USOO6913761B1 (12) United States Patent (10) Patent No.: US 6,913,761 B1 Trigg et al. (45) Date of Patent: Jul. 5, 2005 (54) BIOIMPLANT FORMULATION (52) U.S. Cl. ......................... 424/423; 424/450; 514/12; 514/14; 514/15; 514/16; 514/17; 514/18; (75) Inventors: Timothy Elliot Trigg, Warrawee (AU); 514/19; 514/513; 514/515; 530/328 John Desmond Walsh, Curl Curl (AU); (58) Field of Search ................................. 424/423, 450; Deborah Ann Rathjen, Thornleigh 514/12, 14, 15, 16, 17, 18, 19, 513, 514, (AU) 515; 530/328 (73) Assignee: Peptech Limited, New South Wales (56) References Cited (AU) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 4,578,391 A 3/1986 Kawata et al. patent is extended or adjusted under 35 6,337,318 B1 * 1/2002 Trigg et al. ................... 514/15 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 09/743,059 EP O 523 330 B1 4/1992 (22) PCT Filed: Jul. 20, 1999 EP O 523 330 A1 1/1993 WO 94/O8623 4/1994 (86) PCT No.: PCT/AU99/00585 * cited by examiner S371 (c)(1), Primary Examiner-Carlos A. Azpuru (2), (4) Date: Jan. 4, 2001 (74) Attorney, Agent, or Firm Nixon & Vanderhye (87) PCT Pub. No.: WO00/04897 (57) ABSTRACT PCT Pub. Date: Feb. 3, 2000 A pharmaceutical and/or Veterinary formulation comprising (30) Foreign Application Priority Data about 2-30% (w/w) (on an active basis) of at least one active agent, about 0.5-20.0% (w/w) of a pore-foaming agent and Jul. 20, 1998 (AU) .............................................. PP4730 the balance Stearin. Such formulations provided release of Jul. 20, 1998 (AU) .............................................. PP4731 the at least one active agent in humans and other animals for May 13, 1999 (AU) .............................................. POO324 periods of 7 days up to about 2 years. (51) Int. Cl. ........................... A61F 2/02; A61K 38/20; A61K 31/21, A61K 38/04 40 Claims, 9 Drawing Sheets U.S. Patent Jul. 5, 2005 Sheet 1 of 9 US 6,913,761 B1 FIGURE U.S. Patent Jul. 5, 2005 Sheet 2 of 9 US 6,913,761 B1 FIGURE 2 pouJedBug's€e6eue.AY (Sn) osea eaterwro U.S. Patent US 6,913,761 B1 FIGURE 3 U.S. Patent US 6,913,761 B1 FIGURE A asoon19%9-3SoonIÐ%z'ullajoiseC]spou600 U.S. Patent Jul. 5, 2005 Sheet 5 of 9 US 6,913,761 B1 FIGURE 5 # | | | 3 8 8 (Sn) DST00. BASntuno U.S. Patent Jul. 5, 2005 Sheet 6 of 9 US 6,913,761 B1 FIGURE 6 |(spojcefielew)spojXN U.S. Patent US 6,913,761 B1 FIGURE 7 ||!dou?SIT362]æAV)spol(spou$ U.S. Patent US 6,913,761 B1 FIGURE 8 U.S. Patent Jul. 5, 2005 Sheet 9 of 9 US 6,913,761 B1 FIGURE 9 "No. Sue follow ow.eguro US 6,913,761 B1 1 2 BIOMPLANT FORMULATION pharmaceutical or veterinary Significance and may be any or a combination of peptides (e.g. hormones and antigens), polypeptides and proteins, and nucleic acid compounds and FIELD OF THE INVENTION derivatives Such as DNA and RNA. The present invention relates to pharmaceutical and/or Preferred active agents include: Veterinary formulations for the Sustained release of at least (1) GnRH Agonists one active agent. Preferred active agents include Particularly preferred GnRH peptide agonists are deslore gonadotropin-releasing hormone (GnRH) agonists (e.g. lin (described in U.S. Pat. No. 4,218,439), eulexin deslorelin), GnRH antagonists (e.g. cetrorelix), Somatostatin (described in FR7923545, WO 86/01105 and PT1.00899), analogues (e.g. Somatostatin-14 and octreotide), lipid low goserelin (described in U.S. Pat. Nos. 4,100,274, 4,128,638, ering agents (e.g. Simvastatin), cyclosporins (e.g. GB9112859 and GB9112825), leuprolide (described in U.S. cyclosporin A), angiotensin converting-enzyme inhibitors Pat. Nos. 4,490,291, 3,972,859, 4,008,209, 4,005,063, (e.g. captopril), calcitonins, Substance Pantagonists, pain DE2509783 and U.S. Pat. No. 4,992,421), dioxalan deriva killers (e.g. morphine), opioid antagonists (e.g. naltrexone), tives such as are described in EP 413209, triptorelin anti-depressants (e.g. Venlafaxine) and non-Steroidal anti 15 (described in U.S. Pat. Nos. 4,010,125, 4,018,726, 4,024, inflammatory agents (e.g. naproxen Sodium). 121, EP 364819 and U.S. Pat. No. 5,258,492), meterelin (described in EP 23004), buserelin (described in U.S. Pat. BACKGROUND OF THE INVENTION Nos. 4,003,884, 4,118,463 and 4,275,001), histrelin (described in EP217859), nafarelin (described in U.S. Pat. For reasons including improved efficacy of action and No. 4,234,571, WO93/15722 and EP52510), lutrelin reduced frequency of administration, there is considerable (described in U.S. Pat. No. 4,089,946), leuprorelin interest in the development of pharmaceutical and Veterinary (described in Plosker et al., Drugs 48 930–967, 1994) and formulations capable of controllably releasing active agents LHRH analogues such as are described in EP181236, U.S. for Sustained periods (e.g. up to 6 months or more). Types of Pat. Nos. 4,608,251, 4,656,247, 4,642,332, 4,010,149, pharmaceutical agents that would particularly benefit from 25 3,992,365 and 4,010,149. The disclosures of each the patent the development of Such formulations are those which are Specifications and paperS referred to above are incorporated typically administered by patients themselves over long herein by reference. periods (e.g. insulin for diabetes treatment, and The most preferred GnRH agonists are goserelin, gonadotropin-releasing hormone (GnRH) agonists for repro deslorelin, leuprorelin, triptorelin, meterelin, buSerelin, ductive control and treatment of SeX hormone-dependent histrelin, nafarelin and combinations thereof. The formulae diseases and conditions) and require high levels of patient of these compounds are provided below: compliance. In the Veterinary context, Sustained release Goserelin CsoHNs.O.C.H.O. D-Ser(But)'Azgly'- formulations would reduce the StreSS often caused to the LHRH Acetate 3-5-oxo-L-prolyl-L-tryptophyl-L- animal and Veterinarian/owner alike by the need for repeated seryl-L-tyrosyl-(3-O-tert-butyl)-D-seryl-L-leucyl-L- administration of active agents. 35 arginyl-L-prolyl cabazamide acetate. The present applicant's have found that Sustained release Deslorelin 6-D-tryptophan-9-(N-ethyl-L prolinamide)- of at least one active agent in humans and other animals for 10-deglycinamide PGlutamine-Histidine-Tryptophan periods of 7 days up to about 2 years, can be achieved by Serine-Tyrosine-D Tryptophan-Leucine-Arginine using a Solid formulation comprising Stearin as an excipient Proline-ethylamide. in combination with a Substance which, while not wishing to 40 Leuprorelin CsoHNO2, CHO, Leuprorelin Acetate be bound by theory, appears to form pores and/or cracks in 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L- the excipient to enable the release of the active agent(s). tyrosyl-D-leucyl-L-arginyl-N-ethyl-L-prolinamide SUMMARY OF THE INVENTION acetate. Triptorelin CHNO, CHO, D-TRp-LHRH Thus, in a first aspect, the present invention provides a 45 5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L- pharmaceutical and/or veterinary formulation comprising tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L- about 2-30% (w/w) (on an active basis) of at least one active prolylglycinamide. agent, about 0.5-20.0% (w/w) of a pore-forming agent and the balance Stearin. Meterelin Des Gly'2-methyl-D-Trp-Pro-ethyl-amide 50 LHRH. In a preferred embodiment, the formulation comprises Buserelin CHNO, CHO, D-Ser(But)-Pro9-NEt about 5-10% (w/w) (on an active basis) of at least one active LHRH Acetate Oxo-L-prolyl-L-histidyl L-tryptophyl agent, about 1.0-10.0% (w/w) of a pore-forming agent and L-seryl-L-tyrosyl-O-tert-butyl-D-seryl-L-leucyl-L- the balance Stearin. arginyl-N-ethyl-L-prolinamide acetate. In a more preferred embodiment, the formulation com 55 Histrelin Pro-His-Trp-Ser-Tyr-Leu-D(N-benzyl) His-Arg prises about 5-10% (w/w) (on an active basis) of at least one Pro-N-ethylamide. active agent, about 2.0–5.0% (w/w) of a pore-forming agent Nafarelin CHN, O, XCHOyHOOXO-L-prolyl and the balance Stearin. L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-3-2- In a Second aspect, the present invention provides a naphthyl-D-alanyl-L-leucyl-L-arginyl-N-ethyl-L- method of treating a disease or condition in a human or other 60 prolylglycinaminde acetate hydrate. animal, the method comprising administering to the human Formulations according to the invention which include a or other animal the formulation of the first aspect of the GnRH agonist as the at least one active agent may be used invention. for controlling reproductive function or for the treatment of DETAILED DISCLOSURE OF THE INVENTION any disease or condition wherein reduction of SeX hormone 65 (i.e. testosterone or estradiol) levels over a prolonged period The at least one active agent utilised in the formulation of is beneficial. Examples include prostrate cancer, ovarian and the present invention, may be selected from agents having breast cancer, benign hormone-dependent disorderS Such as US 6,913,761 B1 3 4 endometriosis, myoma and premenstrual tension, uterine Formulations according to the invention which include fibroids, induction of eudometrial atrophy prior to Surgery, Such agents may be used, for example, as antihypertensives. Suppression of germ cell activity in chemotherapy, (7) Calcitonins hirsutism, cyclic auditory dysfunction, porphyria and pre Preferred calcitonins include human, Salmon, and porcine cocious puberty in children, benign prostatic hypertension in calcitonin.