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(12) Patent Application Publication (10) Pub. No.: US 2004/0002482 A1 Dudley Et Al US 2004.0002482A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0002482 A1 Dudley et al. (43) Pub. Date: Jan. 1, 2004 (54) ANDROGEN PHARMACEUTICAL (60) Provisional application No. 60/292,398, filed on May COMPOSITION AND METHOD FOR 21, 2001. TREATING DEPRESSION Publication Classification (76) Inventors: Robert E. Dudley, Kenilworth, IL (US); S. George Kottayil, Long Grove, (51) Int. Cl." ..................................................... A61K 31/56 IL (US); Olivier Palatchi, L' Hay Les (52) U.S. Cl. .............................................................. 514/169 Roses (FR) Correspondence Address: Joses.ph A. Mahoney, Mayer, (57) ABSTRACT Brown, Rowe & Maw P.O. Box 2828 The present invention relates to methods, kits, combinations, Chicago, IL 60690 (US) and compositions for treating, preventing or reducing the risk of developing a depressive disorder, or the Symptoms (21) Appl. No.: 10/098,232 asSociated with, or related to a depressive disorder in a Subject in need thereof. The present invention also relates to (22) Filed: Mar. 15, 2002 a method of administering a Steroid in the testosterone Related U.S. Application Data Synthetic pathway, for example testosterone, to a Subject in need thereof. In addition, the methods, kits, combinations (63) Continuation-in-part of application No. 09/703,753, and compositions may be used in conjunction with other filed on Nov. 1, 2000, which is a continuation-in-part pharmaceutical agents including agents effective at treating, of application No. 09/651,777, filed on Aug. 30, 2000, preventing, or reducing the risk of developing a depressive now Pat. No. 6,503,894. disorder in a Subject. Patent Application Publication Jan. 1, 2004 Sheet 1 of 46 US 2004/0002482 A1 FIG. 1(a) • '50 ring T-gel - - 100 mg T-gel T.Patch - - - - - High Normal s " " - "Low Nortal Time (Hours) S. • e s -50 ring T-ge i - - too mg T-ge T-Patch - - - - - High Normal - - - - low Northa Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 2 of 46 US 2004/0002482 A1 FIG. 1(c) - - - 50 mg T-gel - - 100 mg T-gel -Patch - - - - high Normal - - - - - Low Normal fine (hours) 800 - - - - 50 mg T-gei - - 1 oo ng T-ge 6 O O -as .Patch - - - - High Nortal - * * * * Low Norta Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 3 of 46 US 2004/0002482 A1 FIG. 1(e) 8OO - - - - 50 mg T-gel - - -75 mg T-gel 6 00 - - 100 mg T-gel T.Patch - ... -- High Normal a : - - - low Normal --A d C "r 5 8 O0 9 Day o Eo - - Day 1 - Day 30 3 600 - - -Day 90 U as t Day 180 - - - - High Normat Y5 cc G up ' ' - low Northal C wa W d H Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 4 of 46 US 2004/0002482 A1 FIG. 1 (g) OOO 8 O O a day 0 - - Day 1 -Day 30 O 6 O - - -Day 90 Day 180 - - - - - High Normal - - - - - low Norrina Time (Hours) ac o y w d o s O sY V 2 w Q - time hours) Patent Application Publication Jan. 1, 2004 Sheet 5 of 46 US 2004/0002482 A1 2 o 5 - - - 50 mg T-gel - - 100 mg T-gel T.Patch i - - - - - High Normat - law Normal 2 O 5 - - - - 50 mg T-gel - - 100 mg T-ge T.Patch - - - - - High Normal 10 Low Normal Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 6 of 46 US 2004/0002482 A1 FIG. 2(c) 2 O 5 50 mg T-gel - - 100 ng T-gel T-Patch o - - - - - High Normal 5 Time (Hours) ar *- C r h ser - - - - So Tig T-gel 9 - - -75 mg T-gel te - - 100 mg T-gel T.Patch OP w o - - - - - High Normal ura3. - - - - - tow Normal e U kn Li Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 7 of 46 US 2004/0002482 A1 FIG. 2(e) - - - -Day o s r- - Day Day 30 "- - -Day 90 day 180 g - " - High Normal A C - - - -day o - - Day 1 s -Day 30 c - - -Day 90 O Day 180 - - - - High Normal Od Low Norrmal h s c Time (Hours) Patent Application Publication Jan. 1, 2004 Sheet 8 of 46 US 2004/0002482 A1 FIG. 2(g) Aa - t sh Aure C d e ra u U C d s Gy O Y &J ed8 G o g U - - - - 50 mg T-Gel - - 100 mg T-Gel - Patch - . High Normal - . - . low Normal 5 O Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 9 of 46 US 2004/0002482 A1 FIG. 4 - a a -50 mg. T-Gel - - 100 mg T-Gel a-as Patch - - - - - High Normal - is slow Normat s l g t S. - - - - 50 mg T-Gel s s - - 100 rig T-Gel a-e-Patch - - - - - High Normal s d me c s wa O s Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 10 of 46 US 2004/0002482 A1 FIG. 6 a.E C ar - - - - 50 mg. T-Gel C t - - 100 mg. T-Gel th did HPatch G - . - . High Normal d - - - - - low Normal O Ud 9. t h gid V U Time (Days) FIG. 7 4 O - - - - 50 mg T-Gel 3O - - 100 mg T-Gel mo Patch - . - . High Normal - - - - - low Norral 90 Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 11 of 46 US 2004/0002482 A1 FIG. 8(a) ge | | | | | 5.30 - 50 mg T-Get e 9 25 T - 100 mg.9 T-Gele e 20 N - U-1NTS- ae -1 - e s as a HighPatch Norrnal 15 - - - - - Low Normal n - N - - - - - - - - - Time (Days) FIG. 8(b) E 5 2 - 50 mg T-Gel E. - - 100 mg T-Gel 9. Patch s t O - - - - - High Normal s * * * Low Nofinal e s 9 l Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 12 of 46 US 2004/0002482 A1 FIG. 8(c) --a - 1 5 E m - - - -50 mg T-Gel 2 - - 100 mg T-Gel w E C Patch w 10 - - - - - High Normal t 6 * * * Low Northal Ud C cd s U Time (Days) FIG. 8(d) - - - -50 mg T-Gei - - 100 mg T-Gel Patch - - - - - High Normal low Normal Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 13 of 46 US 2004/0002482 A1 FIG. 9(a) 50 mg T-Gel - - 100 mg T-Gel Patch - - - - - High Normal - - - - Low Normal Time (Days) E E 1 5 S. to - - - - 50 mg T-Gel 55. - - 100 mg T-Gel Patch gif 1 O - - - - - High Normal s - Low Normal 5 3: Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 14 of 46 US 2004/0002482 A1 FIG. 9(c) - - - -50 mg T-Gel - - 100 mg T-Gel Patch - - - - - High Normal * * * * Low Nortal 90 Time (Days) E w s C C C - - - -50 mg T-Gel C c. con - - 100 mg T-Gel M Patch d 6 V - - - - - High Normal U Low Normal C B O C d Time (Days) Patent Application Publication Jan. 1, 2004 Sheet 15 of 46 US 2004/0002482 A1 FIG. 10(a) O 30 60 90 90 120 1SO 18O FIG. 10(b) Days 90-180 O 30 60 90 90 120 150, 18O Patent Application Publication Jan. 1, 2004 Sheet 16 of 46 US 2004/0002482 A1 4.O FIG. 10(c) 3.5 3.0 2.5 2.0 1.5 1.0 O 30 60 90 90 120 150 18O Day FIG. 11(a) 3. O 1.22. 55O 1 O 0. 5 O 30 60 90 90 120 150 180 Patent Application Publication Jan. 1, 2004 Sheet 17 of 46 US 2004/0002482 A1 FIG. 11(b) 80 7 O 6 O 5 O 40 O 30 60 90 90 120 150 180 Patent Application Publication Jan. 1, 2004 Sheet 18 of 46 US 2004/0002482 A1 FIG. 12(a) s 3. E. e - essengrage -- e as a too ring-ge C e-Paleth e - - - - - high Nortal o : s S. es s s s Tina (hours) FIG. 12 (b) a s r. s.S. mel -- as born Tel s ---Paten - . High metrel - - - - - - Neff Tim (hours) Patent Application Publication Jan. 1, 2004 Sheet 19 of 46 US 2004/0002482 A1 FIG. 12 (c) s a E. s 8 5 U o s hire (tours) Patent Application Publication Jan. 1, 2004 Sheet 20 of 46 US 2004/0002482 A1 FIG. 12 (e) S. und ad s 5 g 3. s 8008O Tline (Hours) Patent Application Publication Jan. 1, 2004 Sheet 21 of 46 US 2004/0002482 A1 FIG. 12 (g) g es were t o o perU s 12 Time (hours) FIG. 12 (h) - - - - - - - - - - - - - - - - - - - - - - - - - -----mm : Patent Application Publication Jan. 1, 2004 Sheet 22 of 46 US 2004/0002482 A1 FIG. 13 (a) G e e S. s E t 5 G - - - 50 mg Y-gal d - - 100 mg aga e 2 -Pen - - - -. High Nemel Y 5. 6apo Y. - slow North his e is Patent Application Publication Jan. 1, 2004 Sheet 23 of 46 US 2004/0002482 A1 FIG. 13 (c) Time Hours) re irne (hours Patent Application Publication Jan. 1, 2004 Sheet 24 of 46 US 2004/0002482 A1 FIG. 13 (e) al - * k s E. e AX A w r d s & e s d w8 s s s k Ys s wa t w w 8 a s a us a as a 2 trne (hours Patent Application Publication Jan. 1, 2004 Sheet 25 of 46 US 2004/0002482 A1 FIG. 13 (g) g S t ar Time (Oays) Patent Application Publication Jan. 1, 2004 Sheet 26 of 46 US 2004/0002482 A1 F.G. 15 p en S. - - - -SOrg T-Gei - -- 00 mu T-Ge.
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