INJECTABLE COMPOSITION

Abstract

An injectable depot composition suitable for forming an in situ intramuscular implant is provided. The composition includes sterile biodegradable thermoplastic polymer of polylactic acid (PLA), solvent for the PLA, and drug. After administration to a subject, a corresponding implant administers 0.1-2 milligrams of nonsteroidal aromatase inhibitor every day throughout a dosing period of about six months to about one year. The composition is used to treat subjects in need thereof.

Claims

1-16. (canceled)

17) A kit suitable for preparing an injectable depot composition, the kit comprising PLA (polylactic acid), solvent for PLA, and drug, wherein the particle size distribution of said drug approximates the particle size distribution of said PLA.

18) The kit of claim 17, wherein prior to mixing with said solvent the particle size distribution of the PLA is defined as follows: a) particle size mass distribution with not more than 10% above 300 microns when measured by analytical sieving according to USP<786>; b) particle size mass distribution with not more than 10% above 250 microns when measured by analytical sieving according to USP<786>; c) particle size volume distribution with a D90 not above 330 microns when measured by laser diffraction analysis; d) particle size volume distribution with a D90 not above 280 microns when measured by laser diffraction analysis; e) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; f) particle size volume distribution where less than 10% of the particles have a size below 20 microns, less than 10% of the particles have a size greater than 350 microns, and the D50 is between 70-200 microns, when measured by laser diffraction analysis; g) particle size volume distribution with a D80 not below 135 microns when measured by laser diffraction analysis; h) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; i) particle size mass distribution with not more than 10% above 300 microns, preferably not above 250 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and/or j) particle size volume distribution with a D90 not above 330 microns, preferably not above 280 microns when measured by laser diffraction analysis and with a D80 not below 135 microns when measured by laser diffraction analysis.

19) The kit according to claim 17, wherein the kit comprises at least a first container and a second container, wherein a) the first container contains the drug and PLA, and the second contains the solvent; b) the first container contains the drug, the second contains PLA, and the solvent is in the first container, the second container, and/or in a third container.

20) A method of preparing an injectable depot composition, the method comprising a) providing the kit of claim 17; and b) mixing the components of the containers of the kit, thereby forming said injectable depot composition.

21) The method of claim 20, further comprising sterilizing the DMSO and PLA prior to said mixing.

22) The method of claim 21, wherein said sterilizing is achieved by beta irradiation or filtration.

23) An injectable depot composition consisting essentially of a) 15-35 wt. % drug, 25-35 wt. % PLA, and 30-60 wt. % DMSO; b) 18-28 wt. % drug, 30-35 wt. % PLA, and 37-52 wt. % DMSO; or c) about 23 to about 27 wt. % drug, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO; wherein the weight percentages are with respect to the total weight of said composition; and prior to mixing with said DMSO the PLA has a particle size distribution defined as follows: a) particle size mass distribution with not more than 10% above 300 microns when measured by analytical sieving according to USP<786>; b) particle size mass distribution with not more than 10% above 250 microns when measured by analytical sieving according to USP<786>; c) particle size volume distribution with a D90 not above 330 microns when measured by laser diffraction analysis; d) particle size volume distribution with a D90 not above 280 microns when measured by laser diffraction analysis; e) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; f) particle size volume distribution where less than 10% of the particles have a size below 20 microns, less than 10% of the particles have a size greater than 350 microns, and the D50 is between 70-200 microns, when measured by laser diffraction analysis; g) a particle size volume distribution with a D80 not below 135 microns when measured by laser diffraction analysis; h) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; i) particle size mass distribution with not more than 10% above 300 microns, preferably not above 250 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and/or j) particle size volume distribution with a D90 not above 330 microns, preferably not above 280 microns when measured by laser diffraction analysis and with a D80 not below 135 microns when measured by laser diffraction analysis.

24) A method of administering drug to a subject, the method comprising a) providing an injectable depot composition comprising PLA, solvent for PLA, and said drug; b) intramuscularly administering said injectable depot composition to said subject; wherein prior to mixing with said solvent the PLA has a particle size distribution defined as follows: a) particle size mass distribution with not more than 10% above 300 microns when measured by analytical sieving according to USP<786>; b) particle size mass distribution with not more than 10% above 250 microns when measured by analytical sieving according to USP<786>; c) particle size volume distribution with a D90 not above 330 microns when measured by laser diffraction analysis; d) particle size volume distribution with a D90 not above 280 microns when measured by laser diffraction analysis; e) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; f) particle size volume distribution where less than 10% of the particles have a size below 20 microns, less than 10% of the particles have a size greater than 350 microns, and the D50 is between 70-200 microns, when measured by laser diffraction analysis; g) a particle size volume distribution with a D80 not below 135 microns when measured by laser diffraction analysis; h) particle size mass distribution where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; i) particle size mass distribution with not more than 10% above 300 microns, preferably not above 250 microns, and where not more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; and/or j) particle size volume distribution with a D90 not above 330 microns, preferably not above 280 microns when measured by laser diffraction analysis and with a D80 not below 135 microns when measured by laser diffraction analysis.

25) A method of treating a disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase, said method comprising administering said injectable depot composition prepared from the kit of claim 17, wherein said drug is a nonsteroidal inhibitor of aromatase.

26) A method of treating a disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase, said method comprising administering said injectable depot composition prepared according to the method of claim 20, wherein said drug is a nonsteroidal inhibitor of aromatase.

27) A method of treating a disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase, said method comprising administering said injectable depot composition according to claim 23, wherein said drug is a nonsteroidal inhibitor of aromatase.

28) A method of treating a disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase, said method comprising administering drug according to the method of claim 24, wherein said drug is a nonsteroidal inhibitor of aromatase.

29) The method of claim 25, wherein said disease, disorder, or condition is selected from the group consisting of a) adjuvant treatment (treatment following surgery with or without radiation) of postmenopausal women with hormone receptor-positive early breast cancer; b) metastasis in both pre and post-menopausal women; c) precocious puberty or children with pubertal gynecomastia; d) reducing estrogens, including estradiol, in men; e) hormonally-responsive breast cancer after surgery; f) ovarian stimulation; g) promote spermatogenesis in male patients suffering from nonobstructive azoospermia; h) endometriosis; i) cancer that is estrogen hormone receptor-positive or sensitive (non-small cell lung cancer, uterine leiomyomas); j) infertility in women with polycystic ovarian syndrome; k) ovarian cancer; l) breast cancer that is estrogen hormone receptor positive or sensitive; j) priming for in vitro maturation cycles; k) preoperative treatment with letrozole in premenopausal women undergoing laparoscopic myomectomy of large uterine myomas; l) short stature in peripubertal boys; m) unexplained infertility or infertility with unknown or uncertain etiology; n) idiopathic central precocious puberty in boys; o) gynecomastia; p) endometriosis; q) ER-negative disease in subjects who did not respond to previous tamoxifen therapy; r) early breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy; and s) advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.

30) The method according to claim 25, wherein, following said administering, one or more implants formed from said injectable depot composition continuously releases from about 0.1 to about 2 mg, or from about 0.1 to about 1.25 mg, or from about 0.13 to about 1.25 mg, or from about 0.13 to about 1.15 mg, or from about 0.13 to about 1.1 mg, or from about 0.13 to about 0.8 mg of said drug every day throughout a dosing period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, about 3 months, about 6 months, about 9 months, about 12 months, or from about 6 months to about 12 months.

31) The method according to claim 25, wherein, following said administering, one or more implants formed from said injectable depot composition a) releases an average of about 10-15% of its charge of said drug per 28-day interval for the first four intervals and then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals; b) releases no more than about 60% (or no more than about 55%, or no more than about 50%) of its charge of said drug within the first 112 days (four 28-day intervals) and releases the remainder of its charge of said drug at a rate of about 2-6% per 28-day interval for 8 to 9 intervals (about 224 days to about 252 days; c) releases about 40-55% or about 40-50% of its charge of said drug during the first 3-4 months and about 60-45% or about 60-50%, respectively, of its charge of said drug during the following 8-9 months; d) releases up to a total of about 30% of its charge of said drug during the first 28-day interval, up to a total of about 40% of its charge of said drug during the second 28-day interval, up to a total of about 50% of its charge of said drug during the third 28-day interval, up to a total of about 55% during the fourth 28-day interval, then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals; or e) releases up to a total of about 20-35% of its charge of said drug during the first 28-day interval, up to a total of about 25-40% of its charge of said drug during the second 28-day interval, up to a total of 35-50% of its charge of said drug during the third 28-day interval, up to a total of about 40-55% during the fourth 28-day interval, then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals.

32) The method according to claim 25, wherein said drug is letrozole and, following said administering, one or more implants formed from said injectable depot composition releases letrozole according to any the following profiles TABLE-US-00010 Percentage of Percentage of Mean or average of 28-day letrozole letrozole percentage of interval released* released* letrozole released* 1.sup.st 7-15 9-13 About 11-12 2.sup.nd 5-12 6-11 About 7.5-8.5 3.sup.rd 2-9  3-8  About 3.5-7.5 4.sup.th and on for 0.5-6   1-6  About 2-6 each interval through final interval for at least 8 intervals 1.sup.st Up to 25 Up to 15 Up to 13 2.sup.nd Up to 18 Up to 13 Up to 11 3.sup.rd Up to 12 Up to 10 Up to 8 4.sup.th and on for Up to 10 Up to 8 Up to 6 each interval through final interval for at least 8 intervals *wherein the percentage is relative to the initial charge of letrozole in the implant.

33) The method according to claim 25, wherein, following said administering, one or more implants formed from said injectable depot composition provides a plasma level of said drug between about 1 to about 40 ng/ml, or between about 1.5 to about 30 ng/mL, or between about 1.5 to about 15 ng/mL from about 2 days after administration and continuously throughout a dosing period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, about 3 months, about 6 months, about 9 months, about 12 months, or from about 6 months to about 12 months.

34) The method according to claim 25, wherein, following said administering, one or more implants formed from said injectable depot composition reduces the plasma level of estradiol in said subject to less than 1.0 pg/mL, less than 0.5 pg/mL, less than 0.3 pg/mL, or less than 0.1 pg/mL within about four days after administration and continuously throughout a dosing period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, about 3 months, about 6 months, about 9 months, about 12 months, or from about 6 months to about 12 months.

35) The method according to claim 34, wherein said injectable composition provides an immediate onset of action.

36) The kit of claim 18, wherein said injectable depot composition consists essentially of a) 15-35 wt. % drug, 25-35 wt. % PLA, and 30-60 wt. % DMSO; b) 18-28 wt. % drug, 30-35 wt. % PLA, and 37-52 wt. % DMSO; or c) about 23 to about 27 wt. % drug, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO; wherein the weight percentages are with respect to the total weight of said composition.

37) The kit of claim 18, wherein the amount of said drug present is a) 10 to 500 mg of said drug; b) 10 to 450 mg of said drug; c) 30 to 90 mg of said drug; d) about 50 mg of said drug; e) 80 to 150 mg of said drug; f) about 100 mg of said drug; g) 150 to 250 mg of said drug; h) about 200 mg of said drug; i) 350 to 450 mg of said drug; or j) about 400 mg of said drug.

38) The kit of claim 18, wherein the particle size distribution of said drug approximates the particle size distribution of said PLA.

39) The kit of claim 17, wherein the particle size volume distribution of said drug is such that less than 10% of the particles have a size below 20 microns, less than 10% of the particles have a size greater than 350 microns and the D50 is between 70-200 microns, when measured by laser diffraction analysis.

40) The kit of claim 17, wherein the solvent is DMSO, and said drug is selected from the group consisting of letrozole, anastrozole, salt of either thereof, and metabolite of either thereof.

41) The method of claim 20, wherein the drug is present in said injectable depot composition as a suspension, and the PLA is dissolved in the solvent in said injectable depot composition.

42) The method of claim 20, wherein the PLA has been sized.

43) The composition of claim 23, wherein the PLA is end capped with an ester group.

44) The composition of claim 23, wherein a) the weight ratio of DMSO to PLA is about 1.3:1 to about 1.5:1, or about 1.4:1; b) the weight ratio of DMSO to drug is in the range of about 1.5:1 to about 2:1, about 1.7:1 to about 1.8:1, or about 1.75:1; c) the weight ratio of polymer solution (solvent+PLA) to drug is about 2.8:1 to about 3.2:1, or about 3:1; and/or d) the weight ratio of PLA to drug is about 1.1:1 to about 1.35:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1.25:1.

45) The composition of claim 23, wherein an extended release composition formed from said injectable depot composition a) releases up to 30% of said drug within 30 days, preferably up to 25% of said drug within 30 days; b) releases up to 50% of said drug within 100 days, preferably within 120 days and more preferably within 130 days; c) releases up to 80% of said drug within 140 days, preferably within 180 days, more preferably within 200 days; d) releases up to 80% of said drug within 240 days; e) the implant releases an average of about 10-15% of its charge of said drug per 28-day interval for the first four intervals and then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals; f) releases no more than about 60% (or no more than about 55%, or no more than about 50%) of its charge of said drug within the first 112 days (four 28-day intervals) and releases the remainder of its charge of said drug at a rate of about 2-6% per 28-day interval for 8 to 9 intervals (about 224 days to about 252 days); g) releases its charge of said drug over a period of at least about one year, at least about 365 days, or at least about twelve to thirteen 28-day intervals; h) releases about 40-55% or about 40-50% of its charge of said drug during the first 3-4 months and about 60-45% or about 60-50%, respectively, of its charge of said drug during the following 8-9 months; i) releases up to a total of about 30% of its charge of said drug during the first 28-day interval, up to a total of about 40% of its charge of said drug during the second 28-day interval, up to a total of about 50% of its charge of said drug during the third 28-day interval, up to a total of about 55% during the fourth 28-day interval, then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals; and/or j) releases up to a total of about 20-35% of its charge of said drug during the first 28-day interval, up to a total of about 25-40% of its charge of said drug during the second 28-day interval, up to a total of 35-50% of its charge of said drug during the third 28-day interval, up to a total of about 40-55% during the fourth 28-day interval, then an average of about 2-6% of its charge of said drug per 28-day interval for the following eight to nine intervals; wherein said release is determined in an in vitro dissolution assay performed with horizontal orbital motion at 50 rpm; medium: PBS pH 7.4; temperature: 37±0.5° C.; analytical technique: HPLC/UV; wavelength 230 nm.

46) The composition of claim 23, wherein said drug is letrozole and implant(s) formed in a subject after administration of said injectable depot composition provides the following pharmacokinetic performance: TABLE-US-00011 Dose of drug administered About 50 About 100 (mg) Daily Plasma Concentration About 4.5 (about About 8.8 (about from about 2 days after 0.5 to about 13) 1.5 to about 21) administration (ng/mL) Cmax (ng/mL) About 5 About 11 Tlag (h) 0 h 0 h wherein Tlag corresponds to the delay between the time of dosing and time of appearance of a measurable concentration of letrozole in the plasma and wherein values are mean values.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0095] The following drawings are part of the present specification and are included to further demonstrate certain aspects of the invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of the specific embodiments presented herein.

[0096] FIG. 1 depicts a chart of estradiol (E2) plasma levels (pg/ml) observed versus time after administration of FEMARA® or the composition of the invention (Letrozole ISM). More rapid and sustained estradiol suppression were achieved using substantially lower doses of the composition of the invention (and/or substantially lower plasma levels of letrozole) as compared to FEMARA® dose and plasma level of letrozole.

[0097] FIG. 2 depicts a chart of letrozole plasma levels (ng/ml) observed versus time after administration of FEMARA® or the composition of the invention (Letrozole ISM). The composition of the invention provided a substantially longer sustained letrozole plasma levels. Letrozole plasma levels (ng/ml) observed after administering Femara® or the.

[0098] FIG. 3 depicts a chart of cumulative percentage of released letrozole versus time (d) in an in vitro dissolution test from a composition comprising PLA having a particle size mass distribution where more than 10% of the particles have a particle size of 300 microns or more, when measured by analytical sieving according to USP<786>.

[0099] FIG. 4 depicts a chart of cumulative percentage of released letrozole versus time from a composition of the invention in an in vitro dissolution test.

[0100] FIG. 5 depicts a chart of cumulative percentage of released letrozole versus in an in vitro dissolution test from a composition comprising PLA having a particle size mass distribution wherein at least 80% of the particles have a particle size of 125 microns or less, when measured by analytical sieving according to USP<786>.

[0101] FIGS. 6A and 6B depict chart of estradiol (E2) plasma levels (pg/ml) observed versus time after administration of FEMARA® or the composition of the invention (Letrozole ISM comprising 50 mg of letrozole). The inset depicts an expanded view of the first 15 days.

[0102] FIGS. 7A and 7B depict charts of estradiol (E2) plasma levels (pg/ml) observed versus time after administration of FEMARA® or the composition of the invention (Letrozole ISM comprising 100 mg of letrozole). The inset depicts an expanded view of the first 15 days.

[0103] FIG. 8 depicts a chart of letrozole plasma levels (ng/ml) observed versus time after administration of FEMARA® or the compositions of the invention (Letrozole ISM 50 mg or 100 mg).

[0104] FIG. 9 depicts a chart of the particle size distribution of an exemplary PLA of the composition of the invention measured by laser diffraction analysis (Horizontal axis: particle size in microns; Vertical axis: volume (%), indicating the percentage of particles with the corresponding particle size, measured by laser diffraction by wet dispersion method in water and dispersing by stirring at 3000 rpm).

[0105] An overlay of the charts of FIGS. 6A, 6B, 7A, and 7B depict the plasma levels of E1 (estrone) and E2 (estradiol).

DETAILED DESCRIPTION OF THE INVENTION

[0106] As used herein, the terms “disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase” excludes any disease, disorder or condition that is not therapeutically responsive to nonsteroidal inhibitor of aromatase. The therapeutic responsive of said disease, disorder or condition to nonsteroidal inhibitor of aromatase is determined by administering one or more compositions of the invention to a subject in need thereof, wherein the dose of drug (via the composition) is administered as defined herein to provide one or more implants that release said nonsteroidal inhibitor of aromatase for the period of time as defined herein to provide the plasma levels of said drug or metabolite thereof as defined herein. A clinician then determines whether said disease, disorder or condition responds therapeutically, meaning the clinician determines whether the subject in need has experienced the desired clinical benefit(s). For example, when treating cancer, a therapeutic response may include slowing or reversing the progression of the cancer or might even include remission of the cancer. When treating gynecomastia, a therapeutic response may include reduction in breast size or slowing down the enlargement of the breast. A clinician familiar with nonsteroidal inhibitors of aromatase will be able to follow methods and conventions of the art to determine whether said disease, disorder or condition is therapeutically responsive to said nonsteroidal inhibitor of aromatase.

[0107] As used herein, the term “dosing period” refers to the period from administration of injectable depot composition to termination of release of drug from a corresponding one or more implants. As used herein, the term “treatment period” refers to the period during which a subject receives dose(s) of the injectable depot composition. A treatment period may comprise one or more dosing periods during which time the subject receives one or more corresponding doses.

[0108] As used herein, the terms “letrozole” and “anastrozole” refers to the non-salt and salt forms thereof. The term “active ingredient”, “active agent”, or “drug” refers to a therapeutically active compound, as well as any, derivatives thereof, prodrugs thereof, and pharmaceutically acceptable salts, hydrates and solvates of said compound, derivative(s), and prodrug(s). In the present invention, the active agent is letrozole and/or anastrozole.

[0109] The term “stable sustained release composition” generally refers to the one or more implant(s), which together provide a dose of drug during a dosing period.

[0110] The term “stable” as used herein refers to a pharmaceutical composition comprising letrozole wherein the total content of impurities originating from the decomposition of letrozole does not exceed 5% area, preferably 3% area, more preferably 2% area and most preferably 1% area determined by liquid chromatography (HPLC) at 230 nm if such a composition is stored for 2 months at 40° C. and 75% relative humidity (RH).

[0111] The inventors have unexpectedly determined that the particle size distribution of the PLA (polylactic acid) polymer used in the composition (and corresponding implant(s)) of the invention has an impact upon in vitro and in vivo performance of the implant(s).

[0112] As used herein, “sized” PLA (pr “PLA that has been sized) is PLA that has been processed to provide a particular particle size distribution as described herein. Sizing of the PLA is optional. Methods of sizing PLA, include by way of example and without limitation, milling, comminuting, sieving, classifying, grinding, impacting, homogenizing, sonicating, ultrasonicating, dry milling, wet milling, cryogenic milling or other such processes known in the art of particle size reduction.

[0113] When the PLA particle size is measured by analytical sieving according to USP<786>, the amplitude is 0.65 mm and the shaking time is 5 minutes. When the PLA particle size is measured by laser diffraction analysis, the particle size is determined by wet dispersion method. No sample pre-treatment was applied. The sample was directly added into the dispersion medium (water). Dispersion mechanism was stirring at 3000 rpm.

[0114] The PLA polymer is selected from free acid (not end-capped; uncapped) or end-capped (e.g. alkyl esters such as lauryl ester, methyl ester, etc., referred to herein as PLA-e) terminal carboxylic poly-lactide with polymer. The PLA polymer can be a poly(L-lactic acid) polymer, poly(D,L-lactic acid) polymer, poly (D-lactic acid) or a copolymer of those polymers. Polymers that are end-capped with esters (as opposed to the free carboxylic acid) demonstrate longer degradation half-lives; even so, uncapped polymers having carboxylic acid terminal groups also exhibit the particle size-related improved performance. Suitable grades of PLA are commercially available from Uhde Inventa-Fischer (Berlin, Del.), NatureWorks LLC (Blair, Nebr., USA), Plastic Ingenuity (Cross Plains, Wis., USA), Toyobo, Dai Nippon Printing Co., Mitsui Chemicals, Shimadzu, NEC, Toyota (Japan), PURAC Biomaterials, Hycail (The Netherlands), Galactic (Belgium), Cereplast (U.S.A.), FkuR, Biomer, Stanelco, lnventa-Fischer (Germany), Snamprogetti (China), Boehringer Ingelheim (RESOMER® grades; Ingelheim Am Rhein, Del.), Evonik Industries (RESOMER® grades; Essen, Del.), ALKERMES (Dublin, Ireland) or SIGMA ALDRICH (ST. Louis, Mo.). In some embodiments, the PLA is end-capped with an alkyl alcohol to form an ester end group moiety.

[0115] The PLA polymer exhibits an inherent or intrinsic viscosity in the range of about 0.16-0.60 dl/g, or about 0.20-0.50 dl/g as measured in chloroform at 25° C. at a concentration of 0.1% wt/v with a Ubbelhode size 0c glass capillary viscometer or as measured in chloroform at 30° C. and at a concentration of 0.5% wt/v with a size 25 Cannon-Fenske glass capillary viscometer. The inherent viscosity can be as measured before or after beta irradiation, if such irradiation is employed.

[0116] As used herein, the term “polymeric solution” is taken to mean the fluid composition comprising a combination of the solvent and the polymer dissolved therein. In some embodiments, at least 80%, at least 90%, at least 95%, at least 99% or all of the polymer is dissolved in the solvent. The injectable composition comprises (or consists essentially or consists of) solvent, PLA polymer and drug. Accordingly, the injectable composition comprises (or consists essentially or consists of) polymeric solution and drug.

[0117] In some embodiments, the polymeric solution has a minimum viscosity of about 0.8 Pa.Math.s, although this may preferably be around 1 Pa.Math.s. The viscosity can be about 4 Pa.Math.s or less, about 3 Pa.Math.s or less, about 2 Pa.Math.s or less, about 1.8 Pa.Math.s or less. The viscosity of the polymer solution can range from about 0.7 to about 4 Pa.Math.s, about 0.7 to about 3 Pa.Math.s, about 0.7 to about 2 Pa.Math.s, about 0.8 to about 1.8 Pa.Math.s or about 1 to about 1.8 Pa.Math.s. The viscosity of polymeric solutions in DMSO is measured at 25° C. If not otherwise specified, the viscosity value of the polymeric solution or the injectable composition is given in Pa.Math.s units.

[0118] In some embodiments, the weight ratio of DMSO to PLA is about 1:1 to about 2.3:1, about 1.2:1 to about 1.8:1, about 1.3:1 to about 1.5:1, or about 1.4:1.

[0119] In some embodiments, the weight ratio of DMSO to drug is in the range of about 0.5 to about 3.7, about 1:1 to about 3:1, about 1.5:1 to about 2:1, about 1.7:1 to about 1.8:1, or about 1.75:1.

[0120] In some embodiments, the weight ratio of polymer solution to drug is about 1:1 to about 5.7:1, about, 2.3:1 to 4:1, about 2.8:1 to about 3.2:1, or about 3:1.

[0121] In some embodiments, the weight ratio of PLA to drug is about 0.6:1 to about 2.8:1, about 1.0 to 2.0, about 1.1:1 to 1.6:1, about 1.1:1 to about 1.4:1, about 1.1:1 to about 1.35:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1.25:1.

[0122] In some embodiments, the drug is partially dissolved or completely undissolved in the polymeric solution. In some embodiments, ≤5%, ≤10%, ≤20% wt of the drug is dissolved in the solvent or polymeric solution to form the injectable composition. In some embodiments, >0%, ≥0.5%, ≥1%, ≥5%, or ≥10% wt. of the drug is dissolved in the solvent or polymeric solution to form the injectable composition.

[0123] The expression “immediate onset of action” as used herein means that the estrogen plasma level suppression achieved by the composition of the invention is at least as early as the one achieved by oral therapy with FEMARA®, namely at day 4. For example, FEMARA® (oral) and a composition of the invention (Letrozole ISM) were compared by administering a dose of each to human subjects. The results (depicted in FIG. 1) demonstrate that no estradiol (E2) can be detected, meaning E2 is below the detection limit. Importantly, however, a lower dose of letrozole was administered as Letrozole ISM than as FEMARA®. Accordingly, the composition of the invention is able to reduce the plasma level of E2 to less than 1.0 pg/mL, less than 0.8 pg/mL, less than 0.5 pg/mL, less than 0.3 pg/mL, or less than 0.1 pg/mL within about four days after administration and continuously throughout a dosing period.

[0124] The performance of FEMARA® and a composition of the invention (Letrozole ISM) was compared (FIG. 2) in terms of plasma concentration achieved after administration of a dose to human subject. The FEMARA® composition provided extremely high plasma concentrations of letrozole, which can then be associated with much higher incidence or severity of adverse events. On the other hand, the composition of the invention provided a) no burst release of letrozole; b) substantially longer sustained letrozole plasma levels of letrozole; and c) therapeutically effective plasma levels of letrozole for about 16 weeks (about 4 months) or more.

[0125] The relative impact of particle size distribution of PLA was determined by comparing the in vitro dissolution profile (drug release profile) for various extended release compositions formed from injectable depot compositions comprising PLA of different particle size distributions.

[0126] The impact of the relative content of larger PLA particles was determined. FIG. 3 depicts a chart of cumulative percentage of released letrozole versus time (d) in an in vitro dissolution test from a composition (not according to the invention) comprising PLA having a particle size mass distribution where more than 10% of the particles have a particle size of 300 microns or more, when measured by analytical sieving according to USP<786>. The PLA used in the composition of FIG. 3 had a particle size mass distribution where 18.1% of the particles were bigger than 300 microns and 28.3% of the particles were smaller than 125 microns, measured by analytical sieving according to USP<786>. Said PLA had a particle size volume distribution with a D90 of 421 microns and a D80 of 324 microns when measured by laser diffraction analysis.

[0127] FIG. 4 depicts a chart of cumulative percentage of released letrozole versus time from a composition of the invention in an in vitro dissolution test. The PLA used had a particle size mass distribution where 0.8% of the particles were bigger than 300 microns and 58.5% of the particles were smaller than 125 microns, measured by analytical sieving according to USP<786>. Said PLA had a particle size volume distribution with a D90 of 214 microns and a D80 of 170 microns when measured by laser diffraction analysis. The sustained release was satisfactory and was unexpectedly about two months longer than that provided by the PLA not according to the invention (FIG. 3).

[0128] The impact, upon drug dissolution, of the relative content of smaller PLA particles was determined. FIG. 5 depicts a chart of cumulative percentage of released letrozole versus in an in vitro dissolution test from a composition comprising PLA having a particle size mass distribution wherein at least 80% of the particles have a particle size of 125 microns or less, when measured by analytical sieving according to USP<786>. The PLA used in the composition had a particle size mass distribution where 1.6% of the particles were bigger than 300 microns and 88.8% of the particles were smaller than 125 microns, measured by analytical sieving according to USP<786>. Said PLA had a particle size volume distribution with a D90 of 155 microns and a D80 of 124 microns when measured by laser diffraction analysis. The implant provided satisfactory sustained release results; even though, it formed hard agglomerates during initial mixing of the DMSO, PLA and drug.

[0129] FIGS. 6A and 6B depict chart of estradiol (E2) plasma levels (pg/ml) observed versus time after oral administration of FEMARA® (2.5 mg once daily for 14 days) or intramuscular administration of the composition of the invention (Letrozole ISM; one injection comprising 50 mg of letrozole) according to Example 3 (Cohort 1). The inset depicts an expanded view of the first 15 days. FIGS. 7A and 7B depict charts of estradiol (E2) plasma levels (pg/ml) observed versus time after oral administration of FEMARA® (2.5 mg once daily for 14 days) or intramuscular administration of the composition of the invention (Letrozole ISM; one injection comprising 100 mg of letrozole) according to Example 3 (Cohort 2). The inset depicts an expanded view of the first 15 days. Plasma estrogen levels decreased rapidly from baseline following administration of letrozole. The hormones decreased to stable levels below 1 pg/mL at approximately 4 days post-Femara®/Letrozole ISM treatment (FIGS. 6A, 6b, 7A and 7B). The sustained suppression of estrogen levels was maintained for at least about 365 days (or at least about 6 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months) for Letrozole ISM 50 mg and 100 mg. There were no apparent differences in the extent of hormonal level decrease between Letrozole ISM 50 mg and 100 mg. It is very surprising that a 50 mg dose injectable composition was as effective as a 100 mg dose injectable composition in terms of E2 suppression.

[0130] FIG. 8 depicts a chart of letrozole plasma levels (ng/ml) observed versus time after administration of FEMARA® (2.5 mg once daily for 14 days) or the compositions of the invention (Letrozole ISM 50 mg or 100 mg) corresponding to FIGS. 6 and 7. Letrozole mean maximum exposure concentrations observed for FEMARA® at steady state (2.5 mg QD for 14 days) were approximately 12-fold and 8-fold greater than that observed for Letrozole 50 mg and 100 mg doses, respectively. The much higher plasma concentration provided by FEMARA® would provide corresponding higher severity and/or incidence of adverse events as compared to the much lower and still therapeutically effective plasma concentration provided by the composition(s) of the invention.

[0131] By overlaying the charts of FIGS. 6A, 6B, 7A, and 7B, the 100 mg injectable composition has twice the dose of letrozole as the 50 mg injectable composition, both compositions are effective at maintaining the plasma levels of E1 (estrone) and E2 (estradiol) below the LOQ, the level of quantitation, for at least about 365 days.

[0132] Accordingly, the composition(s) of the invention provide(s) therapeutically effective plasma levels of letrozole for at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, or at least 12 months, while concomitantly providing reduced adverse events.

[0133] The invention provides a method of treating a disease, disorder or condition that is therapeutically responsive to nonsteroidal inhibitor of aromatase. Said nonsteroidal inhibitor can be letrozole, anastrozole, or metabolite of either thereof. Exemplary diseases, disorders or conditions include, for example: a) adjuvant treatment (treatment following surgery with or without radiation) of postmenopausal women with hormone receptor-positive early breast cancer; b) metastasis in both pre and post-menopausal women; c) precocious puberty or children with pubertal gynecomastia; d) reducing estrogens, including estradiol, in men; e) hormonally-responsive breast cancer after surgery; f) ovarian stimulation; g) promote spermatogenesis in male patients suffering from nonobstructive azoospermia; h) endometriosis; i) cancer that is estrogen hormone receptor-positive or sensitive (non-small cell lung cancer, uterine leiomyomas, etc.); j) infertility in women with polycystic ovarian syndrome; k) ovarian cancer; l) breast cancer that is estrogen hormone receptor positive or sensitive; j) priming for in vitro maturation cycles; k) preoperative treatment with letrozole in premenopausal women undergoing laparoscopic myomectomy of large uterine myomas; l) short stature in peripubertal boys; m) unexplained infertility or infertility with unknown or uncertain etiology; n) idiopathic central precocious puberty in boys.

[0134] The invention also provides a method of forming an injectable depot composition, the method comprising mixing solvent, PLA polymer and drug to form the injectable depot composition as defined herein. The solvent, PLA and drug may be in one, two, three or more containers. In one embodiment, PLA and drug are in a container and solvent is in a separate container and the contents of the containers are mixed to form the composition. In another embodiment, PLA, drug, and solvent are in separate containers, and the contents of the containers are mixed to form the composition. In another embodiment, PLA and solvent are in a container, and drug is in a separate container, and the contents of the containers are mixed to form the composition. The container(s) may be part of a pharmaceutical kit. Accordingly, the invention also provides a pharmaceutical kit comprising the one or more containers, wherein the content of the container(s) are as described herein.

[0135] The invention provides a method administering letrozole or anastrozole to a subject. The method comprises administering an amount (or volume) of injectable composition comprising the aromatase inhibitor. The method may further comprise the step of forming the injectable composition before administration thereof. The method may further comprise the step of providing a kit comprising containers with the ingredients of the injectable composition. The composition can be administered every about 30 days, about 45 days, about 60 days, about 90 days, about 120 days, or 150 days, or about every month, about every two months, about every three months, about every four months, about every five months, about every six months, about every nine months, about every ten months, about every eleven months, about every twelve months, or as often as needed for as many times needed to ameliorate the disease, disorder or condition. Combinations of the dosing regimens herein are contemplated. The composition provides therapeutic plasma levels for a period of at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 9 months, at least 10 months, at least 11 months, or at least twelve months following administration of a dose of said composition.

[0136] The injectable composition can be administered to muscle tissue, adipose tissue, peritoneum, or below the skin. Intramuscular administration is preferred. In some embodiments, the composition is administered to the gluteal and/or deltoid muscles. The composition can also be administered to the quadriceps muscle group. A dose can be administered to a single muscular site or can be divided into two or more portions and administered to two or more muscular sites of a subject. For example, a first portion of a dose can be administered to a first section of gluteal muscle and a second portion of the dose can be administered to a second section of gluteal muscle of a subject. A single-body implant will form at each injection site. Such a mode of administration within a same day is considered to be administration of a single dose with a single dosing period. Alternatively, administration can be modified such that there is one point of needle entry into the subject but more than one injection site below the skin, which can be achieved by making a first penetration into the skin and muscle and administering a portion of a dose, then partially withdrawing and redirecting the needle into another section of muscle, while maintaining the tip of the needle beneath the skin, and then injecting another portion of the dose into this other section of muscle. Such a mode of administration is still considered to be administration of a single dose within a single dosing period.

[0137] A dose of the injectable composition typical comprises about 30 to about 90 mg of letrozole, about 80 to about 150 mg of letrozole, about 150 to about 250 mg of letrozole, about 250 to about 350 mg of letrozole, about 350 to about 450 mg of letrozole, about 20 to about 500 mg of letrozole, about 50 mg of letrozole, about 100 mg of letrozole, about 200 mg of letrozole, or about 400 mg of letrozole.

[0138] Following administration to a subject, the composition will form one or more implants (preferably a single implant) in said subject.

[0139] Administration of a single dose is typically considered that amount of injectable composition administered to a subject within a period of up to 24 hours, up to 12 hours, up to 6 hours, up to 3 hours, up to one hour, up to 30 min, up to 15 min or up to 5 min.

[0140] In another embodiment, the injectable depot composition is sterile as a finished product. In another embodiment, the biocompatible polymer is sterilized previously to its aseptic filling process, preferably by irradiation (such as beta irradiation) or by another process, e.g. filtration.

[0141] The implant of the invention can provide substantially improved plasma levels of drug when compared to another injectable formulation (not according to the invention) containing the same drug when administered on an equivalent dose basis.

[0142] The invention also provides an implant comprising PLA and drug (which is letrozole, anastrozole, or salt of either thereof, or metabolite of either thereof), wherein a) the weight ratio of PLA to drug is about 0.6:1 to about 2.8:1, about 1.0 to 2.0, about 1.1:1 to 1.6:1, about 1.1:1 to about 1.4:1, about 1.1:1 to about 1.35:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1.25:1; b) the implant has been prepared from a composition comprising i) 15-35 wt. % letrozole, 25-35 wt. % PLA, and 30-60 wt. % DMSO; ii) 18-28 wt. % letrozole, 30-35 wt. % PLA, and 37-52 wt. % DMSO; iii) about 23 to about 27 wt. % letrozole, about 28 to about 34 wt. % PLA, and about 41 to about 47 wt. % DMSO; or iv) about 24 to about 26 wt. % letrozole, about 29 to about 33 wt. % PLA, and about 42 to about 47 wt. % DMSO, wherein the weight percentages are with respect to the total weight of the composition before formation of the implant. When administered to a subject, the implant releases from about 0.1 to about 2 milligrams of letrozole daily and provides a plasma level of letrozole between about 1 to about 40 ng/ml from about 2 days after administration and continuously throughout a dosing period. Prior to formation of the implant, the particle size distribution of the PLA in the composition is as defined herein according to the invention. The PLA is optionally sized before being included in the composition. The implant may be used in a method of administering or a method of treating as defined herein.

[0143] The invention also provides a method of forming an implant, the method comprising a) mixing DMSO, PLA and drug to form an injectable depot composition; and b) administering the injectable depot composition to a subject. The content and characteristics/properties of the ingredients are as defined herein. The particle size distribution of the PLA, prior to implant formation, is as defined herein. The in vivo and in vitro performance of the implant is as defined herein.

[0144] All values disclosed herein may have standard technical measure error (standard deviation) of ±10%. The term “about” is intended to mean±10%, ±5%, ±2.5% or ±1% relative to a specified value, i.e. “about 20%” means 20±2%, 20±1%, 20±0.5% or 20±0.25%

EXAMPLES

[0145] The following examples are illustrative of the invention and are not to be considered limiting.

Example 1

Compositions

[0146] The following formulations are prepared.

[0147] A ready-to-use formulation can be prepared, for example, and included in a syringe ready for use for intramuscular injection. The same formulation may form part, for example, of a kit of two syringes, one male and one female or two male syringes linked by a connector in which the solution of PLA in DMSO is in one syringe and the letrozole is in solid form in a second syringe. Similarly, the final composition can be obtained by, for example, maintaining one syringe with the PLA and letrozole in solid state and the solvent (DMSO) in a second syringe.

Formulation 1:

[0148]

TABLE-US-00003 Ingredient Amount (mg, % wt) Lactic acid polymer (ester terminal group) of 55.20 (35.8%) intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 82.80 (53.7%) Letrozole 16.20 (10.5%)

[0149] The weight ratio of DMSO to PLA is about 1.5:1. The weight ratio of DMSO to drug is about 5.11:1. The weight ratio of polymeric solution to drug is about 8.52:1. The weight ratio of PLA to drug is about 3.41:1.

Formulation 2: Formulation with Letrozole in Suspension

TABLE-US-00004 Ingredient Amount (mg, % wt) Lactic acid polymer (ester terminal group) of 38.80 (30%) intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 58.30 (45%) Letrozole 32.40 (25%)

[0150] Letrozole particle size in formulation 2 was characterized by the technique of laser ray diffraction (Malvern Mastersizer 2000, suspended in water until obscuration of 9.41%) and had the following distribution (in % volume): d(0.1)=38.21 μm, d(0.5)=141.35 μm and d(0.9)=312.13 μm.

[0151] The weight ratio of DMSO to PLA is about 1.5:1. The weight ratio of DMSO to drug is about 1.8:1. The weight ratio of polymeric solution to drug is about 3:1. The weight ratio of PLA to drug is about 1.2:1.

Formulation 3:

[0152]

TABLE-US-00005 Ingredient Amount (mg) Lactic acid polymer (carboxylic terminal 38.80 group) of intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 58.30 Letrozole 32.40

[0153] The weight ratio of DMSO to PLA is about 1.5:1. The weight ratio of DMSO to drug is about 1.8:1. The weight ratio of polymeric solution to drug is about 3:1. The weight ratio of PLA to drug is about 1.2:1.

Formulation 4:

[0154]

TABLE-US-00006 Ingredient Amount (mg) Lactic acid polymer (ester terminal group) of 38.80 intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 58.30 Letrozole 32.40

[0155] The weight ratio of DMSO to PLA is about 1.5:1. The weight ratio of DMSO to drug is about 1.8:1. The weight ratio of polymeric solution to drug is about 3:1. The weight ratio of PLA to drug is about 1.2:1.

Formulation 5:

[0156]

TABLE-US-00007 Ingredient Amount (mg, % wt) Lactic acid polymer (carboxylic terminal 107.6 (31.1%) group) of intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 151.7 (43.9%) Letrozole 86.5 (25%)

[0157] The weight ratio of DMSO to PLA is about 1.41:1. The weight ratio of DMSO to drug is about 1.75:1. The weight ratio of polymeric solution to drug is about 3:1. The weight ratio of PLA to drug is about 1.25:1.

Formulation 6:

[0158]

TABLE-US-00008 Ingredient Amount (mg) Lactic acid polymer (ester terminal group) of 107.6 intrinsic viscosity of 0.3 dl/g, irradiated as raw material at 10 kGy. Dimethyl sulfoxide 151.7 Letrozole 86.5

[0159] The weight ratio of DMSO to PLA is about 1.41:1. The weight ratio of DMSO to drug is about 1.75:1. The weight ratio of polymeric solution to drug is about 3:1. The weight ratio of PLA to drug is about 1.25:1.

Formulations 7 to 12:

[0160]

TABLE-US-00009 Formulation 7 8 9 10 11 12 Amount Amount Amount Amount Amount Amount Ingredient (% wt) (% wt) (% wt) (% wt) (% wt) (% wt) Lactic acid 28-36 15-42.5 29.6-32.7 polymer (PLA) terminating in a carboxylic group Lactic acid 15-42.5 28-36 29.6-32.7 polymer (PLA) ester terminal group Dimethyl 38.5-52 25-59.5 42.2-45.6 25-59.5 38.5-52 42.2-45.6 sulfoxide Letrozole 20-30 15-50 24-26 15-50 20-30 24-26

[0161] For some preferred compositions, the % w/w in the composition of the active agent was between 20.0 and 27.0%. The % w/w in the composition of the PLA was between 20.0 and 50.0%. The % w/w in the composition of the solvent was between 23.0 and 60.0%. The compositions were mixed in a syringe to form suitable implants.

[0162] Different types of PLA were used for these compositions: [0163] 1. PLA with particle size mass distribution where more than 10% of the particles had a particle size of 300 microns or above when measured by analytical sieving according to USP<786>; [0164] 2. PLA with particle size volume distribution with D90 above 330 microns when measured by laser diffraction analysis; [0165] 3. PLA with particle size mass distribution where no more than 10% of the particles had a particle size above 300 microns and no more than 80% of the particles have a particle size below 125 microns when measured by analytical sieving according to USP<786>; [0166] 4. PLA with particle size volume distribution with D90 not above 330 microns and D80 not below 135 microns when measured by laser diffraction analysis; [0167] 5. PLA with particle size mass distribution where more than 80% of the particles have a particle size below 125 microns, when measured by analytical sieving according to USP<786>; [0168] 6. PLA with particle size volume distribution with D80 below 135 microns when measured by laser diffraction analysis.

[0169] Compositions of the invention were prepared first by dry mixing the active agent with the PLA and then adding the solvent, preferably DMSO to dissolve the PLA and have a suspension of the active agent. The reconstitution process is to be carried out immediately prior to injection, and the time for preparation does not exceed 15 minutes, preferably 10 minutes, more preferably 5 minutes, before the IM composition is administered.

[0170] The implants prepared this way were used for the following dissolution test: horizontal orbital motion at 50 rpm; medium: PBS pH 7.4.; temperature: 37±0.5° C.; analytical technique HPLC/UV; wavelength 230 nm.

[0171] It was observed that for PLAs 1 and 2, the release was not as satisfactory sustained as desired when preferred time of preparation was applied (FIG. 3). However, for PLAs 3 and 4, the sustained release was satisfactory (FIG. 4).

[0172] When PLAs 5 and 6 were used, big and hard agglomerates formed, and the composition could not be prepared within the preferred time of no more than 15 minutes. Thus, this composition was not considered clinically suitable. In any case, the implant was assayed, and sustained release resulted satisfactory (FIG. 5).

Example 2

Particle Size Determination

Analytical Sieving According to USP<786>

[0173] The PLA particle size mass distribution was determined by sieve stack technique using the following sizes: 425>355>300>250>212>180>150>125>106>75. The amplitude was 0.65 mm and the shaking time 5 minutes.

Laser Light Diffraction

[0174] The PLA particle size distribution is expressed as volume distribution and was determined by laser diffraction technique by wet dispersion method. No sample pre-treatment was applied. The sample was directly added into the dispersion medium (water). Dispersion mechanism was stirring at 3000 rpm and the sample was stabilized for 30 seconds before measuring.

Example 3

Clinical Data

Preliminary Phase I Results

[0175] Preliminary results suggest that sustained long-term hormone suppression therapy (HT) may obtain a superior clinical outcome in breast cancer compared to an oral daily dosage treatment.

[0176] Early discontinuation and non-adherence to HT are common and associated with increased mortality—improved treatment compliance with Letrozole ISM® has potential to enhance treatment.

[0177] Sustained lower effective doses (compared to oral treatment) could reduce adverse side effects (bone mass loss, bone/joint/muscle pain, dyslipidemia) due to lower exposure to drug.

[0178] Better safety profile has potential to positively impact treatment duration adherence.

Phase I Results

[0179] This is a Phase I, open label, dose escalation study designed to evaluate the pharmacokinetics, safety, and tolerability of single intramuscular injections of Letrozole ISM at different strengths in approximately 120 voluntary healthy postmenopausal women. The study has four arms: [0180] Experimental: Cohort 1: Letrozole ISM 50 mg: 14 oral doses of 2.5 mg FEMARA® (once daily)+single IM injection of 50 mg Letrozole ISM. [0181] Experimental: Cohort 2: Letrozole ISM 100 mg: 14 oral doses of 2.5 mg FEMARA® (once daily)+single IM injection of 100 mg Letrozole ISM. [0182] Experimental: Cohort 3: Letrozole ISM 200 mg: 14 oral doses of 2.5 mg FEMARA® (once daily)+single IM injection of 200 mg Letrozole ISM. [0183] Experimental: Cohort 4: Letrozole ISM 400 mg: 14 oral doses of 2.5 mg FEMARA® (once daily)+single IM injection of 400 mg Letrozole ISM.

[0184] The objective of this study is to assess the pharmacokinetic profile of a single ascending doses of Letrozole ISM, and secondly, to evaluate safety and tolerability of single ascending doses of Letrozole ISM, measure estrogen levels, and characterize oral letrozole pharmacokinetic profile to be used in subsequent comparison to Letrozole ISM.

[0185] The study is carried out in healthy post-menopausal women who satisfy inclusion and exclusion criteria. The study design includes a screening period and 2 treatment periods. Treatment Period 1 comprises of 14 oral dose administrations of 2.5 mg Femara®. Treatment Period 2 comprises of a single IM dose of 50, 100, 200 and 400 mg Letrozole ISM. The total planned study duration is 71 weeks, approximately.

Inclusion Criteria:

[0186] The inclusion/exclusion criteria for the 120 participants are the following: [0187] Healthy post-menopausal women, 18 and 75 years of age, who have achieved complete menopause, either natural or surgical, and amenorrhea, and have not been on hormone replacement therapy in the last 3 months. [0188] Post-menopausal subjects should have absence of menses for 1 year, and oophorectomized subjects should have absence of menses for at least 6 weeks. For oophorectomized subjects and subjects who have had a hysterectomy, a surgical pathology report documenting the absence of malignant disease is required. In addition, for oophorectomized subjects an operative report documenting bilateral oophorectomy is required. [0189] Baseline follicle-stimulating hormone (FSH) and 17β-estradiol plasma levels should be consistent with the post-menopausal status of the subject (FSH≥40 mIU/mL; 17β-estradiol≤31 pg/mL), confirmed at least 48 hours prior to dosing. [0190] Weight of ≥50 kg and a BMI≥19 and ≤39 kg/m2. [0191] Subjects will be in good health, as determined by medical history, physical examination, vital signs assessments (pulse rate, systolic and diastolic blood pressure, and temperature), clinical laboratory evaluations, and 12-lead ECG. Minor deviations outside the reference ranges will be acceptable, if deemed not clinically significant by the investigator. [0192] Subjects who have not had a mammogram within the last 12 months (documentation required) must be willing to have one performed. [0193] Subjects with an intact uterus and cervix who have not had a Papanicolaou (pap) smear test within the last 6 months (documentation required) must be willing to have one performed. [0194] Subjects will have given their written informed consent to participate in the study and to abide by the study restrictions. [0195] Subjects should be able to communicate with clinic staff.

Exclusion Criteria:

[0196] Subjects who have a history of allergy or hypersensitivity to letrozole or any of the inactive ingredients in the last 3 months. [0197] Subjects who have a history of galactose intolerance, severe hereditary lactase deficiency glucose-galactose malabsorption. [0198] Subjects who have used estrogen or progesterone hormone replacement therapy, thyroid replacement therapy, oral contraceptives, androgens, luteinizing hormone (LH) releasing hormone analogs, prolactin inhibitors, or antiandrogens within 3 months prior to Screening. [0199] Subjects who have regularly taken foods or food supplements that contain high levels of Isoflavinoids, including soybean, soymilk, soynuts, chickpeas, alfalfa, fava beans, kudzu, miso and tofu in the 14 days prior to dosing (Treatment Period 1). The investigator and medical monitor will determine on a case-by-case basis if a subject who intakes food or food supplements containing Isoflavinoids is eligible to participate in the study. [0200] Subjects who have used: [0201] Any medications including St. John's wort, known to be potent or moderate inducers of CYP P450 3A4 in the 3 weeks prior to dosing (Treatment Period 1). [0202] Any medications or products known to be potent or moderate inhibitors of CYP P450 3A4 (e.g. grapefruit juice) in the 7 days prior to dosing on Treatment Period 1. [0203] Any prescribed preparations within 14 days prior to dosing (Treatment Period 1), unless in the opinion of the investigator (or designee) the medication will not interfere with the study procedures or compromise safety. [0204] Any non-prescribed systemic or topical medications within 7 days of dosing (Treatment Period 1) unless in the opinion of the investigator (or designee) the medication will not interfere with the study procedures or compromise safety. Vitamins and minerals including the use of calcium and/or vitamin D for osteoporosis prevention are allowed. [0205] Subjects who have been diagnosed with osteoporosis (previously or results from screening DEXA for this study with a T score <−2.5). Subjects with osteopenia (with the T-score between −1 and −2.5) will be allowed to participate in this study. [0206] Subjects who are not on a stable dose of long- or short-acting bisphosphonates therapy for at least 3 months prior to Screening. [0207] Subjects who are on raloxifene therapy. [0208] Subjects who have an abnormality in heart rate, blood pressure, or temperature at Screening and prior to first dose (Treatment Period 1) that in the opinion of the investigator increases the risk of participating in the study. Resting SBP must be 150 mmHg and resting DBP 95 mmHg. [0209] Subjects who have an abnormality in the 12-lead ECG at Screening and prior to first dose (Treatment Period 1) that in the opinion of the Investigator increases the risk of participating in the study. [0210] Subjects who have any clinically significant abnormal physical examination finding. [0211] Subjects who have any clinically significant abnormal laboratory safety findings at Screening or Check-in, upon repeat testing, as determined by the investigator (1 repeat assessment is acceptable). [0212] Subjects who have ALT or AST>1.5×ULN. For subjects with elevated total bilirubin, direct and indirect bilirubin will be evaluated. [0213] Subjects with elevated cholesterol or triglyceride levels above the ULN must be determined by the Investigator to be not clinically significant. [0214] Subjects who have relevant diseases or clinically significant abnormal relevant findings at Screening, as determined by medical history, physical examination, laboratory, ECG, DEXA, and breast and pelvic examination. [0215] Subjects who have history of any significant chronic disease, such as but not limited to: thrombotic disorders, coronary artery or cerebrovascular disease, liver, kidney or gallbladder dysfunction/disorder(s), diabetes or any other endocrine disease, estrogen dependent neoplasia, post-menopausal uterine bleeding, or endometrial hyperplasia. Subjects with cholecystectomy will be permitted if no medical sequelae post-surgery. [0216] Subjects who have a history of cancer within the past 5 years with the exception of non-melanoma skin cancer. [0217] Subjects who have a history of drug-dependence, and recent history of alcoholism or abuse of alcohol. [0218] Subjects who have a positive result for hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis C antibody, or human immunodeficiency virus (HIV) antibodies. [0219] Subjects with a positive drugs of abuse screen or alcohol breath test at Screening (urine will be screened for the presence of the following: amphetamine, barbiturates, benzodiazepines, cannabinoid, cocaine, opiates, phencyclidine, and methadone). [0220] Subjects with a history of, or difficulty of, access to veins for venipuncture. [0221] Subjects who have donated blood in the 30 days prior to first dose (Treatment Period 1). [0222] Subjects who have received blood products within 2 months prior to Screening. [0223] Subjects who have received a drug in research or have participated in other clinical trials within 30 days, or 5 half-lives (whichever is longer) prior to dosing (Treatment Period 1). [0224] Subjects who have previously taken part in or have withdrawn from this study. (Subjects who have been screened for but not included in a cohort or subjects who dropped out from screening in a previous cohort for non-medical reasons may be eligible to be included in subsequent cohorts.) [0225] Any other unspecified reason that, in the opinion of the investigator (or designee) or Sponsor, makes the subject unsuitable for enrollment.

PK Results

[0226] Letrozole plasma concentrations have been analyzed up to Day 897 and Day 729 following a single intramuscular (IM) injection of Letrozole ISM 50 mg and 100 mg, respectively. Moreover, plasma levels of letrozole has also been analyzed for up to 897 and 729 days. The majority of subjects had sustained quantifiable letrozole plasma concentrations up to the last sampling time points reported in both groups (FIG. 8). Dose-normalized peak exposure (Cmax/D) is comparable between both dose strength of Letrozole ISM. Accordingly, the implant or sustained release composition of the invention provides measurable and therapeutic plasma concentrations levels of letrozole for at least about 2 years, at least about 2.5 years, at least about 2.7 years or at least about 2.8 years.