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(12) United States Patent (10) Patent No.: US 6,503,894 B1 Dudley Et Al

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(12) United States Patent (10) Patent No.: US 6,503,894 B1 Dudley Et Al USOO6503894B1 (12) United States Patent (10) Patent No.: US 6,503,894 B1 Dudley et al. (45) Date of Patent: Jan. 7, 2003 (54) PHARMACEUTICAL COMPOSITION AND 5,460.820 A 10/1995 Ebert et al. METHOD FOR TREATING 5,610,150 A 3/1997 Labrie HYPOGONADISM 5,629,021. A 5/1997 Wright 5,641,504. A 6/1997 Lee et al. (75) Inventors: Robert E. Dudley, Kenilworth, IL 5,643,899 A 7/1997 Elias et al. (US); S. George Kottayil, Long Grove, (List continued on next page.) IL (US); Olivier Palatchi, L'Hayles FOREIGN PATENT DOCUMENTS Roses (FR) DE 3238984 10/1982 (73) Assignees: Unimed Pharmaceuticals, Inc., EP O581.587 A2 2/1994 Marietta, GA (US); Laboratories EP O197753 10/1996 Besins Iscovesco, Herndon, VA (US) EP O804926 4/1997 FR 2515041 4/1983 (*) Notice: Subject to any disclaimer, the term of this FR 2518879 7/1983 patent is extended or adjusted under 35 FR 2519252 7/1983 U.S.C. 154(b) by 0 days. FR 2.705572 12/1994 GB 2109231 6/1983 (21) Appl. No.: 09/651,777 WO WO 93/25168 A1 12/1993 WO 9408590 4/1994 (22) Filed: Aug. 30, 2000 WO 9421230 9/1994 WO 9421271 9/1994 (51) Int. Cl................................................. A61K 31/56 WO WO-96/27372 A1 * 9/1996 .......... A61 K/31/21 (52) U.S. Cl. ........................................ 514/178; 514/177 WO 9636339 11/1996 (58) Field of Search ................................. 514/178, 396, WO 9743989 11/1997 514/406, 415, 177 WO 98O8547 3/1998 WO 9824451 6/1998 (56) References Cited WO WO 98/34621 A1 8/1998 U.S. PATENT DOCUMENTS WO 9837871 9/1998 WO WO-99/24041 A1 * 5/1999 .......... A61 K/31/56 2,155,658 A 4/1939 Herrman et al. WO 9932.107 7/1999 3,068,188 A 12/1962 Beste et al. WO WO 99/66870 A1 12/1999 3.218.283 A 11/1965 Miller WO OO24362 5/2000 3,887,699 A 6/1975 Yolles WO WOOO/66870 A2 8/2000 3,888.995 A 6/1975 Katz et al. WO OO76522 12/2000 3,939,111 A 2/1976 Schollenberger et al. WO WO O1/43775 A2 6/2001 4,009.254. 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The composition comprises an andro 5,326,790 A 7/1994 Thornfeldt genic or anabolic Steroid, a C1-C4 alcohol, a penetration 5,332,577 A 7/1994 Gertner et al. enhancer Such as isopropyl myristate, and water. Also dis 5,340,586 A 8/1994 Pike et al. closed is a method for treating hypogonadism utilizing the 5,362.497 A 11/1994 Yamada et al. composition. 5,413,794. A 5/1995 Suzuki et al. 5,446,070 A 8/1995 Mantelle 42 Claims, 40 Drawing Sheets US 6,503,894 B1 Page 2 U.S. PATENT DOCUMENTS Wang, et al., Effects of Transdermal Testosterone Gel On 5,648,350 A 7/1997 DeLignieres Bone Turnover Markers and Bone Mineral Density in 5,651,973 A 7/1997 Moo-Young et al. Hypogonadal Men, Clinical Endocrinology, vol. 54, pp. 5,654,337 A 8/1997 Roentsch et al. 1–13 (2001). 5,656.286 A 8/1997 Miranda et al. Wang, et al., Transdermal TestosterOne Gel Improves Sexual 5,708,038 A 1/1998 Davis Function, Mood, Muscle Strength, and Body Composition 5,716,638 A 2/1998 Touitou Parameters in Hypogonadal Men, Basic Science. Reproduc 5,719,197 A 2/1998 Kanios et al. tion-Gonadal Control (Male), Male Reproduction Oral Ses 5,723,114 A 3/1998 Thornfeldt et al. 5,744,162. A 4/1998 Okabe et al. sion, No. 1360 (Jun. 24, 2000). 5,760,096 A 6/1998 Thornfeldt et al. Unimed Pharmaceuticals' Androgel Shows Solid Promise 5,770,606 A 6/1998 El Rashidy et al. for Men, Fertility Industry News, www.INCIID.com (Aug. 5,776,923 A 7/1998 Labrie 19, 1998). 5,788.983 A 8/1998 Chien et al. Bentley Pharmaceuticals Announces License Agreement for 5,807,849 A 9/1998 Labrie 5,807,957 A 9/1998 Samour et al. Its Topical Testosterone Gel Formulation, Li, www.UVen 5,837.289 A 11/1998 Grasela et al. tures.com (Dec. 18, 2000). 5,847,128 A 12/1998 Martin et al. Ruggs, Unimed Begins Pivotal Clinical Trial For Innovative 5,855,905 A 1/1999 Oettel et al. Testosterone Gel, Unimed News Release, pp. 1-2 (Mar. 31, 5,874,074. A 2/1999 Smith 1997). 5,908,619 A 6/1999 Scholz 5,908.638 A 6/1999 Huber et al. Androgel 1% (testosterone gel) CIII., www.Androgel.com, 5,932.227 A 8/1999 Higo et al. pp. 1-2. 5,955.455 A 9/1999 Labrie Wang, et al., Effects of Transdermal Testosterone Gel On 5.968919 A 10/1999 Samour et al. Bone Turnover Markers and Bone Mineral Density in 6,010,716 A 1/2000 Saunal et al. Hypogandal Men, Clinical Science. Reproduction 6,019.997 A 2/2000 Scholz et al. (Male)-Prostate, Male Reproduction Poster Session, No. 6,037,346 A 3/2000 Doherty, Jr. et al. 6,075,028 A 6/2000 Graham 2348 (Jun. 22, 2000). 6,077.841 A 6/2000 Sui et al. Swerdloff, et al., Long Term Pharmakonetics of Transdermal 6,087,368 A 7/2000 Macor et al. Testosterone Gel Versus Testosterone Patch in Hypogonadal 6,117,446 A 9/2000 Place Men, Clinical Science. Reproduction (Male)-Prostate, Male 6,127,363 A 10/2000 Doherty et al. Reproduction Poster Session, No. 2347 (Jun. 22, 2000). 6,156,753 A 12/2000 Doherty et al. Trials for the Treatment of Wasting, AIDS Treatment Data 6,238.284 B1 5/2001 Dittgen et al. 6,299,900 B1 10/2001 Reed et al. Network, www.aidsinfonyc.org (Downloaded Oct. 8, 1998). 2001/0018073 A1 8/2001 Dittgen et al. De Lunardo, et al., Determination of Acceptability of 2 2001/0023261 A1 9/2001 Ryoo et al. Cutaneous Estradiol Gels, In A Dose of 1.5 mg Daily, J. 2001/0033870 A1 10/2001 Luo et al. Gynecol. Obstet. Biol. Reprod. (Paris), vol. 29, No. pp. 2001/0036483 A1 11/2001 Luo et al. 509–516, (Sep. 2000). 2001/0051166 A1 12/2001 Luo et al. Zartarian, et al., Comparative Evaluation of the Acceptabil ity of a New Estradiol Gel TX11323(A) and a Reference Gel, OTHER PUBLICATIONS J. Gynecol. Obstet. Biol. Reprod. (Paris), vol. 25, No. 5, pp. Longstreth, et al., Transdermal Testosterone Pharmacoki 451–456 (1996). netics Remain Unchanged With Prolonged Treatment, Simon, et al., The Absorption of Oral Micronized Progest erone. The Effect of Food, Dose Proportionality, and Com Unimed Pharmaceuticals (Oct. 31, 2000). parison With Intramuscular Progesterone, Fertility and Ste Ringham, et al., Dose Proportionality and Systemic Bio rility, vol. 60, No. 1, pp. 26–33 (Jul 1993). availability of a Testosterone Topical Gel In Hypogonadal Vaubourdolle, et al., Effect of Dihydrotestosterone On the Men, Unimed Pharmaceuticals (Oct. 31, 2000). Rate of Ethanol Elimination in Healthy Men, Alcohol Clin. Miller, et al., Androgen Deficiency in Women with Hypopi Exp. Res., vol. 15, No. 2, pp. 238–240 (Mar. 1991). tuitarism, The Journal of Clinical Endocrinology & Metabo Fournier, et al., Value of Percutaneous Estrogen Solution in lism, vol.
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