US008957053B2 (12) United States Patent (10) Patent No.: US 8,957,053 B2 geri et al. (45) Date of Patent: Feb. 17, 2015 (54) PROLIPOSOMAL TESTOSTERONE (56) References Cited FORMULATIONS U.S. PATENT DOCUMENTS (71) Applicants: Guru V. Betageri, Chino Hills, CA 4,744,989 A 5/1988 Payne et al. (US); Ramachandran Thirucote, 5,002.936 A 3, 1991 Lieberman et al. Atherton, CA (US); Veeran Gowda 5,049,388 A 9/1991 Knight Kadaji, North Hollywood, CA (US) 3.33. A 12 Nima et al. 6.214.375 B1 4/2001 Modi (72) Inventors: Guru V. Betageri, Chino Hills, CA 59. R ck 3.38. St. et 1 424/450 (US); Ramachandran Thirucote, 6,849.269wr. B2 2/2005 Betagerieager et al. ............... Atherton, CA (US); Veeran Gowda 6,900.235 B1 5/2005 Agyin et al. Kadaji, North Hollywood, CA (US) 7,879,360 B2 2/2011 Cunningham et al. 2002/0187.189 A1* 12/2002 Betageri ....................... 424/480 (73) Assignees: Tesorx Pharma, LLC, Menlo Park, CA 56334.2004/O115226 A1A $5.46/2004 billetLi et al. al. (US); Western University Health 2005, OOO8688 A1 1/2005 Betageri et al. Sciences, Pomona, CA (US) 2006, OO51406 A1 3/2006 Parmar 2007/0053918 A1 3/2007 Panzner et al. 2007. O154403 A1 7, 2007 Skold (*) Notice: Subject to any disclaimer, the term of this 2009, OO17105 A1 1/2009 Khattar et al. patent is extended or adjusted under 35 3.28. 3. A. 1 58.8 E. 1 U.S.C. 154(b) by 0 days. 2010/0173882 A1 7/2010 Giliyarea. et al. 2011 0123625 A1 5/2011 Balu-lyer et al. (21) Appl. No.: 14/149.227 2012/0027864 A1* 2/2012 Betageri ....................... 424/494 2012fO148675 A1 6/2012 Chickmath et al. 2013,0045271 A1 2/2013 Dadey et al. (22) Filed: Jan. 7, 2014 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data EP O648487 A 4f1995 WO OOfSOOO7 A1 8, 2000 US 2014/O11298.6 A1 Apr. 24, 2014 WO O2/O51426 A2 7, 2002 WO 2006/060325 A3 6, 2006 WO 2008114274 A1 9, 2008 Related U.S. Application Data WO 2012058668 A2 5, 2012 WO WO 2012/058668 A2 * 5, 2012 (63) Continuation of application No. PCT/US2013/040325, filed on May 9, 2013. OTHER PUBLICATIONS (60) Provisional application No. 61/644.996, filed on May Agnihotri et al. Controlled release application of multilamellar 9, 2012. vesicles: a novel drug delivery approache. Drug Delivery (2010), vol. 17, pp. 92-101.* Butler et al. Oral testosterone undecanoate in the management of (51) Int. Cl. delayed puberty in boys: pharmacokinetics and effects on sexual A6 IK9/48 (2006.01) maturation and growth. JClin Endocrinol Metab (1992), vol. 75, pp. A6IP5/00 (2006.01) 37-44. A6 IK3I/56 (2006.01) (Continued) A 6LX 9/50 (2006.01) A6 IK9/20 (2006.01) A 6LX 9/27 (2006.01) Primary Examiner — Melenie McCormick A6 IK3I/568 (2006.01) Assistant Examiner — Taina D Matos Negron A 6LX3/575 (2006.01) (74) Attorney, Agent, or Firm — J.A. Lindeman & Co., A6 IK 9/10 (2006.01) PLLC A6 IK 9/14 (2006.01) A 6LX 9/19 (2006.01) (52) U.S. Cl (57) ABSTRACT CPC ............. A61 K9/1277 (2013.01); A61 K3I/568 Novel testosterone formulations are disclosed where test (2013.01); A61 K3I/575 (2013.01); A61K 9/10 osterone is incorporated into a phospholipid?cholesterol sys (2013.01); A61 K9/127 (2013.01); A61 K9/145 tem to produce a proliposomal powder dispersion. The pro (2013.01); A61 K9/19 (2013.01); A61 K9/2013 liposomal powder dispersions of the invention may be (2013.01); A61 K9/4858 (2013.01); A61 K formulated with pharmaceutically acceptable excipients to 9/4891 (2013.01) form pharmaceutical compositions. Enterically coated oral USPC ............................ 514/170; 424/463; 424/474 dosage forms are disclosed as are methods of treatment for (58) Field of Classification Search testosterone replacement therapy. None See application file for complete search history. 20 Claims, 28 Drawing Sheets US 8,957,053 B2 Page 2 (56) References Cited Estradiol. Biochimica Biophysica Acta (BBA)—Biomembranes. Mar. 1, 1968.retrieved on Sep. 10, 2013). Retrieved from the OTHER PUBLICATIONS Internet. <URL: http://www.sciencedirect.com/science/article?pii/ 0005273.6689.01600). Abstract. Rowe et al. Handbook of Pharmaceutical Excipients (2009) pp. 129 PCT International Search Report and Written Opinion for Interna 134* tional Application No. PCT/US2013/040325. Ross et al. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet and hypogonadal men. European Journal of Endo Butler, et al., “Oral Testosterone Undecanoate in the Management of crinology (2004) vol. 150, pp. 57-63.* Delayed Puberty in Boys: Pharmacokinetics and Effects on Sexual Reply to the Communication according to Art. 94(3) EPC, datedMar. Maturation and Growth”, Journal of Clinical Endocrinology and 30, 2012, in EP 05852301.0. Metabolism, 1992, vol. 75, No. 1, pp. 37-44. Sessa et al. Differential Effects of Etiocholanolone on Phospholipid? Cholesterol Structures 1-10 Containing Either Testosterone or * cited by examiner U.S. Patent Feb. 17, 2015 Sheet 1 of 28 US 8,957,053 B2 FIG. 1 U.S. Patent Feb. 17, 2015 Sheet 2 of 28 US 8,957,053 B2 FIG. 2 U.S. Patent Feb. 17, 2015 Sheet 3 of 28 US 8,957,053 B2 FIG. 3 U.S. Patent Feb. 17, 2015 Sheet 4 of 28 US 8,957,053 B2 :::::::: FIG. 4 U.S. Patent Feb. 17, 2015 Sheet 5 of 28 US 8,957,053 B2 isis: is six:8:8 5 U.S. Patent Feb. 17, 2015 Sheet 6 of 28 US 8,957,053 B2 FIG. 6 U.S. Patent Feb. 17, 2015 Sheet 7 of 28 US 8,957,053 B2 FIG. 7 U.S. Patent Feb. 17, 2015 Sheet 8 of 28 US 8,957,053 B2 FIG. 8 U.S. Patent Feb. 17, 2015 Sheet 9 of 28 US 8,957,053 B2 3 s ise it is FIG. 9 U.S. Patent Feb. 17, 2015 Sheet 10 of 28 US 8,957,053 B2 FIG. 10 U.S. Patent Feb. 17, 2015 Sheet 11 of 28 US 8,957,053 B2 FIG. 11 U.S. Patent Feb. 17, 2015 Sheet 12 of 28 US 8,957,053 B2 FIG. 12 U.S. Patent Feb. 17, 2015 Sheet 13 of 28 US 8,957,053 B2 ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- FIG. 13 U.S. Patent Feb. 17, 2015 Sheet 14 of 28 US 8,957,053 B2 3: ; FIG. 14 U.S. Patent Feb. 17, 2015 Sheet 15 of 28 US 8,957,053 B2 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- FIG. 15 U.S. Patent Feb. 17, 2015 Sheet 16 of 28 US 8,957,053 B2 ii:38 it i:S FIG. 16 U.S. Patent Feb. 17, 2015 Sheet 17 of 28 US 8,957,053 B2 : 8:888 FIG. 17 U.S. Patent Feb. 17, 2015 Sheet 18 of 28 US 8,957,053 B2 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, fiase it is tist's FIG. 18 U.S. Patent Feb. 17, 2015 Sheet 19 Of 28 US 8,957,053 B2 38: ice 3 3 : 3. i:kk is it's FIG. 19 U.S. Patent Feb. 17, 2015 Sheet 20 of 28 US 8,957,053 B2 4.O O 3 5 O 3OO : 250 200: 1OO 5 O O TNP TP 1 2 3 6 7 8 9 10 1 12 13 4 15 Testosterone Standard Formulations FIG. 20 U.S. Patent Feb. 17, 2015 Sheet 21 of 28 US 8,957,053 B2 FIG. 21 U.S. Patent Feb. 17, 2015 Sheet 22 of 28 US 8,957,053 B2 88.888.88-888-888-88-888.888 FIG. 22 U.S. Patent Feb. 17, 2015 Sheet 23 of 28 US 8,957,053 B2 : ... s: &s: 2 agii. 34 ng-i. i28 mg-tis 288 rig-sis FIG. 23 U.S. Patent Feb. 17, 2015 Sheet 24 of 28 US 8,957,053 B2 600.00 - 500.00 400.00 300.00 / .N/.N1. 200.00 100.00 or O OO ics-r O 2 4. 6 8 10 12 4 6 18 20 22 24 Time in hours FIG. 24 U.S. Patent Feb. 17, 2015 Sheet 25 of 28 US 8,957,053 B2 0 2 4 6 8 10 12 14, 16 18 20 22 24 Time in hours FIG. 25 U.S. Patent Feb. 17, 2015 Sheet 26 of 28 US 8,957,053 B2 so -* X--Group 1 (Placebo) OOO as Group 2 (120 mg) 800 x Group 3 (600mg) 600 x Group 4 (1200 mg) 400 200 FIG. 26 U.S. Patent Feb. 17, 2015 Sheet 27 Of 28 US 8,957,053 B2 SOOOOO . 4500,00 4OOOOO 35OOOO 3000.00 2500.00 2000.00 :: x Group 11. (Placebo)P. an Group 2 (120 mg) 500.00 : ...: Group 3 (600mg) 1000.00 : w8x Group 4 (1200 mg) 500.00 O OO --~~~~~~~~~~~~~~~~~~~~~~~~ O 1 2 3 4 S 6 7 8 9 10 11 12 13 1.4 5, 16 17 8 19 23 21 22 23 24 Tire in Hours FIG. 27 U.S. Patent Feb. 17, 2015 Sheet 28 of 28 US 8,957,053 B2 3800 - 3600 .: S 34003200 S 3000 : 2800 S. 2600 2: t X Group 1 (Placebo) 9 2OOO -8 see Group 2 (120 mg) S 1800 ::::::: Group 3 (600 mg) 3s 160014OO . x Group 4 (1200 mg) 1200 . e 1OOO 3OO & 600 - 400 : 2OO O --~~~~~--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- O 1 2 3 4 5 6 7 8 9 O 11 12 13 1.4 5 6 17 1892O 2, 22 23 24 Time in Hours FIG.