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(12) United States Patent (10) Patent No.: US 8,784,893 B2 Daniloff Et Al

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(12) United States Patent (10) Patent No.: US 8,784,893 B2 Daniloff Et Al US008784893B2 (12) United States Patent (10) Patent No.: US 8,784,893 B2 Daniloff et al. (45) Date of Patent: Jul. 22, 2014 (54) POLYMER FORMULATIONS FOR DELIVERY (56) References Cited OF BOACTIVE AGENTS U.S. PATENT DOCUMENTS (75) Inventors: George Daniloff, Los Altos, CA (US); 2002/01285 12 A1 9/2002 Bulpitt et al. David Gravett, Mountain View, CA 2005/0176620 A1 8, 2005 Prestwich et al. (US); Robert C. Spiro, Half Moon Bay, 2005/0256081 A1* 1 1/2005 Peyman .......................... 514/56 CA (US) 2006/0141049 A1* 6/2006 Lyons et al. .................. 424/489 (73) Assignee: Carbylan Therapeutics, Inc., Palo Alto, FOREIGN PATENT DOCUMENTS CA (US) WO WO 2005/056608 A 6, 2005 WO WO 2008/098O19 A3 8, 2008 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 1239 days. Ji (Biomaterials, 27. Published Mar. 23, 2006, pp. 3782-3792).* Ghosh et al. (Tissue Engineering, vol. 12, No. 3, Published 2006, pp. 601-613).* (21) Appl. No.: 12/526,027 Cai, et al., “Injectable glycosaminoglycan hydrogels for controlled release of human basic fibroblast growth factor'. Biomaterials, vol. (22) PCT Filed: Feb. 5, 2008 26, No. 30, pp. 6054-6067 (2005). Ghosh, et al., “Rheological characterization of in situ cross-linkable (86). PCT No.: PCT/US2O08/053108 hyaluranon hydrogels'. Biomacromolecules, vol. 6, No. 5, pp. 2857 2865 (2005). S371 (c)(1), International Search Report from PCT Patent Application No. PCT/ (2), (4) Date: Oct. 18, 2010 US2008/053108 Mailed Mar. 2, 2009, Published as International Publication No. WO 2008/098019 A3 on Aug. 14, 2008. Li, et al., “Synthesis and biological evaluation of a cross-linked (87) PCT Pub. No.: WO2008/098019 hyaluronan-mitomycin Chydrogel'. Biomacromolecules. Vol. 5, No. PCT Pub. Date: Aug. 14, 2008 3, pp. 895-902 (2004). Liu, et al., “Accelerated repair of cortical bone defects using a syn thetic extracellular matrix to deliver human demineralized bone (65) Prior Publication Data matrix”, J. Ortho. Res., vol. 24, No. 7, pp. 1454-1462 (2006). US 2011 FOO33540 A1 Feb. 10, 2011 Prestwich, et al., “Injectible synthetic extracellular matrices for tissue engineering and repair'. Adv, Exp. Med. Biol., vol. 585, pp. 125-133 (2006). O O Shu, et al., “Disulfide cross-linked hyaluranon hydrogels”, Related U.S. Application Data Biomacromolecules, vol. 3, No. 6, pp. 1304-1311 (2002). Shu, et al., “In-situ crosslinkable hyaluranon hydrogels for tissue (60) Provisional application No. 60/888,251, filed on Feb. engineering”. Biomaterials, vol. 25, No. 7-8, pp. 1339-1348 (2004). 5, 2007. Aragona et al., “Long term treatment with sodium hyaluronate-con taining artificial tears reduces ocular Surface damage in patients with (51) Int. Cl. dry eye'. Br. J. Opthalmol., vol. 86, pp. 181-184 (2002). A6 IK3I/58 (2006.01) A 6LX3L/75 (2006.01) * cited by examiner A6 IK9/00 (2006.01) Primary Examiner — Richard Schnizer A6L 27/52 (2006.01) Assistant Examiner — Alma Pipic A 6LX 9/19 (2006.01) (74) Attorney, Agent, or Firm — Susan T. Evans; McDermott A6IL 27/20 (2006.01) Will & Emery LLP A6 IK 47/36 (2006.01) (52) U.S. Cl. (57) ABSTRACT CPC ............... A61K 9/0024 (2013.01); A61L 27/52 Disclosed in the present application are compositions com (2013.01); A61 K9/19 (2013.01); A61L 27/20 prising a bioresorbable polymer matrix and a bio active agent, (2013.01); A61 K47/36 (2013.01) wherein the bioactive agent is dispersed within polymer USPC .............. 424/488; 424/489: 514/174: 514/54 matrix as a solid. Also provided herein are methods for pre (58) Field of Classification Search paring a bioactive agent formulation, wherein the agent is CPC .......... A61L 27/20: CO8L 5AO8 A61K47/36: presentina Solid formand, wherein the agent is occluded into A61K 9.0024. A61k 9/146 a polymeric matrix by polymerization of polymer matrix USPC ............................. 424ss, 486.54,745 precursors or by self assembly of the polymer. See application file for complete search history. 19 Claims, 6 Drawing Sheets U.S. Patent Jul. 22, 2014 Sheet 1 of 6 US 8,784,893 B2 Summary of A Release (mg) per Sampling Point 1 2 3 4 7 8 9 0 4 15, 18 7 18 2 22 23. 28 29 30 Sampling point (day) Figure 1 U.S. Patent Jul. 22, 2014 Sheet 2 of 6 US 8,784,893 B2 Percent Release for 10 mgiriaminolone Acetonide loaded Gels 1 2 3 4 5 6 8 g 10 2 13 15 16 18 20 21 22 23 sampling point day Figure 2 U.S. Patent Jul. 22, 2014 Sheet 3 of 6 US 8,784,893 B2 Percent Release for 20 mg Triarcino one Acetonide loaded Gels OO 90 SO 70 SO 50 40 30 | 20 1) 2 3 4 5 6 8 9 O 11 2 3 5 6 17 8 20, 21 22 23 sampling point (day) Figure 3 U.S. Patent Jul. 22, 2014 Sheet 4 of 6 US 8,784,893 B2 Percent Release for 40 mgiriamcinolone Acetonide Loaded Gels es 7O s re 5 O nea sia t t s w a. 2 3 4 5 6 8 9 0 1 2 3 5 S 17 8 20 21 22 23 sampling point (day) Figure 4 U.S. Patent Jul. 22, 2014 Sheet 5 of 6 US 8,784,893 B2 Preisbe a SX Reese Kiet (DPBS, 37°C, Charging Bifer Every 24 hrs, Two Repeats) es s s s : s s 3. s 50 3. stical Figure 5 U.S. Patent Jul. 22, 2014 Sheet 6 of 6 US 8,784,893 B2 Becomethasone Dipropionate Release kinetic (OPBS, 37°C, Changing Buffer Every 24 hrs, Average of Two Repeats) 30 40 50 so 70 s Eurs of scation Figure 6 US 8,784,893 B2 1. 2 POLYMER FORMULATIONS FOR DELVERY It is well known that the water insolubility of a number of OF BOACTIVE AGENTS important drugs, such as amphotericin B. phenyloin, micona Zole, cyclosporin, diazepam and etoposide, makes their for mulation for administration, such as by intravenous applica This application is a U.S. National Stage of International tion, particularly difficult. These drugs, for example, are Patent Application No. PCT/US2008/053108, filed Feb. 5, currently marketed in cosolvent systems such as polyethylene 2008, which claims the benefit of priority to U.S. Provisional glycol or propylene glycol-ethanol-benzyl alcohol mixtures. Application No. 60/888,251, filed Feb. 5, 2007, the contents However severe toxicity problems, such as thrombophlebitis, of all of which are hereby incorporated by reference in their have been observed with injectable formulations of drugs entireties. dissolved in cosolvents. Alternatives to cosolvent systems are 10 micellar Solutions or emulsions; however, the presence of FIELD OF THE INVENTION toxic Surfactants in those systems makes them undesirable for intravenous administration. Many pharmaceutically useful The present invention relates to methods and pharmaceu compounds have limited Solubility in physiological fluids. tical compositions comprising a polymer and a biologically Delivery of Such compounds presents a formulation chal active agentina Solid form for the administration and delivery 15 lenge and often requires use of hydrophobic carriers which of the biologically active agent. These compositions are use often present undesirable side effects when introduced in contact with the body. In addition, it is also difficult to modu ful as pharmaceutical agents. More particularly, the present late the pharmacodynamic and pharmacokinetic characteris application relates to polymer compositions comprising Solid tics of such formulations in vivo. Therefore a continuing need hydrophobic biologically active agents. exists for novel, stable and nontoxic formulations and com positions for the delivery of hydrophobic drugs. BACKGROUND OF THE INVENTION The present application describes a composition that ulti lizes a biocompatible matrix (hydrophilic or hydrophobic) Available vehicles for the administration of hydrophobic containing a solid form of bioactive agent dispersed in it. drugs, such as water-insoluble or low water soluble com 25 Depending on the size (Surface) of the bioactive agent par pounds often result in undesirable side-effects. Such undes ticles and the nature of the polymeric matrix (i.e. hydrogel, ired side-effects include hemolysis, thrombophlebitis or at elastomer, Solid polymer, hydratable dry polymer, and bio times, blood coagulation. Liposomes and oil-in-water emul degradation properties) the rate of said bioactive agent release sions have been employed as potential carriers for these and duration of the release in vivo may be modulated in much hydrophobic drugs that may reduce Such undesirable side 30 wider range than currently know in the art. In one aspect, the effects. However, there remain significant problems associ formulations described in this application enable new safer ated with stability and drug loading capacity associated with therapeutic products for clinical use. the use of these delivery systems. Implantable medical devices or compositions for the deliv SUMMARY OF THE INVENTION ery of biologically active agents are known in the art. How 35 ever, the placement of metal or polymeric devices in the body The application provides a novel composition of matter are useful for treating a variety of medical conditions, but comprising a solid form(s) of a bioactive agent(s) and a bio often results in complications. These complications may compatible polymer matrix. In one embodiment, there is pro include increased risk of infection, inflammation, fibrous vided a biocompatible polymer matrix that may be used as an encapsulation, and potentially a wound healing response 40 implantable device, wherein the device comprises polymer resulting in hyperplasia and restenosis. materials having inherent properties or biological activity that One approach to reducing these adverse affects is to pro be enhanced when employed in conjunction with the biologi vide biocompatible implantable devices.
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