USOO6613807B2 (12) United States Patent (10) Patent No.: US 6,613,807 B2 Uhrich (45) Date of Patent: *Sep. 2, 2003 (54) THERAPEUTIC POLYANHYDRIDE DE 288387 3/1991 ........... CO8G/67/04 COMPOUNDS FOR DRUG DELIVERY EP O246341 11/1987 ........... A61 L/27/00 EP O 246 341 * 11/1987 (75) Inventor: Kathryn E. Uhrich, Hoboken, NJ (US) NL 9000237 8/1991 .......... A61 K/31/60 WO WO 90/09779 9/1990 ............ A61K/7/16 WO 91/O9831 * 7/1991 (73) ASSignee: ST'State tly, New W. WO-91/09831 7/1991 ......... CO7C/69/035 ersey, New Brunswick, NJ (US) WO WO-97/39738 10/1997 ... A61 K/9/16 (*) Notice: Subject to any disclaimer, the term of this W Wo: to r : patent is extended or adjusted under 35 WO 99/12990 * 3/1999 U.S.C. 154(b) by 0 days. WO WO-99/29885 6/1999 ............. C12P/1/OO This patent is Subject to a terminal dis OTHER PUBLICATIONS claimer. Anastasiou, T.J. "Novel Polyanhydrides with Enhanced Thermal and Solubility Properties”, Macromolecules, 33 (21) Appl. No.: 09/917,231 (17), (2000).pp, 6217–6221. Anastasiou, T.J. "Novel, Degradable Polyanhydrides”, (22) Filed: Jul. 27, 2001 25th Annual Meeting Transactions of the Society for Bio (65) Prior Publication Data materials, Abstract,(1999).p, 79, Anastasiou, T.J. "Synthesis of Novel, Degradable Polyan US 2002/0098161 A1 Jul. 25, 2002 hydrides Containing Para-AminoSalicylic Acid as Drug Delivery Devices for Tuberculosis Treatment', Polymer Related U.S. Application Data Preprints, 41(2), (Aug. 2000),pp. 1366–1367. Attawia, M.A. "Biocompatibility Testing of Poly(anhy (63) Continuation-in-part of application No. 09/627.215, filed on dride-co-imides) Containing Pyromellitylimidoalanine”, Jul. 27, 2000. The 21st Annual Meeting of the Society for Biomaterials, (51) Int. Cl....................... A61K 47/32; A61K 31/195; Abstract.(1994).p. 222. A61K 31/43; A61K 31/74 Attawia, M.A. "Cytotoxicity testing of poly(anhydride (52) U.S. Cl. .................... 514/772.5; 514/197; 514/201; co-imides) for Orthopedic applications”, Journal of Bio 514/567; 424/78.08 medical Materials Research, 29, (1995),pp. 1233-1240. (58) Field of Search .............................. 514/772.5, 197, Attawia, M.A. “In Vitro Bone Biocompatibility of Poly 514/201,567; 424/428, 427, 78.08, 409, (anhydride-co-imides) Containing Pyromellitylimidoala 420 nine”, Journal of Orthopedic Research, 14, (1996),pp. 445-454. (56) References Cited Attawia, M.A. "Proliferation, Morphology, and Protein Expression by Osteoblasts Cultured on Poly(anhydrideco-a- U.S. PATENT DOCUMENTS mides)”, J. Biomed. Mater. Res. (Appl. Biomater), 48, 4,062.855 A 12/1977 Allan et al. ............ 260/295 PA (1999), pp. 322–327. 4,126,445. A 11/1978 Allan et al. .................... 71/94 Attawia, M.A., “Regional drug delivery with radiation for 4,684,620 A 8/1987 Hruby et al. ................. 514/11 the treatment of Ewing's Sarcoma-In Vitro development of 4,757,128 A 7/1988 Domb et al. ... ... 528/271 a taxol release system”, Journal of Controlled Release, 71, 4,792.598 A 12/1988 Ziegast ......... ... 528/2O6 (2001),pp. 193–202. 4,857,311 A 8/1989 Domb et al. .................. 424/78 Attawia, M.A. “The Long Term Osteoblast Response to 4,868.274 A 9/1989 Gupta et al. ................ 528/206 Poly(anhydride-co-imides); A New Degradable Polymer 4,886.870 A 12/1989 D’Amore et al. ........... 528/206 4,888,176. A 12/1989 Langer et al. .... ... 424/426 for Use in Bone", Proc. of the Fifth World Biomaterials 4,891.225 A * 1/1990 Langer et al. ... ... 424/428 Congress, Toronto, Canada, (1996).p. 113. 4,906,474 A 3/1990 Langer et al. ... 424/428 (List continued on next page.) 4,938,949 A 7/1990 Borch et al. .................. 424/10 4997,904 A 3/1991 Domb .......... ... 528/2O6 Primary Examiner Thurman K. Page 4,999,417 A 3/1991 Domb .......... ... 528/271 Assistant Examiner Blessing Fubara 5,082,925 A 1/1992 Shalaby et al. ... 528/354 (74) Attorney, Agent, or Firm-Schwegman, Lundberg, 5,175.235 A 12/1992 Domb et al....... ... 528/271 Woessner & Kluth, PA. 5,259,968 A 11/1993 Emert et al. ... ... 252/51.5 A 5,264,540 A 11/1993 Cooper et al. ... 528/272 (57) ABSTRACT 5,498,729 A 3/1996 Domb .......... ... 548/500 5,514,764 A 5/1996 Frechet et al. ................ 528/10 Polyanhydrides which link low molecular weight drugs 5,545.409 A 8/1996 Laurencin et al. .......... 424/426 containing a carboxylic acid group and an amine, thiol, 5,629,009 A 5/1997 Laurencin et al. .......... 424/426 alcohol or phenol group within their structure into polymeric drug delivery Systems are provided. Also provided are 5,902,110 A 5/1999 Alfano et al. ..... ... 433/215 5,902,599 A 5/1999 Anseth et al. ... 424/426 methods of producing polymeric drug delivery Systems via 5,942.252 A 8/1999 Tice et al. ..... ... 424/501 these polyanhydride linkers as well as methods of adminis 6,071,530 A 6/2000 Polson et al. ............... 424/426 tering low molecular weight drugs to a host via the poly FOREIGN PATENT DOCUMENTS meric drug delivery Systems. DE 2883.11 3/1991 .......... AO1 N/25/10 33 Claims, No Drawings US 6,613,807 B2 Page 2 OTHER PUBLICATIONS Gouin, S.,et al. "New Polyanhydrides Made from a Bile Acid Dimer and Sebacic Acid: Synthesis, Characterization, Beaton, M.L. "Synthesis of a novel poly(anhy and Degradation”, Macrmolecules, 33, (2000),pp. dride-ester)”, The Rutgers Scholar. An Electronic Bulletin of Undergraduate Research, 3, www.rutgerSScholarrut 5379-5383. gers.edu/volume03/beatuhri/beatuhri.html.(2001), 7 pgs. Ibim. S.“Controlled Release Based on Poly(anhydride Bedell, C.,"Processing and Hydrolytic Degradation of Aro co-imides)”, Proc. Intern. Symp. Control. Rel. Bioact. matic, Ortho-Substituted Polyanhydrides”, Journal of Mater, 22, (1995).2 pgs. Applied Polymer Science, 80, (2001), pp. 32–38. Ibim, S.M. "Poly(anhydride-co-imides): In Vivo Biocom Campo, C.J., “Polyanhydrides: the effects of ring substitu patibility in a rat model”, Biomaterials, 19, (1998),pp. tion changes on polymer properties”, Polymer Bulletin, 42, 941-951. (1999), pp. 61-68. Ibim, S.E. "Preliminary In Vivo Report on the Osteocom Chafi, N.," Dosage Form with Salicylic Acid Attached to the patibility of Poly(anhydride-co-imides) evaluated in a Polyanhydride Polymer Dispersed in an Eudragit Matrix”, Tibial Model”, App. Biomater, 43(4), (1998),pp. 374–379. International Journal of Pharmaceutics, 52, (1989),pp. Krogh-Jespersen, E.,"Synthesis of a Novel Aromatic Poly 203-211 anhydride Containing Aminosalicylic Acid', Polymer Pre Conix, A..." Aromatic Polyanhydrides, a New Class of High prints, 41 (1), (2000), pp. 1048–1049. Melting Fiber-Forming Polymers”,Journal of Polymer Sci Langer, R..."New Methods of Drug Delivery”, Science, 249, ence, XXIX, (1958), pp. 343-353. (Sep.1990).pp. 1527–1533. Conix, A..."New High-Melting Fibre-Forming Polymers', Laurencin, C.T. "Poly(andrides-co-imides): In Vivo Bio Die Makromolekulare Chemie, XXIV, (1957), pp. 76–78. compatibility Study', 23rd Annual Meeting of the Society Conix, A..."Poly 1,3-bis(p-carboxyphenoxy)-Propane for Biomaterials, New Orleans, LA, (1997), p. 483. anhydride', Macromolecular Synthesis, 2, (1996),pp. Laurencin, C.T. "The Biocompatibility of Poly(anhydride 95-99. co-imides): High Strength Polymers for Controlled Drug Domb, A.J. "Synthesis and Characterization of Biodegrad Delivery”, Proc. 24th Int'l Symp. Control. Rel. Bioact. able Aromatic Anhydride Copolymers’, Macromolecules, 25, (1992),pp. 12–17. Mater, (1997)pp. 973–974. Dukovic, G..."Novel degradable poly(anhydride-esters) for Laurencin, C.T. "The Bone Biocompatibility of Poly(anhy controlled drug release”, The Rutgers Scholar An Elec dride-co-imides)-A new generation degradable Polymer tronic Bulletin of Undergraduate Research, 1, http://rut for Orthopedic Applications”, 41st Annual Meeting of the gersscholarrutgers.edu/colume(01/uhridukofuhriduko.html, Orthopedic Research Society, Orlando, FL, (1995),pp. (1999), 10 pgs. 143-24. Erdman, L.,et al., “Polymer Prodrugs with Pharmaceuti Laurencin, C.T. "The Controlled Delivery of Radiosensi cally Active Degradation Products”, Polymer Preprints, tizers: Taxol Treatment of Ewing Sarcoma, Proc. of the 38(2), (1997)pp. 570–571. 25th Int'l Symp. Control. Rel. Bioact. Mater, (1998),pp. Erdmann, L.,"Chapter 5: Polymeric Prodrugs: Novel Poly 236-237. mers with Bioactive Components”, In, Tailored Polymeric Macedo, B.,et al. "The in vivo Response to a Bioactive Materials for Controlled Delivery Systems, I. McCulloch, et Biodegadable Polymer”, Journal of Dental Research, 78, al., (Editors), ACS Symposium Series 709, American Abstract No. 2827.(1999).p.459. Chemical Society: Washington, D.C..(1998),pp. 83-91. Macedo, B., "the In Vivo Response to Bioactive Polyanhy Erdmann, L., “Degradable poly(anhydride ester) implants: dride Monofilament”, Journal of Dental Research, 79 effects of localized Salicylic acid release on bone', Bioma (Abstract No. 3872), (2000).p. 627. terials, 21, (2000), pp. 2507-2512. Pinther, P.,"Synthesis of Polyanhydrides Containing Ester Erdmann, L., “Polymeric Prodrugs: Novel Polymers for Groups', Makromol. Chem., Rapid Commun., 11, (1990),pp. Delivery of Salicylic Acid', Annals of Biomedical Engineer 403-408. ing, 26 (Suppl. 1), Abstract No. PB.26, Annual Fall Meeting, Seidel, J.O. "Erosion of Poly(anhydride-co-imides): A Pre (1998).p. S-124. liminary Mechanistic Study”, J. Appl. Polym. Sci., 62(8), Erdmann, L., “Polymeric Salicylic Acid: In Vitro and In Vivo Degradation”, Polymer Preprints, 39(2), (1998).p. (1996), pp. 1277–1283. 224-225. Shen, E., "Morphological Characterization of Erodible Poly Erdmann, L.,"Synthesis and Characterization of a Poly mer Carriers for Drug Release', Proc. 26th Int'l Symp. meric Prodrug”, Proceedings of the American Chemical Control. Rel.