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(12) United States Patent (10) Patent N0.: US 7,309,689 B2 Trigg Et A] US007309689B2 (12) United States Patent (10) Patent N0.: US 7,309,689 B2 Trigg et a]. (45) Date of Patent: *Dec. 18, 2007 (54) SUSTAINED PEPTIDE-RELEASE 5,256,649 A 10/1993 Le Fur et al. FORMULATION 5,340,585 A 8/1994 Pike 5,372,996 A 12/1994 Labrie ....................... .. 514/15 (75) Inventors: Timothy Elliot Trigg, WarraWee (AU); 5,573,781 A 11/1996 Brown et a1. ............. .. 424/484 John Desmond Walsh, Curl Curl (AU); 5,925,619 A 7/1999 Walsh Paul Adam Schober, Beacon Hill (AU) 6,337,318 B1 1/2002 Trigg et al. ................. .. 514/15 FOREIGN PATENT DOCUMENTS (73) Assignee: Peptech Limited, North Ryde (AU) AU A-41059/85 10/1985 ( * ) Notice: Subject to any disclaimer, the term of this EP 0 158 277 10/1985 patent is extended or adjusted under 35 EP 0 254 693 1/1988 U.S.C. 154(b) by 268 days. EP 0 645 136 A2 3/1995 GB 2 052 258 1/1981 JP 62-192327 8/1987 This patent is subject to a terminal dis WO 86/04503 8/1986 claimer. WO 92/18107 10/1992 W0 WO 93/07833 4/1993 WO 92/15722 8/1993 (21) Appl. No.: 10/808,504 WO 96/34012 10/1996 (22) Filed: Mar. 25, 2004 W0 WO 97/00693 1/1997 (65) Prior Publication Data OTHER PUBLICATIONS US 2004/0180832 A1 Sep. 16, 2004 Liu et a1; “E?cects of PituitaryiTesticular Axis Suppression in Utero and during . ”, Journal ofEndocrinology and Related US. Application Data Metabolism, vol. 73, No. 5, pp. 1038*1043 (1991). Hawley’s Condensed Chemical Dictionary, 13th ed., John (62) Division of application No. 09/991,714, ?led on Nov. 26, 2001, now Pat. No. 6,777,386, Which is a continuation of Wiley & Sons, Inc., pp. 666, 1046 and 1047 (1997). application No. 09/242,635, ?led as application No. PCT/ AU97/00560 on Sep. 1, 1997, HOW Pat. No. 6,337,318. Primary Examiner£hristopher R. Tate (30) Foreign Application Priority Data Assistant ExamineriMaury Audet (74) Attorney, Agent, or F irmiNixon & Vanderhye Aug. 30, 1996 (AU) ............................................ .. PC2035 Dec. 6, 1996 (AU) ............................................ .. PC4107 (57) ABSTRACT (51) Int. Cl. A pharmaceutical and/or veterinary formulation for sus A61K 38/00 (2006.01) tained release of a peptide agonist or analogue, comprising about 2*15% (W/W) of at least one peptide agonist or (52) US. Cl. ............................................ .. 514/2; 514/15 analogue other than deslorelin (on an active basis), about (58) Field of Classi?cation Search ................... .. 514/2, 0.5*3.5% (W/W) lecithin and the balance sterin. The formu 514/ 15 lation preferably comprises a GnRH agonist or analogue and See application ?le for complete search history. is used for the treatment of various conditions Where sup pression of sex hormone levels is bene?cial, particularly (56) References Cited prostate cancer, ovarian and breast cancer, and benign pro static hyperplasia in dogs. U.S. PATENT DOCUMENTS 5,039,660 A 8/1991 Leonard 11 Claims, 14 Drawing Sheets U.S. Patent Dec. 18, 2007 Sheet 1 0f 14 US 7,309,689 B2 QmZEIII mogul? 03 1 r cancan0pmon"0mm0mmEN02.c: Each-3C.‘09:5 4 0u0nw. 8.9:a:8E2 1r (Lua) aaualqummgo [210mg U.S. Patent Dec. 18, 2007 Sheet 2 0f 14 US 7,309,689 B2 310 290 702 250 230 210 190 (3mg)Deslorelin2:Figure TreaimentofDays 150130110 50 30 10 ‘r I . -10 v n O a no 181 16 . (ms) aauamnunaaga moms U.S. Patent Dec. 18, 2007 Sheet 3 0f 14 US 7,309,689 B2 nn>>aIT 52:22.0“n0.52“553 8;8ENQ20;O22.8.o:28n8"622"2nSN “5.53;hom>~0 <q41-u QF-bp>P (um) aouaapnnaaga moms U.S. Patent Dec. 18, 2007 Sheet 4 0f 14 US 7,309,689 B2 370 350 M“P0 ‘f’ -_ 1001;o10o2;o1.150250270290230 DeslorelinFigure4:(12mg) TreatmentofDays 110 90 70 l‘14- r I 40 16- N O 0 IO (um) aaueuapunmp moms U.S. Patent Dec. 18, 2007 Sheet 5 0f 14 US 7,309,689 B2 25>“.lol mv>>mIII 33....Lil 82EIf q - q - - n >-n <1-u‘ oncmon’020:nowamoworo01.c2o:on’ovmcanown2Ncom02.on“0..“can £23002:9".5SE8 n25525$;50 a - < > 1 b Op.- (ma) aaumqwnsugg moms U.S. Patent Dec. 18, 2007 Sheet 6 0f 14 US 7,309,689 B2 3;.“III 32Elql 83aIII u0nq<1-<-4~1. q_n1< q unm -~Ih>-np-uqp- -> =8922w8“3w9ac298Q3Q2Q58.atQ2Q:8.ao:8.82.cm382o2. E253;*0260 n-pI-> (ma) aaumqwnmgo mums U.S. Patent Dec. 18, 2007 Sheet 7 0f 14 US 7,309,689 B2 (un) aauaujmmuga "nous U.S. Patent Dec. 18, 2007 Sheet 8 0f 14 US 7,309,689 B2 Om ow AmEu.53.63.;a952... on3am .0E253;as ab - 2o.m9 p D (m) mama laws U.S. Patent Dec. 18, 2007 Sheet 9 0f 14 US 7,309,689 B2 8 8 Q' ‘rt-Ht Control(0mg) ImplantafterDays ConcentrationTestosteronePlasmaFigure9: 140120an100so40 “if“~ ,1It. '1 (nul?u) uonaauoauog wounsuzso 1, U.S. Patent Dec. 18, 2007 Sheet 11 0f 14 US 7,309,689 B2 com mngmIQI 02. our 5E85-2230 c3Q22:on 5:223:00222333.uEmmE"2‘959m 233E123gun om U.S. Patent Dec. 18, 2007 Sheet 12 0f 14 US 7,309,689 B2 com 83ml’... :.>>.Tl: BELL-r gsmlxl 251*. 02 GENS5.9.230 o:92cowon 5:823:00322M332.252m"upaim-n. 233E.3:"mic (mu?u) uogmuoauog auolqsonu U.S. Patent Dec. 18, 2007 Sheet 13 0f 14 US 7,309,689 B2 E585.9.300 8-03c98 5:223:00“Emu-n-952mmach-isms.“: 52%..Ban1.5 U.S. Patent Dec. 18, 2007 Sheet 14 0f 14 US 7,309,689 B2 cum ‘25LIII on>>mlil 025mIXI 025.“.Itl on’ o2 3E8wag-Sass c33.2:on 5:223:0032233“;uEméE"32:2". EuEE.3:““>3 00 v N US 7,309,689 B2 1 2 SUSTAINED PEPTIDE-RELEASE conditions provided that the peptide Was delivered so as to FORMULATION maintain a constant minimum blood level. The prerequisite for a peptide to be active Was the ability to disturb the This application is a divisional of application Ser. No. pulsatile release of endogenous GnRH. This required a 09/991,714, ?led Nov. 26, 2001 now US. Pat. No. 6,777, constant minimum plasma level (this level Was not de?ned). 386, Which is a continuation of application Ser. No. 09/242, They suggested that a mode of delivery Was more important 635, ?led Feb. 19,1999 now US. Pat. No. 6,337,318, Which than minor differences in potency betWeen different GnRH is a 371 of PCT/AU97/00560 ?led Sep. 1, 1997, the entire analogues. These authors also concluded that in a suppressed content of Which is hereby incorporated by reference in this pituitary, the dose of GnRH analogue needed to maintain application. suppression gradually decreased With the duration of treat ment (also explored in SandoW J and DonneZ T (1990) in FIELD OF THE INVENTION Brosens I, Jacobs H S and Rennebaum B (eds) LHRH analogues in Gynaecology pp 17431 Camfor‘th: Parthenon The present invention relates to formulations for the Publishing). sustained release of peptide agonists and analogues. In a The use of GnRH agonists or analogues for the treatment particular application of the invention, the formulation com of various benign hormone-dependent diseases and condi prises a peptide agonist or analogue of gonadotropin releas tions has been described. For example, Kappy M, et al. (J . ing hormone (GnRH) and is used for the treatment of Clin. Endocrinol. Metal. 64 (1987) 132041322) and Lee PA, prostate and breast cancer and other diseases and conditions et al. (J . Pediatr. 114 (1989) 3214324) describe the long-term Where suppression of testosterone or estradiol levels is 20 treatment of precocious puberty in children using the GnRH bene?cial. agonist, leuprolide acetate. The use of this GnRH agonist in BACKGROUND OF THE INVENTION the treatment of hirsutism (Rittmaster R S & Thompson D L, J. Clin. Endocrinol. Metab. 70 (1990) 109641102) and The peptide gonadotropin releasing hormone (GnRH) has endometriosis (SeltZer V L & Benjamin F, Obstet. Gynecol. been the subject of intensive research for many years. It is 25 76 (1990) 929) has also been described. In addition, GnRH a hypothalamic decapeptide Which is synthesised and stored agonists or analogues may be used for treatments of uterine in neurosecretory cells of the medial basal hypothalamus. ?broids (Lumsden M A, et al., Lancet i (1987) 36437; Healy The releasing hormone is released in a pulsatile manner into D L, Gynecol. Endocrinol. 3 (suppl 2) (1989) 33449), cyclic the hypophysial portal circulation and is transported to the auditory dysfunction (Andreyko J L & Jalfe R B, Obstet. anterior pituitary. Here, it regulates the secretion of the 30 Gynecol. 74 (1989) 506), porphyria (BargetZi M J et al., gonadotrophins, leuteinising hormone (LH) and follicle JAMA 261 (1989) 864) and benign prostatic hypertrophy stimulating hormone (FSH), into the systemic circulation. (Gabrilove J L et al., J. Clin. Endocrinol. Metab. 69 (1989) Thus, GnRH is a humoral link betWeen the neural and 629). endocrine components of reproductive function (for revieW Similarly, the use of GnRH agonists or analogues in the see Conn PM (ed) 1996 Gonadotropin-releasing hormone 35 treatment of sex hormone dependent tumours, including Endocrine RevieW 7:1). GnRH binds to a single class of breast cancer and prostate cancer, has been described. For receptors on gonadotrope cells. Prolonged exposure of these example, de Voogt H J et al. (Scand. J. Urol. Nephrol. Suppl. cells to the GnRH results in loss of responsiveness to the 138 (1991) 1314136) describes the results obtained in a hormone, through receptor alteration (revieWed in HaZum E ten-year study of prostatic cancer patients administered and Conn PM (1988) Endocrine RevieW 9: 3794866).
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