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(12) United States Patent (10) Patent No.: US 8,846,077 B2 A61K 95.146

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(12) United States Patent (10) Patent No.: US 8,846,077 B2 A61K 95.146 USOO8846077B2 (12) United States Patent (10) Patent No.: US 8,846,077 B2 DeWitt (45) Date of Patent: Sep. 30, 2014 (54) HIGH THROUGHPUT FABRICATION OF 6,291,013 B1 9, 2001 Gibson et al. NANOPARTICLES 6,485,690 B1 1 1/2002 Pfostet al. 6,551,619 B1 4/2003 Penkler et al. 2002fOO99051 A1 7/2002 Fidler et al. (71) Applicant: Bind Biosciences, Inc., Cambridge, MA 2003/0211164 A1 1 1/2003 Wright et al. (US) 2004/0247680 A1* 12/2004 Farokhzad et al. ........... 424/486 2004/0248778 Al 12/2004 Gloger et al. (72) Inventor: David M. Dewitt, Allston, MA (US) 2005/0142206 A1 6/2005 Brown et al. 2005/0276859 A1* 12/2005 Rickey et al. ................. 424/489 (73) Assignee: Bind Biosciences, Inc., Cambridge, MA 2007/00988O2 A1 5, 2007 Farret al. (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this & 8 patent is extended or adjusted under 35 OC Farokhzad, JM Karp, R Langer Nanoparticle aptamer U.S.C. 154(b) by 0 days. bioconjugates for cancer targeting.' Expert Opinion in Drug Deliv ery, vol. 3(3), 2006, pp. 311-324.* (21) Appl. No.: 13/716,275 E.M.M.D. Valle. “Cyclodextrins and Their Uses: A Review.” Process Biochemistry, vol.39, 2004, pp. 1033-1046.* (22) Filed: Dec. 17, 2012 Avgoustakis, K. “Pegylated Poly(Lactide) and Poly(Lactide-Co Glycolide) Nanoparticles: Preparation, Properties and Possible (65) Prior Publication Data Applications in Drug Delivery Current Drug Delivery, 2004, pp. US 2013/O123351A1 May 16, 2013 321-333to vol. 1. No. 4. s Ressing, M. E. et al. “The Influence of Sucrose, Dextran, and O O Hydroxypropyl-3-cyclodextrinas Lyoprotectants for a Freeze-Dried Related U.S. Application Data Mouse IgG Monoclonal Antibody (MN12) Pharmaceutical (63) Continuation of application No. 12/557,065, filed on Research, 1992, pp. 266-270, vol. 9, No. 2. Sep. 10, 2009, now abandoned. Gref, R. et al. “The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres' Advanced Drug (60) Provisional application No. 61/095,724, filed on Sep. Delivery Reviews, 1995, pp. 215-233, vol. 16. 10, 2008. Martin Del Valle, E. M. "Cyclodextrins and their uses: a review” Process Biochemistry, 2004, pp. 1033-1046, vol. 39. (51) Int. Cl. Farokhzad, O. C. et al. “Nanoparticle-aptamer bioconjugates for A 6LX 9/5 (2006.01) cancer targeting” Expert Opin. Drug Deliv, 2006, pp. 311-324, vol. B825/00 (2011.01) 3, No. 3. 46.3/00 (2006.01) A6 IK 47/48 (2006.01) * cited by examiner (52) U.S. Cl. CPC. A61JA61K 3/00 95.146 (2013.01); (2013.01); B82Y5/00 A61K (2013.01); 47/48969 Primary Examiner Frederick Krass (2013.01); A61 K9/5192 (2013.01); A61 K Assistant Examiner — Isaac Shomer 9/5153 (2013.01) (74) Attorney, Agent, or Firm — Saliwanchik, Lloyd & USPC ......................... 424/449; 514/449; 514/772.1 Eisenschenk (58) Field of Classification Search None See application file for complete search history. (57) ABSTRACT (56) References Cited This application provides a high throughput method of mak ing nanoparticles that utilizes plates comprising wells (e.g., U.S. PATENT DOCUMENTS 96-well plates). 5,654,008 A 8, 1997 Herbert et al. 5,869,103 A 2, 1999 Yeh et al. 29 Claims, 1 Drawing Sheet US 8,846,077 B2 1. 2 HIGH THROUGHPUT FABRICATION OF kDa molecular weight cutoff (MWCO) membrane to filter NANOPARTICLES out small particles like drug micelles (fine filtration). Indi vidual centrifuge filters can also be used if larger MWCO are CROSS-REFERENCE TO RELATED required. The fine filtration is performed in a centrifuge at APPLICATIONS 4000 rpm and at 4°C. until all liquid is filtered away. The particles can then be washed by diafiltration which involves This application is a continuation of U.S. Ser. No. 12/557, the addition of water or buffers to the filter plate and centrifu 065, filed Sep. 10, 2009, which claims the benefit of U.S. gation to remove the added water or buffers. This step can be, Provisional Application Ser. No. 61/095,724, filed Sep. 10, optionally, repeated 1, 2, 3, 4, 5, or 10 times to remove any 2008, the disclosure of which is hereby incorporated by ref 10 excess material including organic solvents not incorporated erence in its entirety, including all figures, tables and amino into the nanoparticles. After the final wash, the nanoparticles acid or nucleic acid sequences. can be resuspended in water or an aqueous solution, frozen This invention was made with United States Government using liquid nitrogen or lyophilized for future use. support under Cooperative Agreement Number First Stock Solution (Active Agents and Polymers) 70NANB7H7021 awarded by the National Institute of Stan 15 As discussed above, a first stock Solution comprising an dard and Technology (NIST). The United States Government organic phase which contains drug and polymers admixed has certain rights in the invention. with organic solvents is provided. Thus, the first stock solu tion can contain polymers comprising a targeting agent BRIEF SUMMARY OF THE INVENTION coupled to a PEG (poly(ethylene glycol)) polymer (via the C. terminus) that is then coupled to biocompatible and biode This application provides a high throughput method of gradable hydrophobic polymer (polyester) blocks. Alterna making nanoparticles that utilizes plates comprising wells tively, the polymer can comprise PEG coupled to biocompat (e.g., 96-well plates). ible and biodegradable hydrophobic polymer (polyester) blocks (without a targeting agent). Exemplary polyesters Suit BRIEF DESCRIPTION OF THE FIGURE 25 able for use in the disclosed methods copolymers comprising lactic acid and glycolic acid units, such as poly(lactic acid FIG.1—Illustration of high throughput process. co-glycolic acid) and poly(lactide-co-glycolide), collectively referred to herein as “PLGA'; and homopolymers compris DETAILED DISCLOSURE OF THE INVENTION ing glycolic acid units, referred to herein as “PGA.” and lactic 30 acid units, such as poly-L-lactic acid, poly-D-lactic acid, This application provides a high throughput method of poly-D.L-lactic acid, poly-L-lactide, poly-D-lactide, and making nanoparticles that utilizes plates comprising wells poly-D.L-lactide, collectively referred to herein as “PLA.” In (e.g., 96-well plates). In this aspect of the invention, Stock Some embodiments, exemplary polyesters include, for Solutions can be made which comprise: example, polyhydroxyacids; PEGylated polymers and a) a first stock solution comprising an oil phase which 35 copolymers of lactide and glycolide (e.g., PEGylated PLA, contains drug and polymers admixed with organic solvents; PEGylated PGA, PEGylated PLGA, and derivatives thereof. b) a second stock Solution comprising a Surfactant and In Some embodiments, polyesters include, for example, poly Solvents (typically an aqueous phase); anhydrides, poly(ortho ester) PEGylated poly(ortho ester), c) a third stock solution comprising a water or buffer poly(caprolactone), PEGylated poly(caprolactone), polyl quench; and 40 ysine, PEGylated polylysine, poly(ethylene inline), PEGy d) a fourth phase comprising a drug solubilizer. lated poly(ethylene imine), poly(L-lactide-co-L-lysine), poly In one aspect of the invention, an aqueous phase is first (serine ester), poly(4-hydroxy-L-proline ester), polya-(4- pipetted by hand or via a fluid handling robot into a standard aminobutyl)-L-glycolic acid, and derivatives thereof. Yet multi-well polypropylene plate (e.g., 250 u is pipetted into a other embodiments provide polymers that may be one or 96 well polypropylene plate). A stock Solution comprising an 45 more acrylic polymers. In certain embodiments, acrylic poly oil phase can then be pipetted into the aqueous phase already mers include, for example, acrylic acid and copolymers, present in the plate by hand or robot. The preferred water:oil methyl methacrylate copolymers, ethoxyethyl methacrylates, ratio is 5:1 but ranges from 1:1 to 1:15 will also form emul cyanoethyl methacrylate, aminoalkyl methacrylate copoly sions and can be used in this aspect of the invention. In certain mer, methacrylic acid alkylamide copolymer, poly(methyl embodiments, the stock Solution comprising an oil phase can 50 methacrylate), aminoalkyl methacrylate copolymer, glycidyl be added to the plate first and the stock solution comprising an methacrylate copolymers, polycyanoacrylates, and combina aqueous phase can be added to the Solution containing the oil tions comprising one or more of the foregoing polymers. The phase. Following the admixture of the first and second stock acrylic polymer may comprise fully-polymerized copoly Solutions, Sonication is performed on the combined Stock mers of acrylic and methacrylic acid esters. In some other Solutions to form an emulsion. The emulsion can then be 55 embodiments, polymers can be cationic polymers. In general, added to a high volume (1 or 2 or 5 mL per well) multi-well cationic polymers are able to condense and/or protect nega plate loaded with the third stock Solution comprising a water tively charged strands of nucleic acids (e.g. DNA, RNA, or or buffer quench and cooled to 4°C. The quench solution can derivatives thereof). Amine-containing polymers such as poly be, optionally, premixed with a drug solubilizer (e.g., (lysine) (Zauner et al., 1998, Adv. Drug Del. Rev., 30:97; and TWEEN-80 or Hydroxypropyl-beta-cyclodextrin) or a drug 60 Kabanov et al., 1995, Bioconjugate Chem., 6:7), poly(ethyl solubilizer can be added to the quench solution to dissolve ene imine) (PEI; Boussif et al., 1995, Proc. Natl. Acad. Sci., unencapsulated drug. USA, 1995, 92:7297), and poly(amidoamine) dendrimers In a further aspect of the invention, the nanoparticle solu (Kukowska-Latalo et al., 1996, Proc. Natl. Acad. Sci., USA, tion can then transferred to a multi-well filter plate for rough 93:4897: Tang et al., 1996, Bioconjugate Chem., 7:703; and filtration.
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