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(12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson Et Al

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(12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson Et Al US006235.712B1 (12) United States Patent (10) Patent No.: US 6,235,712 B1 Stevenson et al. (45) Date of Patent: May 22, 2001 (54) NON-AQUEOUS POLARAPROTIC PEPTIDE Helm, et al., “Stability of Gonadorelin and Triptorelin in FORMULATIONS Aqueous Solution”, Pharm. Res., 7/12, pp. 1253-1256 (1990). (75) Inventors: Cynthia L. Stevenson; Steven J. Johnson, et al., “Degradation of the LH-RHAnalog Nafare Prestrelski, both of Mountain View, CA lin Acetate in Aqueous Solution”, Intl. J. Pharm., 31, pp. (US) 125-129 (1986). 73) Assignee:9. ALZA Corporation,p Mountain View, Lupron (leuprolide acetate for Subcutaneous injection), Phy CA (US) sician's Desk Ref, 50th Ed., pp. 2555-2556 (1996). Lupron Depot (leuprolide acetate for depot Suspension), * ) Notice: Subject to anyy disclaimer, the term of this Physician's Desk Ref, 50th Ed., pp. 2556-2562 (1996). patent is extended or adjusted under 35 Lutrepulse (gonadorelin acetate for IV injection), Physi U.S.C. 154(b) by 0 days. cian's Desk Ref, 50th Ed., pp.980–982 (1996). Okada, et al., “New Degradation Product of (21) Appl. No.: 09/514,951 Des-Gly'-NH-LH-RH-Ethylamide (Fertirelin) in Aque (22) Filed: Feb. 28, 2000 ous Solution”, J. Pharm. Sci., 80/2, pp. 167–170 (1991). Okada, et al., “Preparation of Three-Month Depot Injectable Related U.S. Application Data MicroSpheres of Leuprorelin Acetate Using Biodegradable Polymers”, Pharm. Res., 11/8, pp. 1143–1147 (1994). (62) Division of application No. 09/293,839, filed on Apr. 19, 1999, now Pat. No. 6,124,261, which is a continuation of Oyler, et al., “Characterization of the Solution Degradation application No. 08/874.233, filed on Jun. 13, 1997, now Pat. Products of Histrelin, a Gonadotropin Releasing Hormone No. 5,932,547 (LH/RH) Agonist”, J. Pharm. Sci., 80/3, pp. 271-275 (60) Provisional application No. 60/022,699, filed on Jul. 3, (1991). 1996. Powell, et al., “Parenteral Peptide Formulations: Chemical (51) Int. Cl. ........................... A61K38/00; CO7K5/00; and Physical Properties of Native Luteinizing Hormone-R- CO7K 7/00 eleasing Hormone (LHRH) and Hydrophobic Analogues in (52) U.S. Cl. ............................... 514/11; 514/12; 530/300; Aqueous Solution”, Pharm. Res., 8/10, pp. 1258-1263 530/313; 530/317; 530/324 (1991). (58) Field of Search ........................ 514/11, 12; 530/300, Powell, et al., “Peptide Liquid Crystals: Inverse Correlation 530/313, 317, 324 of Kinetic Formation and Thermodynamic Stability in Aque ous Solution”, Pharm. Res., 11/9, pp. 1352–1354 (1994). (56) References Cited Powers, et al., “Solution Behavior of Leuprolide Acetate, U.S. PATENT DOCUMENTS and LHRH Agonist, as Determined by Circular Dichroism Spectroscopy”, Intl. J. Pharm., 108, pp. 49-55 (1994). 3,914,412 10/1975 Gendrich et al. .................... 424/177 4,547,370 10/1985 Roeske ................................... 514/15 Shi, et al., “Long-Term Stability of Aqueous Solutions of 4,661,472 4/1987 Rivier et al. ........................... 514/15 Luteinizing Hormone-Releasing Hormone ASSessed by an 4,689,396 8/1987 Roeske et al. ....................... 530/313 In-Vitro Bioassay and Liquid Chromatography”, J. Pharm. 4,851,385 7/1989 Roeske ................................... 514/15 Sci., 73/6, pp. 819–821 (1984). 5,034,229 7/1991 Magruder et al. ... ... 424/422 Toguchi, “Pharmaceutical Manipulation of Leuprorelin 5,057,318 10/1991 Magruder et al. ... ... 424/438 5,110,596 5/1992 Magruder et al. ... ... 424/438 Acetate to Improve Clinical Performance”, J. Intl. Med. 5,198,533 3/1993 Schally et al. ....................... 530/313 Res., 18, pp. 35–41 (1990). 5,480,868 1/1996 Kamei et al. .......................... 514/15 Zoladex (goserelin acetate implant), Physician's Desk Ref, FOREIGN PATENT DOCUMENTS 50th Ed., pp. 2858–2861 (1996). 1098151 12/1964 (GB). Primary Examiner Avis M. Davenport 2008.403A 11/1978 (GB). (74) Attorney, Agent, or Firm-Pauline A. Clarke; Mary 2119248A 4/1983 (GB). Ann Dillahunty; Steven F. Stone WO92/20711 11/1992 (WO). WO94/1902O 9/1994 (WO). (57) ABSTRACT WO95/00168 1/1995 (WO). WO95/04540 2/1995 (WO). This invention relates to stable non-aqueous polar aprotic WO97/27840 8/1997 (WO). formulations of peptide compounds. These stable formula tions comprise peptide in non-aqueous polar aprotic Solvent. OTHER PUBLICATIONS They may be Stored at elevated temperatures for long Factrel (gonadorelin HCI for subcutaneous or IV injection), periods of time and are especially useful in implantable Physician's Desk Ref, 50th Ed., pp. 2877–2878 (1996). delivery devices for long term delivery of drug. Fu Lu, et al., “Percutaneous Absorption Enhancement of Leuprolide", Pharm. Res., 9/12, pp. 1575-1576 (1992). 19 Claims, 8 Drawing Sheets U.S. Patent May 22, 2001 Sheet 1 of 8 US 6,235,712 B1 O.O O.O 2O.O 3O.O 4O.O Time (min) FIG. 1 Mononer O.O. O.O 2O.O 3O.O 4O.O Time (min) FIG. 2 U.S. Patent May 22, 2001 Sheet 2 of 8 US 6,235,712 B1 in KobS DMSO OOO28 O.0029 OOO3O OOO31 OOO32 OOO33 1 / T FIG. 3 U.S. Patent May 22, 2001 Sheet 3 of 8 US 6,235,712 B1 120 6 O % Leuprolide % Chemical 40 % O/Trimer Mass Balance 20 O 2 4 6 8 Time (months) FIG. 4 U.S. Patent May 22, 2001 Sheet 4 of 8 US 6,235,712 B1 4.4 4. 2 4.0 - 3.8 O 2 4 6 8 Time (months) FIG. 5 U.S. Patent May 22, 2001 Sheet 5 of 8 US 6,235,712 B1 3 X aC > O) ON are e or se X ON k osco 3S : 2 E CD4 LL y3 x O O 8 CDO 3 SO 3 OS. S.O S. 2 O O eploudne% U.S. Patent May 22, 2001 Sheet 6 of 8 US 6,235,712 B1 o C ac C e o o O O O o o o O N. N ves eploudnel 9, U.S. Patent May 22, 2001 Sheet 7 of 8 US 6,235,712 B1 E s i d s s eploudnel 6 U.S. Patent May 22, 2001 Sheet 8 of 8 US 6,235,712 B1 o C C C O O GN V v eoue to % US 6,235,712 B1 1 2 NON-AQUEOUS POLAR APROTIC PEPTIDE 20. Lupron (leuprolide acetate for Subcutaneous injection), FORMULATIONS Physicians Desk Reference, 50th Edition, pages 2555-2556 (1996). CROSS-REFERENCE TO RELATED 21. Lupron depot (leuprolide acetate for depot Suspension), APPLICATIONS 5 Physicians Desk Reference, 50th Edition, pages This application is a divisional, of application Ser. No. 2556–2562 (1996). 09/293.839, filed Apr. 19, 1999, now U.S. Pat. No. 6,124, 22. “Pharmaceutical Manipulation of Leuprorelin Acetate to 267, which is a continuation of application Ser. No. 08/874, Improve Clinical Performance', H. Toguchi, J. of Intl. 233, filed Jun. 13, 1997. now U.S. Pat. No. 5,932,547. Medical Research, 18, pages 35-41 (1990). This application claims priority under 35 U.S.C. 119(e) to 10 23. “Long-Term Stability of Aqueous Solutions of Lutein U.S. application Ser. No. 60/022,699 filed Jul. 3, 1996, the izing Hormone-Releasing Hormone ASSessed by an disclosure of which is incorporated herein by reference. In-Vitro Bioassay and Liquid Chromatography', Y. F. Shi, R. J. Sherins, D. Brightwell, J. F. Gallelli, D. C. Chatterji, FIELD OF THE INVENTION J. of Pharmaceutical Sciences, 73/6, pages 819-821 This invention relates to Stable non-aqueous polar aprotic 15 (1984). formulations of peptide compounds and more particularly to 24. “Peptide Liquid Crystals: Inverse Correlation of Kinetic formulations of peptide compounds at high concentrations. Formation and Thermodynamic Stability in Aqueous BACKGROUND OF THE INVENTION Solution”, M. F. Powell, J. Fleitman, L. M. Sanders, V. C. Si, Pharmaceutical Research, 11/9, pages 1352-1354 References 2O (1994). The following references are referred to by numbers in 25. “Solution Behavior of Leuprolide Acetate, an LHRH brackets () at the relevant portion of the specification. Agonist, as Determined by Circular Dichroism 1. Zoladex (goserelin acetate implant), Physician's Desk Spectroscopy”, M. E. Powers, A. Adejei, M.Y. Fu Lu, M. Reference, 50th Edition, pages 2858-2861 (1996). C. Manning, Intl. J. of Pharmaceutics, 108, pages 49-55 U.S. Pat. No. 3,914,412, issued Oct. 21, 1975. 25 (1994). U.S. Pat. No. 4,547,370, issued Oct. 15, 1985. 26. “Preparation of Three-Month Depot Injectable Micro U.S. Pat. No. 4,661,472, issued Apr. 28, 1987. Spheres of Leuprorelin Acetate Using Biodegradable U.S. Pat. No. 4,689,396, issued Aug. 25, 1987. Polymers”, Pharmaceutical Research, 11/8, pages U.S. Pat. No. 4,851,385, issued Jul. 25, 1989. 1143–1147 (1994). U.S. Pat. No. 5,198,533, issued Mar. 30, 1993. 3O The disclosure of each of the above publications, patents . U.S. Pat. No. 5,480,868, issued Jan. 2, 1996. or patent applications is hereby incorporated by reference in WO92/20711, published Nov. 26, 1992. its entirety to the same extent as if the language of each 10. WO95/00168, published Jan. 5, 1995. individual publication, patent and patent application were 11. WO95/04540, published Feb. 16, 1995. Specifically and individually incorporated by reference. 12. "Stability of Gonadorelin and Triptorelin in Aqueous 35 Luteinizing hormone-releasing hormone (LHRH), also Solution”, V. J. known as gonadotropin releasing hormone (GnRH), is a Helm, B. W. Muller, Pharmaceutical Research, 7/12, pages decapeptide with the Structure: 1253-1256 (1990). 13. “New Degradation Product of Des-Gly'-NH-LH-RH pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.
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