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WO 2017/147274 Al 31 August 2017 (31.08.2017) P O P C T

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WO 2017/147274 Al 31 August 2017 (31.08.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/147274 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 9/14 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, PCT/US20 17/0 19092 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, 23 February 2017 (23.02.2017) KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, (25) Filing Language: English NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (26) Publication Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, (30) Priority Data: ZA, ZM, ZW. 62/299,257 24 February 2016 (24.02.2016) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: EASTERN VIRGINIA MEDICAL kind of regional protection available): ARIPO (BW, GH, SCHOOL [US/US]; Office Of Technology Transfer, 72 1 GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Fairfax Avenue, Suite 120, Norfolk, VA 23507 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors: MCCORMICK, Timothy, J.; 219 Hawthorne DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lane, Wilmington, DE 19803 (US). DONCEL, Gustavo, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, F.; 1524 Bordeaux Place, Norfolk, VA 23507 (US). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, CLARK, Meredith, Roberts; 4607 Maple Avenue, Beth- GW, KM, ML, MR, NE, SN, TD, TG). esda, MD 20814 (US). SCHWARTZ, Jill; 4704 Clyde Avenue, Garrett Park, MD 20896 (US). Published: (74) Agents: WISZ, Jamie, T. et al; Wilmer Cutler Pickering — with international search report (Art. 21(3)) Hale and Dorr LLP, 1875 Pennsylvania Avenue, NW, Washington, DC 20006 (US). (54) Title: AN IMPROVED FORMULATION OF LONG-ACTING LEVONORGESTREL BUTANOATE INJECTABLE DEPOT SUSPENSION a 1200 1440 Time ( !nj 6.5 n - - 3 µ - ο -30 .3 ηΊ 34. m ig. 2 (57) Abstract: An improved long-acting injectable depot suspension formulation of LB displaying progestational effects which overcomes the aggregation and physical instability of LB injectable depot products, and also provides a longer duration of action of at least 4 months. Potential uses of this formulation include but are not limited to contraception and treatment or prevention of pro - - gestin/progesterone-sensitive reproductive tract dysfunctions and disorders. AN IMPROVED FORMULATION OF LONG-ACTING LEVONORGESTREL BUTANOATE INJECTABLE DEPOT SUSPENSION CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional Application No. 62/299,257, filed February 24, 2016, the contents of which are hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under GPO-A-00-05-0022-00 (FHI Subagreement FHI/FCO #172015) and GPO-A-00-08-00001-00 (FHI Subagreement FHI/FCO #890071) using funds awarded by NICHD-USAID under Interagency Agreement #Yl-HD-0082. The government has certain rights in the invention. TECHNICAL FIELD OF THE INVENTION [0003] The present invention relates to an improved formulation of a long-acting injectable depot suspension of Levonorgestrel Butanoate (LB) for contraceptive use and treatment or prevention of reproductive tract disorders. BACKGROUND OF THE INVENTION [0004] Contraceptive compositions based on esters of Levonorgestrel (LNG) have been disclosed in European Patent EP0129947B1. LNG is a safe and effective progestin contraceptive agent however its duration of action is relatively short when dosed orally and must be taken daily. LB is an esterified version of LNG with longer acting contraceptive properties especially when injected as an aqueous suspension depot formulation (Long- Acting Contraceptive Agents: Design of the WHO Chemical Synthesis Programme. Steroids. 1983 Mar; 41(3):243-53). [0005] Progestin-only contraceptives are advantageous since they have a long-track record of safety and effectiveness and avoid estrogen-related side effects (Benefits and Risks of Oral Contraceptives. Am J Obstet Gynecol. 1999 Jun; 180(6 Pt 2): S343-8). Furthermore, long-acting progestin-only injectable contraceptives are desirable since they do not require daily dosing like oral contraceptives and are very effective when given at the required intervals. There are currently two injectable progestins, medroxyprogesterone acetate and norethindrone enanthate (also known as norethisterone enanthate), in use as long-acting contraceptive agents. Depot medroxyprogesterone acetate (DMPA) is an aqueous suspension depot formulation given at a dose of 150 mg (in 1 mL) every 3 months. Norethindrone enanthate (NET-EN) is formulated in an oil vehicle and given at a dose of 200 mg (in 1 mL) every 2 months. [0006] More than 40 million women worldwide use injectable contraceptives. Use is particularly high in sub-Saharan Africa, where more than one-third of contraceptive users choose injectables. However, despite their popularity, discontinuation rates are high, often due to missed follow-up appointments. Currently available injectables are effective for only 1 to 3 months (depending on the formulation), requiring women to return to their provider 4 to 12 times per year. A longer acting injectable would help address this problem, as users would not have to return to the clinic as frequently for re-injections. Longer intervals between injections may lead to higher compliance and continuation rates (Development of a Longer-Acting Injectable Contraceptive. FHI 360, http://www.M360.org/projects/development-longer-acting-injectable-contraceptive ). [0007] Development of a long-acting LB injectable is particularly advantageous since LB is more potent than the two existing agents (DMPA and NET-EN) exerting its contraceptive activity for a longer period while allowing for a decreased steroid load. LB has been shown to suppress ovulation in women for 5-6 months when injected at a single dose of 50 mg formulated as a micronized aqueous suspension (Garza-Flores J, Hall PE, Perez-Palacios G . Long-Acting Hormonal Contraceptives for Women. J Steroid Biochem Molec Biol 1991;40: 697-704). Unfortunately, earlier formulations of injectable LB were found to aggregate over time, resulting in loss of product stability and reproducibility of the clinical batches. A new stable formulation of LB has been developed and clinical testing at a dose of 20 mg (in 1 mL) showed a 3-month suppression of ovulation (Levonorgestrel Butanoate Intramuscular Injection Does Not Reliably Suppress Ovulation for 90 Days in Obese and Normal BMI Women: A Pilot Study, http://dx.doi .Org/10.1016/i.contraception.2016.07.018 ) . While the duration of action of new LB formulation is similar to that of DMPA and NET-EN, it falls short of the previously demonstrated 5-6 months and the preferred target product profile. Additional optimization of the formulation was conducted, and tested in non-human primates. With an improved and stable particle size formulation, duration of action up to 6 months was observed in non-human primates. [0008] The decreased steroid load of LB may reduce the potential for undesirable side effects such as amenorrhea and hypoestrogenism which is frequently seen with DMPA. Unlike other progestins, DMPA is also increasingly being associated with higher risk for sexual HIV acquisition, possibly related to its significant hypoestrogenism (DMPA Use and HIV Acquisition: Time to Switch to NET-EN? The Lancet HIV, http://dx.doi.org/10.1016/S2352-3018(15)00076-4: Risk of HIV- 1 Acquisition Among Women Who Use Different Types of Injectable Progestin Contraception in South Africa: A Prospective Cohort Study. The Lancet HIV, http://dx.doi.org/10. 1016/52352-3018(15)00058- 2). LNG and LNG-derived injectables, such as LB, hold advantages of convenience and safety for women globally and in particular for those who are at high risk for sexual HIV transmission. In addition to contraception, long-acting progestins, such as LB, may be useful in the treatment or prevention of dysfunctional uterine bleeding, endometrial hyperplasia and cancer, endometriosis, fibroids, PMS, and other reproductive tract disorders. SUMMARY OF THE INVENTION [0009] An improved long-acting injectable depot suspension formulation of LB displaying progestational effects has been developed which overcomes the aggregation and physical instability of previous LB injectable depot products, and also provides a longer duration of action of at least 4 months. Potential uses of this formulation include but are not limited to contraception and treatment or prevention of progestin/progesterone-sensitive reproductive tract dysfunctions and disorders. [0010] The present application discloses modified formulation compositions and manufacturing processes that address the limitations of earlier compositions. [0011] In accordance with one embodiment, the present invention provides an extended duration injectable depot composition of Levonorgestrel Butanoate (LB) where the composition is a sterile aqueous depot suspension
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