspheres containing the desirable for the microparticles to have as high a content of molecule that is the active agent or therapeutic agent of inter the compound as possible, in a form that maintains its activity est, or promotes stability of the resulting microspheres, or for concentrated delivery and therapeutic efficacy. facilitates transportation of the resulting microsphere to the 0005 Previous methods of producing microparticles or target (cells, tissues, etc.) of interest. In some embodiments, nanoparticles of compounds have involved complex steps, the carrier can be a material. Such as gelatin or dextran, which Such as blending with organic polymers and/or forming a is capable of forming a hydrogel. Further, provided herein are lattice array with polymers; spray drying, spray freeze-drying microparticles containing these properties for administration, or Supercritical fluid antisolvent techniques that use special for example, as a therapeutic or nutritional Supplement, as a ized and complex equipment; or lyophilization followed by diagnostic or in a cosmetic product. pulverization or milling that often results in non-uniform 0009. The methods of making the microparticles of the particles that must further be sorted. Often such methods compounds, including macromolecular microparticles and include processing steps, such as heating, that inactivate the Small-molecule microparticles, the compositions themselves, compounds and compromise their activity (e.g., denaturation combinations and articles of manufacture provided below are of a protein). In addition, Some methods do not provide a characterized by a variety of component ingredients, steps of quantitative recovery of the compound from Solution into the preparation, and biophysical, physical, biochemical and solid microparticle formulation. Other methods, such as chemical parameters. As would be apparent to one of skill in directly precipitating a compound out of Solution by adding the art, the compositions and methods provided herein US 2009/00982O7 A1 Apr. 16, 2009 include any and all permutations and combinations of the or at 1000 or 1000 to about or at 200,000 or 200,000 Daltons; ingredients, steps and/or parameters described below. about or at 1000 or 1000 to about or at 100,000 or 100,000 0010. The methods provided herein can include the steps Daltons; about or at 1000 or 1000 to about or at 50,000 or of: 50,000 Daltons; about or at 1000 or 1000 to about or at 25,000 0.011 a) adding a counterion to a solution containing the or 25,000 Daltons; about or at 1000 or 1000 to about or at compound in a solvent; 15,000 or 15,000 Daltons; about or at 1000 or 1000 to about 0012 b) adding an antisolvent to the solution; and or at 10,000 or 10,000 Daltons; about or at 1000 or 1000 to 0013 c) gradually cooling the solution to a temperature about or at 5,000 or 5,000 Daltons; about or at 1000 or 1000 below about 25°C., to about or at 3,000 or 3000 Daltons; or about or at 1000 or whereby a composition containing microparticles of the com 1000 to about or at 2,000 or 2000 Daltons. pound is formed. In the method, steps a), b) and c) can be performed simultaneously, sequentially, intermittently, or in 0018. The macromolecule can be a polynucleotide, a any order. nucleic acid, a polypeptide, a glycopeptide, a protein, a car 0014. In some examples, the counterion is not a polymer. bohydrate, a lipid, a fatty acid, a polysaccharide, carbohy In further examples, the antisolvent is not a polymer. The drate- or polysaccharide-protein conjugate, virus, virus par temperature at which the steps are performed also can be ticle, viroid, prion or mixture thereof. In other examples, the altered. In some embodiments, the compound is dissolved in macromolecule is a hormone, prostaglandin, antibiotic, che the solvent at a temperature of about or at 30° C. or below motherapeutic agent, hematopoietic, anti-infective agent, prior to step a). In other embodiments, the compound is antiulcer agent, antiallergic agent, antipyretic, analgesic, dissolved in the solvent at a temperature of about or at 25°C. anti-inflammatory agent, antidementia agent, antiviral agent, or below. In one aspect, none of the solutions of steps a)-c) are antitumor agent, antidepressant, psychotropic agents, cardio heated and/or maintained at a temperature above about or at tonics, diuretic, antiarrhythmic agent, vasodilator, antihyper 30°C.