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(12) United States Patent (10) Patent No.: US 8,232,322 B2 East Et Al

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(12) United States Patent (10) Patent No.: US 8,232,322 B2 East Et Al US008232322B2 (12) United States Patent (10) Patent No.: US 8,232,322 B2 East et al. (45) Date of Patent: Jul. 31, 2012 (54) HIGH MOLECULAR WEIGHT POLYMERS, FOREIGN PATENT DOCUMENTS DEVICES AND METHOD FOR MAKING AND EP O51 1292 B1 4/2000 USING SAME GB 2226821 A 7, 1990 WO WO 89.01005 2, 1989 WO WOO1/41753 6, 2001 (75) Inventors: Anthony East, New Brunswick, NJ WO WO 03/046034 6, 2003 (US); Alan Letton, New Brunswick, NJ (US); Suseela Kanamathareddy, New OTHER PUBLICATIONS Brunswick, NJ (US); Bryant J. Pudil, Peter Pinther, Manfred Hartmann, Synthesis of Polyanyhdrides con New Brunswick, NJ (US); Stephen taining ester groups, May 21, 1990, Makromol. Chem. Rapid. Com Goodrich, New Brunswick, NJ (US); mun. 11.403-408, (1990.* Michael B. Hicks, New Brunswick, NJ Domb, et al., “Biodegradable Polymers Derived from Amino Acids.” Polymer Preprints, Division of Polymer Chemistry, ACS, 30(2), 189 (US); Yun Choe, New Brunswick, NJ 190, (1989). (US) Domb, et al., “Excretion of a radiolabelled anticancer biodegradable polymeric implant from the rabbit brain.” Biomaterials, 16, 1069 (73) Assignee: Rutgers, The State University of New 1072, (1995). Domb, et al., “Poly(anhydrides). 2. One-Step Polymerization using Jersey, New Brunswick, NJ (US) Phosgene or Diphosgene as Coupling Agents'. Macromolecules, 21. 1925-1929, (1988). (*) Notice: Subject to any disclaimer, the term of this Erdmann, L., et al., “Degradable poly(anhydride ester) Implants: patent is extended or adjusted under 35 effects of localized salicylic acid release on bone'. Biomaterials, 21. U.S.C. 154(b) by 333 days. 2507-2512, (2000). Kricheldorf, et al., “Polyanhydrides, XI. Poly(ester-anhydride)s (21) Appl. No.: 12/500,438 Derived from 4-Hydroxybenzoic Acid, Vanillic Acid and Aliphatic Dicarboxylic Acids.” J.M.S.—Pure Appl. Chem. A35(2), 359-373, (1998). (22) Filed: Jul. 9, 2009 Leong, et al., “Synthesis of Polyanhydrides: Melt-Polycondensation, Prior Publication Data Dehydrochlorination, and Dehydrative Coupling” Macromolecules, (65) 20, 705-712 (1987). US 2010/O152410 A1 Jun. 17, 2010 Pinther P. et al., “Synthesis of polyanhydrides containing ester groups', Makromol. Chem. Rapid Commun. I I, 403-408, (1990). Related U.S. Application Data Patent Cooperation Treaty, International Searching Authority, Inter national Search Report for PCT/US2004/17916, 2 pages, Aug. 24. (62) Division of application No. 10/861,881, filed on Jun. 4, 2005. 2004, now Pat. No. 7,662,864. Patent Cooperation Treaty, International Preliminary Report on Pat entability for PCT/US2004/17916, 19 pages, Feb. 8, 2006. (60) Provisional application No. 60/475,766, filed on Jun. Domb et al., “Biodegradable polymers derived from amino acids”. 4, 2003. Biomaterials, vol. 11, pp. 686-689, 1990. Erdmann, et al., “Synthesis and degradation characteristics of (51) Int. C. Salicylic acid-derived poly(anhydride-esters). Biomaterials, 21, pp. A6 IK 47/32 (2006.01) 1941-1946, 2000. A6 IK3I/43 (2006.01) Kumar et al., “Polyanhydrides: an overview”. Advanced Drug Deliv (52) U.S. Cl. ..................... 514/772.5: 514/197; 514/201; ery Reviews, 54, pp. 889-910, 2002. 514/567 * cited by examiner (58) Field of Classification Search .................. 514/197, 514/201,567 Primary Examiner — Michael G. Hartley See application file for complete search history. Assistant Examiner — Jagadishwar Samala (74) Attorney, Agent, or Firm — Viksnins Harris & Padys (56) References Cited PLLP U.S. PATENT DOCUMENTS (57) ABSTRACT 4,757,128 A 7, 1988 Domb et al. 4,857,311 A 8, 1989 Domb et al. Anhydride polymers that release active or activatable agent(s) 4,886,870 A 12/1989 D'Amore et al. have pre-selected properties such as molecular weight, flex 4,888,176 A 12/1989 Langer et al. ibility, hardness, adhesiveness, and other valuable properties. 4,916,204 A 4, 1990 Domb et al. The polymers are Suitable for use in compositions, formula 4,933,431 A 6, 1990 Domb et al. 4,997,904 A 3, 1991 Domb tions, coatings, devices, and the like that benefit from the 4,999,417 A 3, 1991 Domb controlled release of an agent(s) over a period of time. The 5,019,379 A 5, 1991 Domb et al. polymers are prepared by a process involving various alter 5,264,540 A 1 1/1993 Cooper et al. native and sequential steps that allow the design a priori of 5,902,599 A 5, 1999 Anseth et al. products with specific characteristics. The polymers are Suit 6,486,214 B1 * 1 1/2002 Uhrich ....................... 514,772.5 7,411,031 B2 8, 2008 Uhrich et al. able as delivery systems, either by themselves, as composi 7,662,864 B2 2/2010 Kanamathareddy et al. tions, formulations or devices. 2003, OO86895 A1 5, 2003 Hanes et al. 2008/0234235 A1 9, 2008 Uhrich et al. 18 Claims, 1 Drawing Sheet US 8,232,322 B2 1. 2 HIGH MOLECULAR WEIGHT POLYMERS, three main synthetic routes. In the first method, a mixed DEVICES AND METHOD FOR MAKING AND anhydride is prepared by reaction of a diacid with a low USING SAME molecular weight aliphatic acid anhydride, e.g. acetic or pro pionic acid, and the mixed anhydride is heated under reduced RELATED APPLICATIONS pressure to form a polyanhydride in the molten state. Because of its low molecular weight, the acid anhydride may be dis This application is a divisional of and also claims priority carded as a Volatile by-product. to U.S. application Ser. No. 10/861,881, filed Jun. 4, 2004 and A second method involves reacting stochiometric amounts U.S. Provisional Application Ser. No. 60/475,766, filed Jun. of an acid chloride of a diacid with a free diacid in the 4, 2003, which are hereby incorporated by reference herein 10 presence of an acid-acceptor, e.g. triethylamine, to generate a their entireties. polyanhydride. A third method relies on the polymerization-dehydration FIELD OF THE INVENTION of a diacid with a dehydrating agent Such as phosgene, diphosgene, triphosgene, or organophosphorus derivative, to This invention relates to novel polymers that release active 15 or activatable compounds having desirable properties, such as obtain a pre-polyanhydride that is then polymerized. high molecular weight (MW), rigidity, stability, flexibility, Each of these methods, however, has disadvantages. The adhesiveness, temperature range, etc. These polymers are synthesis of polyanhydride-esters by melt condensation poly useful for delivering compounds in situ, preventing and treat merization using a pre-polymer intermediate is generally ing diseases, coating and protecting Surfaces and articles, and conducted at high temperature, e.g. about 180 C, under for multiple other applications. vacuum. The increasing viscosity of the polymer melt as the reaction proceeds slows polymerization considerably and BACKGROUND results in polymers of low molecular weight. Moreover, por tions of the polymer melt undergo local decomposition due to The safe and effective delivery of an active agent(s) to a 25 the occurrence of localized high temperatures and incomplete specific location enables a site-specific delivery that generally mixing, and produce undesirable brownish polymers. is associated with lesser side effects than more widespread Certain applications require the use of resilient materials delivery. Site-specific delivery is particularly desirable for the and tenacious films that require polymers of Substantial treatment of localized health conditions such as cancer, car molecular weight (MW), many times in excess of 100,000 diovascular disease, orthopedic conditions, dental condi 30 Dalton. As is known in the art, the physical characteristics of tions, wounds and auto-immune diseases such as arthritis or a polymer depend on its molecular structure; discreet mono gastrointestinal (G.I.) conditions. Such site-specific delivery mer units of regular structure tend to form crystalline or is also desirable for the protection of inanimate products semi-crystalline materials, whereas polymers of irregular including marine, construction, and articles that are exposed structure Such as random copolymers tend to be amorphous. to water and biological contamination, among others. The use 35 For other applications, polymers need to be solvent-cast into of polymers for drug delivery began in the 1960s as con tough films or coatings, or molded under pressure into shaped trolled-release oral formulations of an agent coated with a articles, and then Subjected to sterilization by ionizing radia non-therapeutic polymer. Many such formulations, however, tion or electron beam bombardment, which seriously affect induce inflammation or host responses at the delivery site, or the polymer’s molecular weight. It has heretofore been prob have low and/or unpredictable potency, breakdown products, 40 lematic to increase a polymer’s molecular weight while non-zero-order release rates, burst effects (drug delivery retaining other desirable qualities. These polymers either fail spikes), or other untoward effects. to achieve a desired molecular weight, or form insoluble gels Devices such as stents, grafts, implants, and Surgical and requiring extensive heating in the melt, or develop a high wound healing devices frequently induce, or are associated polydispersity index (MW/Mn), or both, due to the occur with, undesirable side effects that include pain, inflammation, 45 rence of side reactions. In the case of step-growth polymers, Swelling, infection, adjacent tissue hyperproliferation, cap the polydispersity index (MW/Mn) often greatly exceeds a Sule, and foreign body response, such as granuloma or theoretical value of 2.0, possibly due to chain branching fibroma formation Surrounding an implant. Although more and/or interference from large ring macrocyclic oligomers. biocompatible polymer coatings and other Surface technolo Thus, there is a need for polymers, and for drug and other gies were developed in order to reduce these effects, the 50 formulations and medical devices employing them, that polymers employed are either not biodegradable, or are inher exhibit a range of improved characteristics such as flexibility ently highly inflammatory and unpredictable in nature.
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