USOO5916582A United States Patent (19) 11 Patent Number: 5,916,582 Stevenson et al. (45) Date of Patent: Jun. 29, 1999 54 AQUEOUS FORMULATIONS OF PEPTIDES WO95/O1183 1/1995 WIPO. WO95/04540 2/1995 WIPO. 75 Inventors: Cynthia L. Stevenson, Mountain View; WO96/07398 3/1996 WIPO. Sally A. Tao, San Jose; Steven J. WO97/27840 8/1997 WIPO. Prestrelski, Mountain View; James B. OTHER PUBLICATIONS Eckenhoff, deceased, late of Los Altos, by Bonnie J. Eckenhoff, Jeremy C. Fu Lu, et al., “Percutaneous Absorption Enhancement of Wright, Los Altos; John J. Leonard, Leuprolide”, Pharmaceutical Research, 9/12, pp. Jr., Cupertino, all of Calif. 1575-1576 (1992). Helm, et al., “Stability of Gonadorelin and Triptorelin in 73 Assignee: ALZA Corporation, Palo Alto, Calif. Aqueous Solution”, Pharmaceutical Research, 7/12, pp. 1253–1256 (1990). 21 Appl. No.: 08/874,694 Johnson, et al., “Degredation9. of the LH-RHAnalog9. Nafare lin Acetate in Aqueous Solution”, Int. J. of Pharmaceutics, 22 Filed: Jun. 13, 1997 31, pp. 125-129 (1986). O O Okada, et al., “Preparation of Three-Month Depot Injectable Related U.S. Application Data MicroSpheres of Leuprorelin Acetate Using Biodegradable Polymers”, Pharmaceutical Research, 11/8, pp. 1143–1147 60 Provisional application No. 60/021,199, Jul. 3, 1996. (1994) (51) Int. Cl." ........................................................ A61F 2/02 Okada, et al., “New Degradation Product of 52 U.S. Cl. ............................................. 424/423; 424/426 Des-Glv'-NH-LH-RH-Ethvlamidey 2 y (Fertirelin) in AqueC 58 Field of Search ...................................... 424/423,426 ous Solution", J. of Pharmaceutical Sciences, 80/2, pp. s 167–170 (1991). 56) References Cited Oyler, et al., “Characterization of the Solution Degradation Products of Histrelin, a Gonadotropin Releasing Hormone U.S. PATENT DOCUMENTS (LH/RH) Agonist”, J. of Pharmaceutical Sciences, 80/3, pp. 3,914,412 10/1975 Gendrich et al. ....................... 424,177 271-275 (1991). 4,547,370 10/1985 Roeske ...................................... 514/15 4,661,472 4/1987 Rivier et al. .............................. 514/15 (List continued on next page.) 4,689,396 8/1987 Roeske et al. 530/313 Primary Examiner—Carlos A. Azpuru 2. S. retal.".3. Attorney, Agent, or Firm-Pauline Ann Clarke; Stephen F. 5,057,3182 - - -2 10/1991 Magruderagruder et al. ... - - - E. Stone; Mary Ann Dillahunty 5,110,596 5/1992 Magruder et al. ... ... 424/438 57 ABSTRACT 5,198,533 3/1993 Schally et al. ... ... 530/313 5,413,990 5/1995 Haviv et al. .............................. 514/15 This invention relates to stable liquid aqueous formulations (List continued on next page.) of peptide compounds at high concentrations. These stable page. formulations comprise at least about 10% peptide in water. FOREIGN PATENT DOCUMENTS They may be Stored at elevated temperatures for long periods of time and are especially useful in implantable wo...I RE Span Pat. Off. delivery devices for long term delivery of drug. WO94/1902O 9/1994 WIPO. WO95/OO168 1/1995 WIPO. 12 Claims, 5 Drawing Sheets Peptide O.O 1O. O. 2O, O 3O.O 4OO Time (min) 5,916,582 Page 2 U.S. PATENT DOCUMENTS Toguchi, “Pharmaceutical Manipulation of Leuprorelin Acetate to Improve Clinical Performance”, J. of Intl. Medi 5,480,868 1/1996 Kamei et al. ............................. 514/15 5,482.931 1/1996 Harris et al. .............................. 514/15 cal Research, 18, pp. 35-41 (1990). 5,498.598 3/1996 Harris ........................................ 514/11 OTHER PUBLICATIONS Factrel (gonadorelin HCI for subcutaneous or IV injection), Physician's Desk Reference, 50th Edition, pp. 2877–2878 Powell, et al., “Peptide Liquid Crystals: Inverse Correlation of Kinetic Formation and Thermodynamic Stability in Aque (1996). ous Solution”, Pharmaceutical Research, 11/9, pp. Lupron (leuprolide acetate for Subcutaneous injection), Phy 1352–1354 (1994). Powell, et al., “Parenteral Peptide Formulations: Chemical sician's Desk Reference, 50th Edition, pp. 2555-2556 and Physical Properties of Native Luteinizing Hormone-R- (1996). eleasing Hormone (LHRH) and Hydrophobic Analogues in Aqueous Solution”, Pharmaceutical Research, 8/10, pp. Lupron Depot (leuprolide acetate for depot Suspension), 1258–1263 (1991). Physician's Desk Reference, 50th Edition, pp. 2556-2562 Powers, et al., “Solution Behavior of Leuprolide Acetate, an (1996). LHRH Agonist, as Determined by Circular Dichroism Spec troscopy”, Intl. J. of Pharmaceutics, 108, pp. 49-55 (1994). Lutrepulse (gonadorelin acetate for IV injection), Physi Shi, et al., “Long-Tem Stability of Aqueous Solutions of cian's Desk Reference, 50th Edition, pp.980–982 (1996). Luteinizing Hormone-Releasing Hormone ASSessed by an In-Vitro Bioassay and Liquid Chromatography”, J. of Phar Zoladex (goserelin acetate implant), Physician's Desk Ref maceutical Sciences, 73/6, pp. 819-821 (1984). erence, 50th Edition, pp. 2858–2861 (1996). U.S. Patent Jun. 29, 1999 Sheet 1 of 5 5,916,582 Peptide OO 1O.O 2O, O 3OO 4O.O Time (min) FIG. f. Mor Orner Fragments O. O 1O.O 2OO 30 O 40. O Time (min) FIG 2 U.S. Patent Jun. 29, 1999 Sheet 2 of 5 5,916,582 WOter y = 29.251 - 1.0543e-f- 4x R^2 = O. 985 S -2 Q-Q In kobs hao 3 S -3 S - 4 - 5 OOO28 OOO29 OOO3O OOO31 OOOJ2 OOO,55 o 2 Leuprolide S & 2 Cherrical S. 2 Di/Timer R o Moss Balance N NS Time (months) FIG. 4 U.S. Patent Jun. 29, 1999 Sheet 3 of 5 5,916,582 o 37C o 5OC S 65C s o 80C S. N N FIG. 5 Time (months) Long Term Stability - H2O/HDPE - 37C Chemical Stability Time (days) FIG. 6 U.S. Patent Jun. 29, 1999 Sheet 4 of 5 5,916,582 uOl) O Jueduo) Q Q 00|| 06 09 OZ 09 o7-H M?g peuluelep So Milung U.S. Patent Jun. 29, 1999 Sheet S of 5 5,916,582 .S. hu S (S s S S S & S 2, Oeuv 5,916,582 1 2 AQUEOUS FORMULATIONS OF PEPTIDES 22. “Pharmaceutical Manipulation of Leuprorelin Acetate to Improve Clinical Performance', H. Toguchi, J. Of Intl. CROSS-REFERENCE TO RELATED Medical Research, 18, pages 35-41 (1990). APPLICATIONS 23. “Long-Term Stability of Aqueous Solutions of Lutein 5 izing Hormone-Releasing Hormone ASSessed by an In-Vitro This application claims priority under 35 U.S.C. 119(e) to Bioassay and Liquid Chromatography', Y. F. Shi, R. J. U.S. application Ser. No. 60/021,199 filed Jul. 3, 1996, the Sherins, D. Brightwell, J. F. Gallelli, D. C. Chatterji, J. of disclosure of which is incorporated herein by reference. Pharmaceutical Sciences, 73/6, pages 819-821 (1984). FIELD OF THE INVENTION 24. “Peptide Liquid Crystals: Inverse Correlation of Kinetic Formation and Thermodynamic Stability in Aque This invention relates to Stable aqueous formulations of ous Solution', M. F. Powell, J. Fleitman, L. M. Sanders, V. peptide compounds at high concentrations. C. Si, Pharmaceutical Research, 11/9, pages 1352–1354 BACKGROUND OF THE INVENTION (1994). 25. “Solution Behavior of Leuprolide Acetate, an LHRH References Agonist, as Determined by Circular Dichroism 15 Spectroscopy”, M. E. Powers, A. Adejei, M.Y. Fu Lu, M. C. The following references are referred to by numbers in Manning, Intl. J. of Pharmaceutics, 108, pages 49-55 brackets () at the relevant portion of the specification. (1994). 1. Zoladex (goserelin acetate implant), Physician's Desk 26. “Preparation of Three-Month Depot Injectable Micro Reference, 50th Edition, pages 2858-2861 (1996). Spheres of Leuprorelin Acetate Using Biodegradable 2. U.S. Pat. No. 3,914,412, issued Oct. 21, 1975. Polymers”, Pharmaceutical Research, 11/8, pages U.S. Pat. No. 4,547,370, issued Oct. 15, 1985. 1143–1147 (1994). U.S. Pat. No. 4,661,472, issued Apr. 28, 1987. The disclosure of each of the above publications, patents or patent applications is hereby incorporated by reference in U.S. Pat. No. 4,689,396, issued Aug. 25, 1987. its entirety to the same extent as if the language of each U.S. Pat. No. 4,851,385, issued Jul. 25, 1989. 25 individual publication, patent and patent application were U.S. Pat. No. 5,198,533, issued Mar. 30, 1993. Specifically and individually incorporated by reference. U.S. Pat. No. 5,480,868, issued Jan. 2, 1996. Luteinizing hormone-releasing hormone (LHRH), also WO92/20711, published Nov. 26, 1992. known as gonadotropin releasing hormone (GnRH), is a 10. WO95/00168, published Jan. 5, 1995. decapeptide with the Structure: 11. WO95/04540, published Feb. 16, 1995. 12. "Stability of Gonadorelin and Triptorelin in Aqueous pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH. Solution”, V. J. Helm, B. W. Muller, Pharmaceutical Research, 7/12, pages 1253–1256 (1990). It is Secreted by the hypothalamus and binds to receptors on 13. “New Degradation Product of Des-Gly-NH-LH the pituitary gland, releasing luteinizing hormone (LH) and RH-Ethylamide (Fertirelin) in Aqueous Solution”, J. Okada, 35 follicle stimulating hormone (FSH). LH and FSH stimulate T. Seo, F. Kasahara, K. Takeda, S. Kondo, J. of Pharma the gonads to Synthesize Steroid hormones. Numerous ana ceutical Sciences, 80/2, pages 167-170 (1991). logs of LHRH are known, including peptides related to 14. “Characterization of the Solution Degradation Product LHRH which act as agonists and those which act as antago of Histrelin, a Gonadotropin Releasing Hormone (LHRH) nists. 1-15 LHRH analogs are known to be useful for Agonist”, A. R. Oyler, R. E. Naldi, J. R. Lloyd, D. A. 40 treating hormone-dependent diseaseS Such as prostate Graden, C. J. Shaw, M. L. Cotter, J. of Pharmaceutical cancer, benign proStato megaly, endome triosis, Sciences, 80/3, pages 271-275 (1991). hysteromyoma, metrofibroma, precocious puberty, or mam 15. “Parenteral Peptide Formulations: Chemical and mary cancer and as contraceptives. 8. Sustained release Physical Properties of Native Luteinizing Hormone administration is preferred for both agonist LHRH-related Releasing Hormone (LHRH) and Hydrophobic Analogues 45 compounds, which reduce the number of available receptors in Aqueous Solution”, M.