Improved aromatase inhibitor dosing schedules and compositions

Abstract

NOT VISIBLE DUE TO STATUS OF PATENT

Description

COMPOSITIONS AND DOSING SCHEMES OF IMPROVED AROMATASE INHIBITORS FIELD OF INVENTION

[0001] The present invention provides improved compositions and dosage schedules for intramuscular administration of compositions containing aromatase inhibitors such as letrozole for use in the treatment of letrozole-responsive diseases, conditions, or disorders. Two doses of long-acting injectable composition are administered sequentially to provide superior control of letrozole plasma concentration and superior estrogen suppression. The long-acting composition comprises a sterile, biodegradable thermoplastic polymer of polylactic acid (PLA) and a solvent for the polymer. The long-acting composition forms an intramuscular implant in situ at the administration site, and the implant releases approximately 0.1-2 milligrams of letrozole daily after administration to a subject in need thereof. BACKGROUND OF THE INVENTION

[0002] Undoubtedly, it is necessary to develop better cancer treatments, not only new molecular entities but also pharmacological products to improve patients' quality of life. The development of long-acting compounds represents a breakthrough because it allows for a reduction in the total dose administered, increases the duration of each dose, and increases the number of administrations, thus creating a positive impact on the patient's emotional state.

[0003] Letrozole (4,4'-(1H,2,4-triazol-1-yl)methyl)dibenzonitrile) and anastrozole (2,2'-[5-(1H-1,2,4-trlazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropanenitrile)) belong to a class of drugs called nonsteroidal aromatase inhibitors and work by lowering the amount of estrogen in the body. This may slow or stop the growth of many types of breast cancer-producing cells that need estrogen to grow.

[0004] There is currently no letrozole formulation on the market capable of controlling drug release over an extended period. Letrozole is currently only available as a tablet for daily oral administration (FEMARA®).

[0005] In breast cancer treatment, as in cancer treatment in general, the patient's psychological state is very important; therefore, the development of a three-monthly formulation of letrozole and / or anastrozole would result in a substantial improvement in her quality of life, reducing the impact of daily treatment. Furthermore, medical examinations during disease follow-up are typically performed at 3 and 6 months during the first few years, so administration of the formulation could coincide with doctor visits.

[0006] Similar reasoning has led to the emergence on the market of formulations such as ZOLADEX®, a preformed implant of goserelin for quarterly subcutaneous application for the treatment of treatment of prostate cancer, and Implanon®, a preformed etonogestrel implant used as a contraceptive. However, these preformed implants have several disadvantages, including: - The preparation of implants by extrusion requires the use of high temperatures, which can cause degradation of the active ingredient and the generation of potentially toxic impurities; - Low homogeneity of the product obtained when active ingredients are included at low doses; - Need for surgical procedures to implant or inject the implant using large diameter needles.

[0007] The literature also discloses implantable compositions of letrozole and / or anastrozole. For example, WO 2008 / 041245 A2, published April 10, 2008, by Panacea Biotec LTD, describes implantable compositions comprising a wide variety of active ingredients, such as certain aromatase inhibitors, including anastrozole, in a wide variety of delivery forms, from preformed microparticles suspended in an aqueous vehicle to formulations that gel in situ. Although it is doubtful that the present document can sufficiently cover all the combinations of active ingredients and delivery forms that may arise, the examples always refer to preformed microparticles, i.e., it never describes directly "in situ" implant formation systems. Finally, it should be noted that none of the examples show a duration of more than 60 days.

[0008] WO 2010 / 065358 A1, published June 10, 2010, by Glaser, describes compositions for the delivery of medicaments containing testosterone and an aromatase inhibitor for the continuous delivery of testosterone and for preventing its conversion to estradiol. Although the disclosure considers the possibility that the delivery form could be an implant, the only example of a delivery form is pellets.

[0009] Likewise, WO 2012 / 074883 A1, published June 7, 2012, by Durect Corp., describes biodegradable compositions for drug delivery. These compositions require the use of water-insoluble solvents such as benzyl benzoate or benzyl alcohol to maintain the implant in a liquid or semi-solid state. These solvents have previously been shown to provide sudden releases and are therefore not suitable for the long-acting compositions of the present invention.

[0010] US 2008 / 0206303 A1 to AstraZeneca describes long-acting anastrozole compositions comprising a PLA or PLGA polymer which may be accompanied by a wide variety of solvents; however, in embodiments of the invention, the solvents used are benzyl alcohol and N-methyl-2-pyrrolidone (NMP), solvents which give rise to a very high instantaneous release followed by almost no subsequent release. In fact, the The instantaneous release acceptable to the present inventors herein was 25-30% in one day, a very high value, and because of this, none of their examples lasted more than 60 days; in particular, in dogs, animals similar to humans, the release did not continue for more than 35 days. Finally, no mention was made in that document of the particle size of letrozole or of the importance of this factor in the performance of the formulation.

[0011] Las composiciones inyectables son divulgadas por Jain et al. ("Inyectable formulations of poly(lactic acid) and its copolymers in clinical use" en Adv. Drug Deliv. Rev. (2016), 107 (14), 213- 227), Kranz et al. (“A novel in situ forming drug delivery system for controlled parenteral drug delivery” en Inter. J. Pharma. (2007), 332(1 -2), 107-114, D’Souza et al. (“Methods to assess in vitro drug release from injectable polymeric particulate systems” en Pharm. Res. (2006), 23(3), 460-474), Li et al. (“Microfluidic fabrication of microparticles for biomedical applications” en Chem. Soc. Rev. (2018), 47(15), 5646-5683), Bassyouni et al. (“Advances and new technologies applied in controlled drug delivery system” en Res. Chem. Interm. (2013), 41 (4), 2165-2200), Kissel et al. (“Parenteral depotsystems on the basis of biodegradable polymers” en J. Contr. Rel. (1991), 16(1-2), 27-41), Gomathi et al.(“Fabrication of letrozole formulation using chitosan nanoparticles through ionic gelation method” en Inter. J. Biol. Macromol. (2017), 104(7), 1820-1832), y Muralidhar et al. (“Controlled release injectable drug delivery: an overview” in J. Biomat. Res. (2017), 3(1), 6-15).

[0012] Las composiciones inyectables también se divulgan en los documentos WO 2014 / 019972A1 , ES 2390439A1 , US 10285936B2, US 2019 / 0231682A1 , US 2019 / 0365643A1 , WO 2011 / 151356A2, EP 2394663A1 , US 10058504B2, US 2019 / 0151230A1 , US 2021 / 0154302 A1 , US 2021 / 0168778 A1 , WO 2019 / 238740 A1 , US 10195138B2, US 10933015B2 y US 10912735B2 de Laboratorios Farmacéuticos ROVI, S.A. y documento W02009060473A2 de Panacea Biotec Limited.

[0013] None of the known techniques disclose the sequential intramuscular administration of two or more doses of the long-acting composition as described and claimed herein, and none of the known techniques recognize the unexpected advantage that such a dosing regimen provides control of the plasma letrozole concentration and, consequently, of the plasma estrogen concentration, i.e., estrogen suppression. COMPENDIUM OF THE INVENTION

[0014] The present invention seeks to overcome one or more of the disadvantages of known methods of using long-acting compositions for the treatment of cancer, particularly for the adjuvant treatment of postmenopausal women with hormone receptor-positive advanced breast cancer or with locally advanced or metastatic cancer. Additional indications are also contemplated herein.

[0015] The present invention provides improved estrogen inhibition over a period of one year compared to the inhibition provided by daily oral administration of 2.5 mg of letrozole (e.g., in FEMARA®) and compared to administration of a single composition. long-acting. In some embodiments, the dose of aromatase inhibitor in the long-acting composition is about 50 mg or more, about 75 mg or more, or about 100 mg or more.

[0016] The invention provides compositions and dosage regimens for the intramuscular administration of a drug, e.g., letrozole and / or anastrozole, to a subject in need thereof. Throughout this document, all references to methods of drug administration or dosage regimens for drug administration are to be construed as also referring to the compounds, compositions, and medicaments for use in such regimens or methods.

[0017] A first aspect of the invention provides a long-acting injectable composition comprising polylactic acid (PLA), DMSO and at least one aromatase inhibitor drug selected from the group consisting of letrozole, anastrozole and combinations thereof, characterized in that the particle size distribution of the PLA is as follows: - a mass particle size distribution with no more than 10% of particles above 300 microns and no more than 80% of particles below 125 microns, when measured by analytical sieving according to USP <786> ; and - a volume particle size distribution where less than 10% of particles are smaller than 20 microns, less than 10% of particles are larger than 350 microns, D50 is between 70-200 microns, D80 is not less than 135 microns, and D90 is not greater than 330 microns, when measured by laser diffraction analysis.

[0018] A second aspect of the invention provides a composition as described above for use in the treatment of a subject in need thereof, and in particular in the treatment of a disease, condition or disorder responsive to an aromatase inhibitor in the subject, comprising administering to the subject said composition according to a dosage regimen comprising a) intramuscularly administering to a subject an amount of long-acting injectable composition comprising a first dose of aromatase inhibitor; and b) subsequently, after a delay period, administering intramuscularly an amount of long-acting injectable composition comprising a second dose of aromatase inhibitor, wherein the delay period is about 6 weeks or more after administering said first dose of composition.In some embodiments, a) the amount of drug in the first dose is approximately the same as the amount of drug in the second dose; b) the amount of drug in the first dose is less than the amount of drug in the second dose; or c) the amount of drug in the first dose is greater than the amount of drug in the second dose.

[0019] For subjects requiring continued treatment with aromatase inhibitor, the invention further comprises intramuscular administration of a third dose of the long-acting composition at about 50-60 weeks, about 50-112 weeks, about 50-60 weeks, about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, or about 54 weeks after administration of a previous dose of long-acting composition. In some embodiments, the third dose of the long-acting composition is administered about 48-60 weeks after administration of the first long-acting composition or about 48-60 weeks after administration of the second long-acting composition. In some embodiments, the subject receives the first two doses of long-acting composition, but does not receive a third dose of long-acting composition during the treatment period.In other embodiments, the subject receives a dose of long-acting composition approximately annually after the first two doses during a treatment period.

[0020] The long-acting composition can be administered to adipose tissue or muscle tissue. In preferred embodiments, the long-acting composition is administered intramuscularly.

[0021] In some embodiments, the treatment period ranges from about 1 to 10 years, or is about 1 year or more, about 2 years or more, about 2 to 7 years, about 2 to 5 years, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, or about 10 years.

[0022] In some embodiments, a subject will experience remission, regression, or at least lack of cancer progression after administration of a single dose of the long-acting composition. In other embodiments, a subject will experience remission, regression, or at least lack of cancer progression after administration of two or more doses of the long-acting composition, with each dose administered approximately annually.

[0023] The amount of aromatase inhibitor in the subsequent dose may be the same as, less than, or greater than the amount of aromatase inhibitor in the previous dose of the long-acting composition. In some embodiments of the first aspect of the invention, the amount of aromatase inhibitor in both long-acting compositions is approximately the same and may be about 100 mg or more of aromatase inhibitor per dose.

[0024] In some embodiments of the first aspect of the invention, a non-long-acting injectable (nLAI) composition is administered instead of the first dose of long-acting composition (LAI). For example, a subject is administered a dose of non-long-acting composition and about 6-10 weeks later, about 7-9 weeks later, or about 8 weeks later, the subject is administered a first dose of composition. long-acting. The non-long-acting composition comprises at least one pharmaceutical excipient and a drug, which is letrozole and / or anastrozole.

[0025] The doses of the long-acting composition are administered sequentially, meaning that a first dose of the long-acting composition is administered first, and after a delay period, a second dose of the long-acting composition is administered. The first dose of the long-acting composition provides therapeutically effective plasma levels of drug for a first dosing period, and the second dose of the long-acting composition provides therapeutically effective plasma levels of drug for a second dosing period. For the first aspect of the invention, the beginnings of the respective dosing periods are offset by about 6-10 weeks, about 7-9 weeks, or about 8 weeks, and each respective dosing period lasts about 48-60 weeks, about 48-56 weeks, about 50-54 weeks, or about 52 weeks.For the second aspect of the invention, the beginnings of the respective dosing periods are offset by about 48-60 weeks, about 48-56 weeks, about 50-54 weeks, or about 52 weeks, and each respective dosing period lasts about 48-60 weeks, about 48-56 weeks, about 50-54 weeks, or about 52 weeks.

[0026] If a non-long-acting composition is administered, the non-long-acting composition provides a dosing period (period during which a therapeutic drug of plasma concentration is present in a subject) of at least 6 weeks, at least 7 weeks, or at least 8 weeks. The non-long-acting composition is administered before the long-acting composition. The long-acting composition is administered toward the end or at the end of the non-long-acting composition dosing period. The long-acting composition may be administered during the last 2 weeks, the last week, at the end of, or after the completion of the non-long-acting composition dosing period.In some embodiments, the dosing period of the non-long-acting composition is about 7-9 weeks or about 8 weeks, and the long-acting composition is administered about 7 weeks, about 8 weeks, or about 9 weeks after administration of the non-long-acting composition.

[0027] Compared to administering a single dose of the long-acting composition alone, the dosage regimens of the invention, i.e., sequential administration of at least two doses of the long-acting composition wherein their respective dosing periods of about 1 year overlap and offset each other by about 6-10 weeks or about 8 weeks (first aspect of the invention) or are compensated for in approximately 50-54 weeks or approximately 52 weeks (second aspect of the invention), providing improved control of plasma drug concentrations in the post-administration period. The dosage regimens of the invention thus provide improved E2 suppression and, ultimately, greater therapeutic efficacy.

[0028] The invention also provides a method of administering letrozole or anastrozole to a subject. The method comprises administering a first amount (or volume) of long-acting composition comprising aromatase inhibitor and subsequently (after a delay period) administering a second amount (or volume) of long-acting composition comprising the aromatase inhibitor. The delay period may be in the range of about 6-10 weeks, about 7-9 weeks, or about 8 weeks for the first aspect of the invention and in the range of about 48-60 weeks, about 50-54 weeks, or about 52 weeks for the second aspect of the invention.

[0029] The invention also provides a method of administering a drug, which is letrozole and / or anastrozole, to a subject. In some embodiments of the first aspect of the invention, the method comprises a) providing a first long-acting drug-containing composition comprising drug; b) administering a first dose of said long-acting composition to a subject in need thereof; c) providing a second long-acting drug-containing composition; d) after about 6 weeks, about 7 weeks, about 8 weeks, or about 9 weeks of administration of said first dose, administering a dose of said second long-acting drug-containing composition to the subject.In some embodiments of the second aspect of the invention, the method comprises a) providing a first long-acting drug-containing composition comprising drug; b) administering a first dose of said long-acting composition to a subject in need thereof; c) providing a second long-acting drug-containing composition; d) after about 48-60 weeks, about 50-54 weeks, or about 52 weeks of administration of said first dose, administering a dose of said second long-acting drug-containing composition to the subject. In some embodiments, the method may further comprise administering another dose of the long-acting composition to the subject about 50-54 weeks or about 52 weeks after administration of the previous dose of the long-acting composition.The delivery method may be independent of a treatment method; alternatively, the delivery method may also be part of a treatment method. The release of the drug from the implant (a sustained (extended) release composition) may be as specified herein. In some. In embodiments, the long-acting composition comprises (consists essentially of or consists of) drug, DMSO and PLA.

[0030] After administration, the long-acting composition may form one or more implants. The composition may be administered to adipose tissue, muscle tissue, subcutaneous tissue, or the peritoneum.

[0031] In some embodiments, a) the amount of drug in the first dose approximates the amount of drug in the second dose; b) the amount of drug in the first dose is less than the amount of drug in the second dose; or c) the amount of drug in the first dose is greater than the amount of drug in the second dose. In some embodiments, the amount of drug in doses subsequent to the first and second doses a) approximates the amount of drug in the second dose; b) is less than the amount of drug in the second dose; or c) is greater than the amount of drug in the second dose.

[0032] The first aspect of the invention also provides a method of administering the drug, which is letrozole and / or anastrozole, to a subject, the method comprising a) intramuscularly administering a first dose of long-acting drug-containing composition; and b) subsequently, within a delay period of about 6-10 weeks, intramuscularly administering a second dose of long-acting drug-containing composition. The amount of drug in a dose of long-acting composition is independently selected on each occasion from the group consisting of about 50-450 mg, about 50-100 mg, about 75 mg, about 80-150 mg, about 150-250 mg, about 350-450, about 100 mg, about 200 mg, or about 400 mg.The second dose of the long-acting composition may be administered approximately 6-10 weeks, approximately 7-9 weeks, or approximately 8 weeks after administration of the first dose of the long-acting composition.

[0033] The second aspect of the invention provides a method of administering the drug, which is letrozole and / or anastrozole, to a subject, the method comprising a) administering intramuscularly a first higher dose of long-acting drug-containing composition; and b) subsequently, after a delay period of about 48-60 weeks, administering intramuscularly a second lower dose of long-acting drug-containing composition. The amount of drug in the first dose of the long-acting composition is about 200-400 mg, and the amount of drug in the second dose of the long-acting composition is about 75-100 mg. The second dose of the long-acting composition can be administered about 50-54 weeks, or about 52 weeks after administration of the first dose of the long-acting composition.

[0034] The delivery methods may be used, or are used, as methods to treat a letrozole-sensitive or anastrozole-sensitive disease, condition, or disorder.

[0035] The first aspect of the invention thus provides compositions and methods for treating a disease, condition or disorder responsive to an aromatase inhibitor in a subject, the method comprising administering an amount (or volume) of long-acting composition comprising an aromatase inhibitor and subsequently (after a delay period) administering an amount (or volume) of long-acting composition comprising the aromatase inhibitor, wherein the delay period is about 6-10 weeks.

[0036] The second aspect of the invention provides compositions and methods for treating an aromatase inhibitor-responsive disease, condition or disorder in a subject, the method comprising administering an amount (or volume) of long-acting composition comprising a first, higher dose of aromatase inhibitor and subsequently (after a delay period) administering an amount (or volume) of long-acting composition comprising a second, lower dose of aromatase inhibitor, wherein the delay period is about 50-54 weeks or about 52 weeks.

[0037] Administration may be by injection. In some embodiments, long-acting compositions have a dosage period of about 50-54 weeks, about 52 weeks, or about 1 year.

[0038] The administration method and treatment method of the invention employ a dosage regimen comprising a) providing a long-acting composition comprising an aromatase inhibitor, wherein said long-acting composition provides a dosing period of about 1 year; b) administering a first dose of said long-acting composition; and c) after a delay period of about 6-10 weeks or about 50-54 weeks from said administration, administering a second dose of said long-acting composition. The method optionally further comprises administering another dose of said long-acting composition about 1 year after said first dose or said second dose.The method optionally further comprises administering a dose of said long-acting composition annually for a total treatment period of about three years or more, about 5 years or more, about 7 years or more, or about 10 years. Intramuscular administration of the long-acting composition is preferred.

[0039] In some embodiments of the first aspect of the invention, the amount of drug in the first dose and the second dose is independently selected on each occasion from the group consisting of about 50-150 mg, about 75-125 mg, and about 100 mg. In some embodiments, the amount of drug in the first dose and the second dose is about 100 mg.

[0040] In some embodiments of the second aspect of the invention, the amount of drug in the first dose is independently selected from the group consisting of about 200-400 mg, about 200 mg, about 300 mg, and about 400 mg, and the amount of drug in the second dose is independently selected from the group consisting of about 50-150 mg, about 75-100 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, and about 150 mg.

[0041] In the present invention, the active ingredients letrozole and anastrozole have been selected as candidate drugs for this type of long-acting composition, because they are the first-line active ingredients in the adjuvant treatment of postmenopausal women with hormone receptor-positive advanced breast cancer for whom there is no alternative therapy beyond the daily administration of a tablet.

[0042] The present invention seeks to overcome the disadvantages of and / or provide improvements over other injectable depot compositions comprising letrozole and / or anastrozole.The present invention includes one or more injectable depot compositions, one or more implants formed from said one or more injectable depot compositions, one or more methods of forming said one or more implants, one or more kits comprising components used to form said one or more injectable depot compositions, one or more methods of administering letrozole and / or anastrozole by administering said one or more injectable depot compositions, and one or more methods of treating one or more diseases, one or more conditions, or one or more disorders that are therapeutically responsive to letrozole, anastrozole, or metabolites of any thereof by administering said one or more injectable depot compositions.

[0043] The present invention employs a long-acting composition containing letrozole or containing anastrozole suitable for forming one or more intramuscular implants in situ that can continuously maintain the required plasma levels of drug for hormonal suppression for or on average for about 3 months or more, about 6 months or more, about 9 months or more, or about 12 months or more. The implant formed in situ with the injectable composition of the invention overcomes most of the drawbacks presented by current formulations based on preformed implants. It offers a practical and effective alternative therapy for the patient that achieves therapeutic profiles that last at least 60 days, at least 120 days, at least 180 days, at least 240 days, at least 300 days, or at least one year.

[0044] This long-term hormone suppression therapy has been shown to provide a superior clinical outcome in humans compared to oral daily dosing treatment. The formulations described herein allow for therapeutic plasma drug levels to be achieved from baseline and continuously for a dosing period of at least approximately six months or at least about 12 months, avoiding the need for a daily oral dosing regimen, thereby improving the patient's quality of life. Furthermore, the dosing regimen of the invention provides a smoother plasma concentration profile of the drug during the post-administration period compared to administration of a single dose of the long-acting composition.

[0045] The invention also provides a composition, and uses thereof, that provide sustained, yet still effective, lower plasma drug levels at lower doses (compared to oral treatment on a mg of drug per kg of body weight basis) of the injectable composition. The reduced plasma levels reduce dose-related adverse side effects of the drug (bone loss, bone / joint / muscle pain, dyslipidemia) due to the lower drug exposure resulting from the lower dose, while still maintaining therapeutically effective plasma levels. Furthermore, the present invention provides an improved safety profile (lower incidence, lower frequency of occurrence, and / or lower severity of adverse events) that positively impacts adherence to treatment duration.

[0046] The present inventors have found that the drug dose required for clinical efficacy is much lower than previously thought or disclosed in the art using oral dosage forms. Therefore, the compositions, and uses thereof, of the present invention provide effective therapy for aromatase inhibition at least as early as oral therapy from the time of administration, with much smaller doses than prior compositions, thereby providing sustained and stable release of such low doses over long periods of time (about 6 months or more, about 11 months or more, or at least 12 months) and reducing adverse side effects.

[0047] An aspect of the invention provides a method for reducing adverse events associated with the administration of a certain dose of drug (letrozole, anastrozole, salt of any thereof, or metabolite of any thereof) in an extended release composition, the method comprising administering a lower dose of the drug in an injectable depot composition (or one or more respective implants) of the invention, whereby said lower dose provides lower adverse events but substantially the same efficacy as a higher dose of the drug in another injectable depot composition not of the invention.

[0048] After administration of the long-acting composition and formation of the respective one or more implants, said one or more implants may provide the following pharmacokinetic behavior approximately (approximately): where Tlag corresponds to the delay between dosing and the appearance of a median letrozole concentration in plasma. The above values ​​are approximate and should be considered average values.

[0049] The invention employs an injectable depot composition (and its respective implants) and uses a lower dose of drug, relative to other injectable depot compositions not belonging to the invention, while still providing therapeutically effective plasma levels of said drug for a period of at least about six months or more.

[0050] In some embodiments, the long-acting composition comprises PLA having the following particle size distribution: mass distribution of particle size with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP <786> and / or said PLA has a particle size volume distribution with a D90 of no more than 330 microns, preferably no more than 280 microns when measured by laser diffraction analysis; and / or wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns, when measured by analytical sieving according to USP <786> and / or said PLA has a particle size volume distribution with a D80 of not less than 135 microns when measured by laser diffraction analysis.

[0051] In some embodiments, the long-acting composition comprises a sterile biodegradable thermoplastic polymer of polylactic acid (PLA), wherein said PLA has been optionally sized and has a) a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP <786> ; b) particle size volume distribution with a D90 of no more than 330 microns, preferably no more than 280 microns when measured by laser diffraction analysis; c) a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, and where no more than 80% of the particles have a particle size below 125 microns, as measured by analytical sieving in accordance with USP <786> ;d) a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns, when measured by analytical sieving according to USP <786> ; e) a particle size volume distribution with a D90 of no more than 330 microns, preferably no more than 280 microns, when measured by laser diffraction analysis and with a D80 of no less than 135 microns when measured by analysis of; laser diffraction; of) has a particle size volume distribution with a D80 of not less than 135 microns when measured by laser diffraction analysis.

[0052] In some embodiments, the long-acting composition comprises 10 to 500 mg of letrozole and a sterile biodegradable thermoplastic polymer of polylactic acid (PLA), wherein said PLA has been optionally sized; and / or wherein said PLA has a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP. <786> and / or said PLA has a particle size volume distribution with a D90 of no more than 330 microns, preferably no more than 280 microns when measured by laser diffraction analysis;and / or wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns, when measured by analytical sieving according to USP <786> and / or said PLA has a particle size volume distribution with a D80 of not less than 135 microns when measured by laser diffraction analysis; and wherein the percentage release of the active agent from the implant ranges from about 2-30% every 28 day interval for at least three or four intervals, preferably from about 5-25% every 28 day interval for at least three to four intervals; and / or wherein the composition releases from 0.1 to 2 milligrams of letrozole every day, preferably from 0.13 to 0.80 milligrams of letrozole every day.;

[0053] In some embodiments, the implant formed from the long-acting composition comprises about 50 mg of drug (letrozole and / or anastrozole) and releases an average of about 0.1 mg or more, about 0.12 mg or more, about 0.15 mg or more, about 0.1-0.15 mg, about 0.12-0.14 mg, or about 0.13 mg of drug per day for a period of at least about 337-365 days, wherein the average is based on daily drug release over such period. In some embodiments, the implant comprises about 100 mg of drug (letrozole and / or anastrozole) and releases an average of about 0.2 mg or more, about 0.25 mg or more, about 0.2-0.3 mg, about 0.3 mg or more, about 0.24-0.28 mg, or about 0.27 mg of drug, per day for a period of at least 337-365 days, wherein the average is based on daily drug release over such entire period.

[0054] In some embodiments, the implant releases an average of about 10-15% of its load per 28-day interval for the first four intervals and then an average of about 2-6% of its load per 28-day interval for the next eight to nine intervals. In some embodiments, the implant releases no more than about 60% (or no more than about 55%, or no more than about 50%) of its drug load within the first 112 days (four 28-day intervals) and releases the remainder of its drug load at a rate of about 2-6% per 28-day interval for 8 to 9 intervals (of about 224 days to about 252 days). In some embodiments, the implant releases its drug load over a period of at least about one year, at least about 365 days, or at least about twelve to thirteen 28-day intervals. In some embodiments, the implant releases about 40-55% or about 40-50% of its drug load during the first 3-4 months and about 60-45% or about 60-50%, respectively, of its load during the following 8-9 months.In some embodiments, the implant releases up to a total of about 30% of its charge during the first 28-day interval, up to a total of about 40% of its charge during the second 28-day interval, up to a total of about 50% of its charge 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 per 28-day interval for the next eight to nine intervals.In some embodiments, the implant releases up to a total of about 20-35% of its charge during the first 28-day interval, up to a total of about 25-40% of its charge during the second 28-day interval, up to a total of 35-50% of its charge 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 per 28-day interval for the next eight to nine intervals.

[0055] In some embodiments, the implant releases letrozole according to any of the following profiles. 'where the percentage is relative to the initial load of letrozole in the implant.

[0056] In a preferred embodiment, the long-acting composition comprises a water-miscible solvent, wherein the solvent is preferably dimethyl sulfoxide (DMSO).

[0057] In a preferred embodiment, the extended release (ER) composition (implants) formed from the long-acting composition releases up to 30% of the drug in 30 days, preferably up to 25% of the drug in 30 days; or up to 50% of the drug in 100 days, preferably in 120 days and more preferably in 130 days; or said ER composition releases up to 80% of the drug in 140 days, preferably in 180 days, more preferably in 200 days; or the ER composition releases up to 80% of the drug in 240 days, in an in vitro dissolution test performed with horizontal orbital motion at 50 rpm; medium: PBS pH 7.4; temperature: 37 ± 0.5 s C; analytical technique: HPLC / UV; wavelength 230 nm.

[0058] In a preferred embodiment, the long-acting composition comprises 10 to 450 mg of drug. In a preferred embodiment, the composition comprises 30 to 90 mg or about 50 mg of drug. In a preferred embodiment, the composition comprises 80 to 150 mg or about 100 mg of drug. In a preferred embodiment, the composition comprises 150 to 250 mg or about 200 mg of drug. In a preferred embodiment, the composition comprises 350 to 450 mg or about 400 mg of drug.

[0059] In preferred embodiments, the drug is letrozole.

[0060] In a preferred embodiment, the terminal group of the PLA is an ester group.

[0061] In a preferred embodiment, the particle size distribution of the drug is such that less than 10% of the particles have a size smaller than 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 (volume distribution).

[0062] An aspect of the invention also provides a pharmaceutical kit comprising a drug, PLA, and a solvent for PLA, wherein the particle size distribution for said drug approximates the particle size distribution for said PLA. Said particle size distributions may be a combination of any of the particle size distributions disclosed herein.

[0063] The invention also provides a pharmaceutical kit for preparing a long-acting composition containing a drug. The pharmaceutical kit may comprise a container containing a drug and a biodegradable polymer and a container containing a solvent. pharmaceutically acceptable carrier for said biodegradable polymer. The drug, solvent, and liquid may be defined as herein.

[0064] In a preferred embodiment, the long-acting composition comprises 5-40% by weight of drug, 20-40% by weight of PLA, 20-80% by weight of DMSO, relative to the total weight of the composition before administration. Preferably, the composition comprises 15-35% by weight of drug, 25-35% by weight of PLA and 30-60% by weight of DMSO, relative to the total weight of the composition before administration. Preferably, the long-acting composition comprises 18-28% by weight of drug, 30-35% by weight of PLA and 37-52% by weight of DMSO, relative to the total weight of the composition before administration. Alternatively, the long-acting composition comprises from about 23 to about 27% by weight of drug, from about 28 to about 34% by weight of PLA, and from about 41 to about 47% by weight of DMSO, based on the total weight of the composition prior to administration.The long-acting composition may also comprise from about 24 to about 26% by weight of drug, from about 29 to about 33% by weight of PLA, and from about 42 to about 47% by weight of DMSO, based on the total weight of the composition prior to administration.

[0065] A preferred embodiment of the invention employs a stable long-acting composition for intramuscular administration suitable for forming an in situ intramuscular implant comprising, preferably consisting essentially of, preferably consisting of: 30 to 90 mg of letrozole, DMSO, and a sterile biodegradable PLA, wherein the terminal group of the PLA is an ester group, wherein said PLA has a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP. <786> and wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns, when measured by analytical sieving according to USP <786> and wherein the release of the active agent from the implant is between 2% and 30% of the active agent every 28-day interval,preferably between 5% and 25% of the active agent every 28-day interval; and wherein the particle size of the letrozole is such that less than 10% of the particles are smaller than 20 microns, less than 10% of the particles are larger than 350 microns, and the D50 is between 70-200 microns, when measured by laser diffraction analysis (volume distribution); and wherein the composition comprises 15-35% by weight of letrozole, 25-35% by weight of PLA, and 30-60% by weight of DMSO, based on the total weight of the composition before administration; and wherein the composition releases 0.1 to 2 milligrams of letrozole each day; and wherein the stable, sustained-release composition provides a plasma level of letrozole between about 1 and about 40 ng / ml from about 2 days after administration of the, implant and continuously over a dosing period. The release of letrozole from this embodiment may be as otherwise specified herein.

[0066] A preferred embodiment of the invention employs a stable, long-acting, sustained-release composition containing letrozole for intramuscular administration suitable for forming one or more intramuscular implants in situ comprising, preferably consisting essentially of, preferably consisting of: 80 to 150 mg of letrozole, DMSO, and a sterile biodegradable PLA, wherein the terminal group of the PLA is an ester group, wherein said PLA has a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP. <786> and wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns,when measured by analytical sieving according to USP <786> and wherein the release of the active agent from the implant is between 2 and 30% of the active agent every 28-day interval, preferably between 5 and 25% of the active agent every 28-day interval; and wherein the particle size of letrozole is such that less than 10% of the particles have a size less than 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 (volume distribution); and wherein the composition comprises 15-35% by weight of letrozole, 25-35% by weight of PLA, and 30-60% by weight of DMSO, based on the total weight of the composition before administration; and wherein the composition releases about 0.1 to about 2 milligrams of letrozole daily for a dosing period; and wherein the stable, sustained-release composition provides a plasma level of letrozole between about 1 and about 40 ng / ml starting about 2 days after implant administration and continuously for a dosing period. The release of letrozole from this embodiment may be as otherwise specified herein.

[0067] A preferred embodiment of the invention employs a stable, long-acting, sustained-release composition containing letrozole for intramuscular administration suitable for forming one or more intramuscular implants in situ comprising, preferably consisting essentially of, preferably consisting of: 150 to 250 mg of letrozole, DMSO, and a sterile biodegradable PLA, wherein the terminal group of the PLA is an ester group, wherein said PLA has a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP. <786> and wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns,when measured by analytical sieving according to USP <786> and wherein the release of the active agent from the implant is between 2% and 30% of the active agent every 28-day interval, preferably between 5% and 25% of the active agent every 28-day interval, and wherein the particle size of the letrozole is such that, less than 10% of the particles have a size less than 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 (volume distribution); and wherein the composition comprises 15-35% by weight of letrozole, 25-35% by weight of PLA, and 30-60% by weight of DMSO, based on the total weight of the composition before administration; and wherein the composition releases 0.1 to 2 milligrams of letrozole each day of a dosing period; and wherein the stable, sustained-release composition provides a plasma level of letrozole between about 1 and about 40 ng / ml from about 2 days after administration of the implant and continuously throughout a dosing period. The release of letrozole of this embodiment may be as otherwise specified herein.

[0068] A preferred embodiment of the invention employs a stable, sustained-release letrozole-containing composition for intramuscular administration suitable for forming one or more intramuscular implants in situ comprising, preferably consisting essentially of, preferably consisting of: 350 to 450 mg of letrozole, DMSO, and a sterile biodegradable PLA, wherein the terminal group of the PLA is an ester group, wherein said PLA has a particle size mass distribution with no more than 10% greater than 300 microns, preferably no more than 250 microns, when measured by analytical sieving according to USP. <786> and wherein said PLA has a particle size mass distribution where no more than 80% of the particles have a particle size less than 125 microns,when measured by analytical sieving according to USP <786> and wherein the release of the active agent from the implant is in the range of about 2-30% of the active agent every 28-day interval, preferably between 5 and 25% of the active agent every 28-day interval; and wherein the particle size of letrozole is such that less than 10% of the particles have a size less than 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 (volume distribution); and wherein the composition comprises 15-35% by weight of letrozole, 25-35% by weight of PLA, and 30-60% by weight of DMSO, based on the total weight of the composition before administration; and wherein the composition releases 0.1 to 2 milligrams of letrozole each day of a dosing period; and wherein the stable, sustained-release composition provides a plasma level of letrozole between about 1 and about 40 ng / ml starting about 2 days after implant administration and continuously throughout the dosing period. The release of letrozole from this embodiment may be as otherwise specified herein.

[0069] In a preferred embodiment, letrozole and PLA are combined in a first component (first syringe) of the composition, and the solvent is a separate second component (second syringe) of the composition. The long-acting composition is then formed by mixing the two components.

[0070] In another aspect, the present invention employs a kit suitable for the in situ preparation of the long-acting composition, wherein the kit comprises at least two containers or syringes, the first container or syringe comprising letrozole and PLA, and the second container or syringe comprising the solvent, preferably DMSO. The injectable depot composition is then formed by mixing the contents of at least the first and second containers.

[0071] In a second aspect, the present invention employs a method for preparing the long-acting composition containing stable, sustained-release letrozole, the method comprising mixing the components of the composition prior to administration. The components may be mixed for as long as desired, or for 30 minutes or more, 30 minutes or less, 20 minutes or less, 15 minutes or less, preferably 10 minutes or less, and more preferably 5 minutes or less prior to administration. In a preferred embodiment, the active ingredient and the PLA are provided together and that combination is mixed with the solvent.

[0072] In some embodiments, the long-acting composition and / or the non-long-acting composition after preparation is a suspension. For the long-acting composition, the PLA is preferably dissolved in the solvent after all the components have been mixed.

[0073] In a preferred embodiment, the long-acting composition is prepared by mixing the solvent, preferably DMSO, with a pre-mixed solid combination (blend) of letrozole and PLA. In a preferred embodiment, the long-acting composition is prepared (reconstituted) by first mixing the active agent with the PLA and then adding the solvent.

[0074] The invention also provides the use of the stable, long-acting, sustained-release composition for administering to a subject 0.1-2 milligrams of drug each day and continuously over a dosage period.

[0075] In a preferred embodiment, the stable, long-acting, sustained-release drug-containing composition is used to administer to a subject, optionally a subject in need thereof, from 0.1 to 1.25 milligrams (mg) of letrozole each day and continuously over a dosing period. Preferably, the composition is used to administer to a subject, optionally a subject in need thereof, from 0.1 to 1.20 mg, preferably from 0.13 to 1.15 mg, more preferably from 0.13 to 1.10 mg, even more preferably from 0.13 to 0.8 mg of letrozole each day and continuously over a dosing period, following formation of one or more implants from said composition. The release of letrozole may be as otherwise specified herein.

[0076] In a preferred embodiment, the long-acting composition provides a plasma level of letrozole between about 1 and about 40 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the long-acting composition forms one or more implants of ER (extended release) implants that provide a plasma level of letrozole between about 1 and about 40 ng / ml from about 2 days after administration and continuously for a dosing period of at least six months, or 6 to 12 months, or at least 12 months. In some embodiments, the ER implant or sustained release composition of the invention provides mediocre and therapeutic levels of plasma concentrations 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.

[0077] In a preferred embodiment, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole in the range of about 1.5-30 ng / ml or about 2-30 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole between about 1.5 and about 30 ng / ml from about 2 days after administration and continuously over a dosing period of at least six months, or 6 to 12 months, or about 12 months or more.

[0078] In a preferred embodiment, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole in the range of about 1.5-25 ng / ml or about 2-25 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole between about 1.5 and about 25 ng / ml from about 2 days after administration and continuously for at least six months, or 6 to 12 months, or about 12 months or more.

[0079] In a preferred embodiment, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole in the range of about 1.5-20 ng / ml or about 2-20 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole between about 1.5 and about 20 ng / ml from about 2 days after administration and continuously over a dosing period of at least six months, or 6 to 12 months, or about 12 months or more.

[0080] In a preferred embodiment, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole in the range of about 1.5-5 ng / ml or about 2-15 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole between about 1.5 to about 15 ng / ml from about 2 days after administration and continuously for a dosing period of at least six months, or 6 to 12 months, or about 12 months or longer.

[0081] In a preferred embodiment, the stable sustained-release composition provides one or more implants and a plasma level of letrozole in the range of about 1.5-10 ng / ml or about 2-10 ng / ml from about 2 days after administration and continuously over a dosing period. Preferably, the stable sustained-release composition forms one or more implants and provides a plasma level of letrozole between about 1.5 and about 10 ng / ml from about 2 days after administration and continuously over a dosing period of at least six months, or 6 to 12 months, or about 12 months or more.

[0082] In a preferred embodiment, the stable sustained-release composition is used to suppress plasma estradiol levels to less than 1 pg / ml after 4 days from administration of the implant and continuously for a dosing period. Said suppressed plasma estradiol level is maintained for at least 1 month, preferably at least 3 months, at least six months, from about 6 to about 12 months, at least 12 months, continuously from about 1 to about 12 months, continuously from about 9 to about 12 months, more preferably continuously from about 1 to about 10 months, even more preferably continuously from about 1 to about 6 months.

[0083] In a preferred embodiment, the stable sustained-release composition forms one or more implants that release the drug with an immediate onset of action and continuously for at least 1 month, preferably at least 3 months, more preferably at least 6 months, even more preferably at least 12 months. In a preferred embodiment, the stable sustained-release composition forms one or more implants that release the drug with an immediate onset of action and continuously for about 1 to about 12 months, or for about 9 to about 12 months, for about 1 to about 10 months, or for about 1 to about 6 months.

[0084] In some embodiments, the stable sustained-release composition forms one or more implants and releases the drug with an immediate onset of action and continuously over a dosage period of about 3 to about 6 months or about 3 to about 9 months or about 3 to about 12 months.

[0085] In a preferred embodiment, the stable sustained-release composition is formed from an injectable intramuscular depot and a sterile composition suitable for forming one or more solid, semi-solid, or gel implants in situ in a subject. In a preferred embodiment, the stable sustained-release composition is a single implant.

[0086] The composition(s) and the implant(s) of the Invention are preferably used in humans.

[0087] In another aspect, the present invention relates to the use of a long-acting composition containing letrozole suitable for forming an in situ intramuscular implant comprising a sterile biodegradable thermoplastic polymer of polylactic acid (PLA), for administering to a subject from about 0.1 to about 2 milligrams each day over a dosage period. Preferably, the use is for administering to a subject from about 0.13 to about 1.25 milligrams each day over a dosage period.

[0088] In a preferred embodiment, the long-acting composition forms one or more implants and provides a plasma level of letrozole of about 1 to about 40 ng / ml after 2 days of administration and continuously over a dosing period. More preferably, the composition forms one or more implants and provides a plasma level of letrozole of about 1.5 to about 30 ng / ml after 2 days of administration and continuously over a dosing period.

[0089] In a preferred embodiment of this aspect, the long-acting composition (the one or more implants formed therefrom) is used to suppress plasma estradiol levels to less than about 1 pg / ml after 4 days from administration of the Implant and continuously over a dosing period.

[0090] In a preferred embodiment of this aspect, the long-acting composition is used for aromatase inhibition, preferably in humans. In a preferred embodiment of this aspect, the composition is used for treating breast cancer. In a preferred embodiment of this aspect, the composition is used for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, or for the extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior conventional adjuvant therapy with tamoxifen, or for the first- and second-line treatment of postmenopausal women with hormone receptor-positive or unknown advanced breast cancer, or any combination thereof.

[0091] The invention also provides a method of treating a disease, disorder, or condition that is therapeutically responsive to the nonsteroidal aromatase inhibitor, which may be selected from the group consisting of letrozole, anastrozole, and a metabolite of any thereof. The disease, disorder, or condition may be selected from the group consisting of hormone-sensitive breast cancer, local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women, hormone receptor-positive early breast cancer in postmenopausal women, early breast cancer in postmenopausal women who have received prior adjuvant therapy with letrozole, anastrozole, and a metabolite of any thereof. conventional tamoxifen, advanced breast cancer in postmenopausal women with disease progression after tamoxifen therapy, ER-negative disease in subjects who did not respond to prior tamoxifen therapy, gynecomastia, and endometriosis. The breast cancer may be early-stage breast cancer or advanced-stage (late-stage) breast cancer. The composition may be administered as part of adjuvant therapy, first-line therapy, or second-line therapy. The composition may also be used to induce ovulation in a female subject or to promote spermatogenesis in a male subject (e.g., one suffering from non-obstructive azoospermia).

[0092] In some embodiments, the subject in need thereof is a woman with breast cancer, optionally a postmenopausal woman with breast cancer. In some embodiments, the subject is not being administered tamoxifen simultaneously.

[0093] The dosage regimen of the invention may be practiced before and / or after surgery in a subject.

[0094] Another aspect of the present invention employs a long-acting drug-containing composition suitable for intramuscular administration and comprising a sterile biodegradable thermoplastic polymer of polylactic acid (PLA), wherein the long-acting composition releases 0.1-2 milligrams each day and continuously over a dosage period.

[0095] In a preferred embodiment of this aspect, the long-acting composition releases the drug with an immediate onset of action and continuously for at least 1 month, preferably at least about 3 months or more, more preferably at least about 6 months or more, even more preferably at least about 12 months or more. In a preferred embodiment of this aspect, the long-acting composition releases the drug with an immediate onset of action and continuously for at least 1 month, at least about 2 months or more, at least about 3 months or more, at least about 4 months or more, at least about 5 months or more, at least about 6 months or more, at least about 7 months or more, at least about 8 months or more, at least about 9 months or more, at least about 10 months or more, at least about 11 months or more, or at least about 12 months or more.In a preferred embodiment, the long-acting composition releases the drug with an immediate onset of action and continuously for at least about 12 months or more. In another preferred embodiment, the long-acting composition releases the drug with an immediate onset of action and continuously for between about 3 and about 6 months.

[0096] In a preferred embodiment of this aspect, the long-acting composition is a sterile injectable intramuscular depot composition suitable for forming a solid, semi-solid, or gel implant in situ in an organism.

[0097] This long-term sustained hormone suppression therapy has been shown to provide superior clinical outcomes in humans compared to daily oral dosing. Furthermore, the sustained lower effective plasma letrozole level at lower doses (compared to oral treatment) reduces adverse side effects (bone loss, bone / joint / muscle pain, dyslipidemia) due to lower drug exposure. Furthermore, the present invention provides an improved safety profile, positively impacting adherence to treatment duration.

[0098] The invention includes all combinations of the aspects, embodiments, sub-embodiments, and clauses disclosed herein. Other features, advantages, and embodiments of the invention will become apparent to those skilled in the art from the following description, accompanying examples, and appended claims. BRIEF DESCRIPTION OF THE FIGURES

[0099] The following drawings are part of this 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 conjunction with the detailed description of specific embodiments presented herein.

[0100] Figure 1 shows a graph of observed plasma estradiol (E2) levels (pg / ml) versus time after administration of FEMARA® or the long-acting composition (Letrozole ISM). More rapid and sustained suppression of estradiol was achieved using substantially lower doses of the composition of the invention (and / or substantially lower plasma levels of letrozole) compared to the FEMARA® dose and plasma level of letrozole.

[0101] Figure 2 shows a graph of observed plasma letrozole levels (ng / ml) versus time after administration of FEMARA® or the long-acting composition (Letrozole ISM). The composition of the invention provided substantially longer and more sustained plasma letrozole levels. Plasma letrozole levels (ng / ml) observed after administration of FEMARA®.

[0102] Figure 3 shows a graph of the cumulative percentage of letrozole released versus time (d) in an in vitro dissolution test of a composition comprising PLA with a particle size mass distribution in which more than 10% of the particles have a particle size equal to or greater than 300 microns, when measured by analytical sieving according to USP. <786> .

[0103] Figure 4 shows a graph of the cumulative percentage of letrozole released versus time from a composition of the invention in an in vitro dissolution test.

[0104] Figure 5 shows a graph of the cumulative percentage of letrozole released versus an in vitro dissolution test of a composition comprising PLA having a distribution of mass of particle size where at least 80% of the particles have a particle size of 125 microns or less, when measured by analytical sieving according to USP <786> .

[0105] Figures 6A and 6B show the graph of plasma estradiol (E2) levels (pg / ml) observed versus time after administration of FEMARA® or the long-acting composition (Letrozole ISM comprising 50 mg of letrozole). The inset shows an enlarged view of the first 15 days.

[0106] Figures 7A and 7B show graphs of observed plasma estradiol (E2) levels (pg / ml) versus time after administration of FEMARA® or the long-acting composition (Letrozole ISM comprising 100 mg of letrozole). The inset shows an enlarged view of the first 15 days.

[0107] Figure 8 shows a graph of plasma levels of letrozole (ng / ml) observed versus time after administration of FEMARA® or after administration of the long-acting compositions of the invention (Letrozole ISM 50 mg or 100 mg).

[0108] Figure 9 shows a graph of mean and interindividual variability plasma levels of the 95th percentiles. a and 5 a of letrozole (ng / ml), observed versus time after intramuscular administration of a single 100 mg dose of the long-acting composition of the invention.

[0109] Figure 10 shows a graph of the average and the level of interindividual variability of the 95th percentiles. a and 5 a of the percentage of E2 suppression observed versus time following intramuscular administration of a single 100 mg dose of the long-acting composition of the invention.

[0110] Figure 11 shows a graph of the average and the level of interindividual variability of the 95th percentiles. a and 5 aof the percentage of E2 suppression observed versus time following intramuscular administration of a first 100 mg dose of the long-acting composition of the invention, and wherein approximately 8 weeks after administration of the first dose, intramuscular administration of a second 100 mg dose of the long-acting composition of the invention occurs. This is one of the preferred embodiments of the invention.

[0111] Figure 12 shows three illustrative embodiments of dosing regimens of the invention, wherein "DP1" denotes "dosing period 1", "DP2" denotes "dosing period 2", "DP3" denotes "dosing period 3", "TP" denotes "treatment period", "1 a LAI" denotes "first dose of long-acting composition" "2 a LAI" denotes "second dose of long-acting composition", "3 a"LAI" denotes "third dose of long-acting compound"; "HD" denotes "higher dose", and "LD" denotes "lower dose". DETAILED DESCRIPTION OF THE INVENTION

[0112] As used herein, the terms "non-steroidal aromatase inhibitor therapeutically responsive disease, disorder, or condition" exclude any disease, disorder, or condition that is not therapeutically responsive to a non-steroidal aromatase inhibitor. The therapeutic response of said disease, disorder, or condition to a non-steroidal aromatase inhibitor is determined by administering one or more compositions of the invention to a subject in need thereof, wherein the dose of the drug (via the composition) is administered as defined herein, to provide one or more implants that release said non-steroidal aromatase inhibitor over the time period defined herein, to provide plasma levels of said drug or metabolite thereof as defined herein.A clinician then determines whether the disease, disorder, or condition is therapeutically responsive, meaning the clinician determines whether the individual in need has experienced the desired clinical benefits. For example, when treating cancer, a therapeutic response may include slowing or reversing the progression of the cancer, or it may even include remission of the cancer. When treating gynecomastia, a therapeutic response may include reduction in breast size or slowing breast enlargement. A clinician familiar with nonsteroidal aromatase inhibitors will be able to follow the methods and conventions of the art to determine whether the disease, disorder, or condition is therapeutically responsive to the nonsteroidal aromatase inhibitor.

[0113] As used herein, the term "dosing period" refers to the period from administration of the long-acting composition to the completion of drug release from one or more corresponding implants. As used herein, the term "treatment period" refers to the period during which a subject receives one or more doses of the injectable depot composition. A treatment period may comprise one or more dosing periods during which the subject receives one or more corresponding doses. The treatment period preferably comprises at least the first dosing period and the second delayed and overlapping dosing period. The treatment period may last from about one to ten years, about two years or more, about three years or more, about five years or more, about seven years or more, or about ten years or more.The treatment period includes at least the administration of the first two doses of the long-acting composition and may additionally include approximately annual administration of the long-acting composition.

[0114] As used herein, the terms "letrozole" and "anastrozole" refer to the non-saline and saline forms thereof. The terms "active ingredient", "active agent", or "drug" refer to a therapeutically active compound, as well as any derivative 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 (drug) is letrozole and / or anastrozole. The preferred drug is letrozole.

[0115] The term "stable sustained-release composition" generally refers to one or more implants, which together provide a dose of drug over a dosing period.

[0116] The term "stable" as used herein refers to a pharmaceutical composition comprising letrozole wherein the total content of impurities from the decomposition of letrozole does not exceed 5 area %, preferably 3 area %, more preferably 2 area %, and most preferably 1 area % as determined by liquid chromatography (HPLC) at 230 nm if such composition is stored for 2 months at 40°C and 75% relative humidity (RH).

[0117] The use of a non-long-acting composition as the first dose of the drug in the dosage regimen of the invention is optional. As used herein, a non-long-acting injectable (nLAI) composition is an injectable composition that excludes an extended (sustained, controlled) release polymer. The non-long-acting composition comprises drug and at least one pharmaceutically acceptable liquid excipient, which is preferably aqueous. Additional pharmaceutically acceptable excipients are optionally included in the non-long-acting composition.

[0118] The drug may be completely suspended or partially dissolved / partially suspended in the liquid carrier of the non-long-acting composition or the long-acting composition. In preferred embodiments, at least part of the drug is suspended as particles in an aqueous liquid carrier or a water-miscible liquid carrier. In some embodiments, the liquid carrier (which may also be referred to herein as a solvent) comprises DMSO or NMP (N-methylpyrrolidone). Suitable liquid carriers are non-toxic, biocompatible, and suitable for parenteral injection, and are preferably biocompatible so as not to cause severe tissue irritation or necrosis at the injection site. The liquid carrier is preferably classified as class II or III, and more preferably class III, according to the ICH Guidelines.For in situ implant formation, the liquid excipient should preferably diffuse rapidly from the polymer solution into the surrounding tissues when exposed to physiological fluids. Accordingly, the liquid excipient is preferably miscible with water and more preferably has a dipole moment of about 3.9-4.3 D at 25°C. e C. Preferred liquid excipients are DMSO (dimethyl sulfoxide) and PEG (poly(ethylene glycol, such as PEG having an average molecular weight in the range of about 200, about 300 or about 400). Grades of PEG that are liquid at room temperature (20-30°C) can be used. The most preferred liquid excipient is DMSO. The invention You can also use a long-acting composition that has a combination of two or more of these liquid excipients.

[0119] As used herein, a long-acting injectable composition of the invention comprises a drug, at least one liquid excipient, and at least one biodegradable extended-release (controlled, sustained) polymer. The polymer may be a homopolymer or a copolymer. The drug may be completely dissolved, partially dissolved / partially suspended, or completely suspended as particles in the long-acting composition prior to administration. The polymer may be completely dissolved, partially dissolved / partially suspended, or completely suspended as particles in the long-acting composition prior to administration. The drug and polymer may be present together as drug-containing particles suspended in at least one liquid excipient. The composition may further comprise one or more pharmaceutical excipients.

[0120] In preferred embodiments, the long-acting composition comprises drug, at least one biodegradable extended-release polymer, and at least one solvent (liquid carrier) for the polymer. Particularly preferred embodiments of the long-acting composition comprise drug, PLA, and solvent for PLA. The amount of solvent in the long-acting composition is preferably sufficient to dissolve the PLA. The drug may be partially or completely suspended as particles in the polymer solution (PLA dissolved in the solvent) or solvent. In some embodiments, about 50% or more of the drug is suspended as particles. In other embodiments, about 60% or more, about 70% or more, about 80% or more, or about 90% or more of the drug is suspended as particles.

[0121] As used herein, "sized" PLA ("PLA that has been sized") is PLA that has been processed to provide a particular particle size distribution as described herein. Sizing of PLA is optional. Methods of sizing PLA include, by way of example and not limitation, milling, fracturing, sieving, classifying, crushing, impacting, homogenizing, sonication, ultrasonication, dry milling, wet milling, cryogenic milling, or other similar processes known in the art of particle size reduction.

[0122] When PLA particle size is measured by analytical sieving according to USP <786> , the amplitude is 0.65 mm, and the stirring time is 5 minutes. When measuring PLA particle size by laser diffraction analysis, the particle size is determined by the wet dispersion method. No pretreatment was applied to the sample. The sample was added directly to the dispersion medium (water). The dispersion mechanism was stirred at 3000 rpm.

[0123] The PLA polymer is selected from free acid (non-capped; uncapped) or polylactide having capped carboxylic terminal groups (e.g., alkyl esters such as lauryl ester, methyl ester, etc., referred to herein as PLA-e) 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 capped with esters (as opposed to the free carboxylic acid) demonstrate longer degradation half-lives; however, uncapped polymers having carboxylic acid terminal groups also exhibit improved performance related to particle size.Suitable grades of PLA are commercially available from Uhde Inventa-Fischer (Berlin, DE), NatureWorks LLC (Blair, NE, USA), Plastic Ingenuity (Cross Plains, WI, USA), Toyobo, Dai Nippon Printing Co., Mitsui Chemicals, Shimadzu, NEC, Toyota (Japan), PURAC Biomaterials, Hycail (Netherlands), Galactic (Belgium), Cereplast (USA), FkuR, Biomer, Stanelco, Inventa-Fischer (Germany), Snamprogetti (China), Boehringer Ingelheim (RESOMER® grades; Ingelheim Am Rhein, DE), Evonik Industries (RESOMER® grades; Essen, DE), ALKERMES (Dublin, Ireland), or SIGMA ALDRICH (ST. Louis, MO). In some embodiments, the PLA is capped with an alkylated alcohol to form an ester end group moiety.

[0124] In some embodiments, 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 measured in chloroform at 25 °C. SC at a concentration of 0.1% w / v with a Ubbelohde glass capillary viscometer size 0c or measured in chloroform at 30 s C and at a concentration of 0.5% w / v using a Cannon-Fenske size 25 glass capillary viscometer. The inherent viscosity can be measured before or after beta irradiation, if such irradiation is used.

[0125] As used herein, the term "polymer solution" is understood 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 long-acting composition comprises (or consists essentially of or consists of) solvent, PLA polymer, and drug. Accordingly, the long-acting composition comprises (or consists essentially of or consists of) polymer solution and drug.

[0126] In some embodiments, the polymer solution has a minimum viscosity of about 0.8 Pa.s, although it may preferably be about 1 Pa.s. The viscosity may be about 4 Pa.s or less, about 3 Pa.s or less, about 2 Pa.s or less, about 1.8 Pa.s or less. The viscosity of the polymer solution may range from about 0.7 to about 4 Pa.s, about 0.7 to about 3 Pa.s, about 0.7 to about 2 Pa.s, about 0.8 to about 1.8 Pa.s, or about 1 to about 1.8 Pa.s. The viscosity of polymer solutions in DMSO are measured at 25 a C. Unless otherwise specified, the viscosity value of the polymer solution or injectable composition is given in units of Pa.s.

[0127] In some embodiments, the weight ratio of DMSO to PLA is from about 1:1 to about 2.3:1, from about 1.2:1 to about 1.8:1, from about 1.3:1 to about 1.5:1, or about 1.4:1.

[0128] 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.

[0129] In some embodiments, the weight ratio of the polymer solution to the drug is from about 1:1 to about 5.7:1, from about 2.3:1 to about 4:1, from about 2.8:1 to about 3.2:1, or about 3:1.

[0130] In some embodiments, the weight ratio of PLA to drug is from about 0.6:1 to about 2.8:1, from about 1.0 to 2.0, from about 1.1:1 to 1.6:1, from about 1.1:1 to about 1.4:1, from about 1.1:1 to about 1.35:1, from about 1.1:1 to about 1.3:1, from about 1.2:1 to about 1.3:1, or about 1.25:1.

[0131] In some embodiments, the drug is partially dissolved or not dissolved at all in the polymer solution. In some embodiments, <5%, <10%, <20% by weight of the drug is dissolved in the solvent or polymer solution to form the injectable composition. In some embodiments, >0%, >0.5%, >1%, >5%, or >10% by weight of the drug is dissolved in the solvent or polymer solution to form the injectable composition.

[0132] The term "immediate onset of action," as used herein, means that the suppression of plasma estrogen levels achieved by the composition of the invention is at least as early as that achieved by oral FEMARA® therapy, i.e., by 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) is detectable, meaning that E2 is below the detection limit. However, it is important to note that a lower dose of letrozole was administered as letrozole ISM than as FEMARA®.Accordingly, the long-acting composition is capable of reducing 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 approximately four days after administration and continuously over a dosing period.

[0133] The performance of FEMARA® and a composition of the invention (Letrozole ISM) (FIG. 2) was compared in terms of plasma concentration achieved after administration of a dose to human subjects. The FEMARA® composition provided plasma concentrations extremely high levels of letrozole, which may then be associated with a much higher incidence or severity of adverse events. On the other hand, the composition of the invention provided a) no large instantaneous release of letrozole; b) substantially longer and sustained plasma levels of letrozole; and c) therapeutically effective plasma levels of letrozole for about 16 weeks (about 4 months) or longer.

[0134] The relative impact of PLA particle size distribution was determined by comparing the in vitro dissolution profile (drug release profile) for several Long Acting (ER) Compositions formed from injectable depot compositions comprising PLA of different particle size distributions.

[0135] The impact of the relative content of larger PLA particles was determined. FIG. 3 shows a graph of the cumulative percentage of letrozole released versus time (d) in an in vitro dissolution test of 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 larger, as 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 greater than 300 microns and 28.3% of the particles were less than 125 microns, as measured by analytical sieving according to USP <786> . Such 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.

[0136] FIG. 4 shows a table of cumulative percentage of letrozole released versus time from a long-acting composition in an in vitro dissolution test. The PLA used had a particle size mass distribution where 0.8% of the particles were greater than 300 microns and 58.5% of the particles were less than 125 microns, as measured by analytical sieving according to USP. <786> . This PLA had a particle size 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 unexpectedly lasted approximately two months longer than that provided by PLA not according to the invention (FIG. 3).

[0137] The impact of the relative content of smaller PLA particles upon drug dissolution was determined. FIG. 5 shows a graph of the cumulative percentage of letrozole released versus an in vitro dissolution test of a long-acting 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, as 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 greater than 300 microns and 88.8% of the particles were less than 125 microns, as 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; although it formed hard agglomerates during the initial mixing of DMSO, PLA, and drug.

[0138] FIGS. 6A and 6B show the graph of plasma estradiol (E2) levels (pg / ml) observed versus time after oral administration of FEMARA® (2.5 mg once daily for 14 days) or intramuscular administration of the long-acting composition (Letrozole ISM; an injection comprising 50 mg of letrozole) according to Example 3 (Cohort 1). The inset shows an enlarged view of the first 15 days. FIGS. 7A and 7B show graphs of plasma estradiol (E2) 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; an injection comprising 100 mg of letrozole) according to Example 3 (Cohort 2). The inset shows an enlarged view of the first 15 days. Plasma estrogen levels decreased rapidly from baseline after letrozole administration.Hormones decreased to steady-state levels below 1 pg / ml approximately 4 days after treatment with Femara® / Letrozole ISM (FIG. 6A, 6b, 7A and 7B). 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 degree of hormone 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.

[0139] FIG. 8 shows a graph of observed letrozole plasma levels (ng / ml) versus time following 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. The mean maximum letrozole exposure concentrations observed for FEMARA® at steady state (2.5 mg QD for 14 days) were approximately 12-fold and 8-fold higher than those observed for letrozole doses of 50 mg and 100 mg, respectively. The much higher plasma concentration provided by FEMARA® would provide a corresponding greater severity and / or incidence of adverse events compared to the much lower, but still therapeutically effective, plasma concentration provided by the composition(s) of the invention.

[0140] By overlaying the tables in FIGS. 6A, 6B, 7A and 7B, the long-acting 100 mg composition has twice the letrozole dose of the 50 mg injectable composition, both compositions are effective in maintaining plasma levels of E1 (estrone) and E2 (estradiol) below the LOQ, the level of quantification, for at least about 365 days or longer.

[0141] Accordingly, the long-acting composition(s) provide 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 at the same time providing fewer adverse events.

[0142] FIG. 9 shows a graph of the time-dependent change in mean plasma concentration of letrozole (ng / ml) following intramuscular administration of a single 100 mg dose of a long-acting composition comprising letrozole, PLA, and DMSO. The shaded area above and below the line represents the intersubject variability observed at the 95th and 5th percentiles in plasma concentration.

[0143] FIG. 10 depicts the percentage of E2 suppression corresponding to the plasma profile of FIG. 9. The level of E2 suppression exhibits a substantial undesirable (disadvantageous) decrease (change) between approximately 112-224 days after a single administration of the long-acting composition (single 100 mg dose). The consequence of this change is that a subject receiving the long-acting composition may or may not receive the full therapeutic benefit of the drug during that time period and may be at greater risk for cancer progression during the period of decreased E2 suppression.

[0144] The present inventors developed a combined dosage regimen that overcame the disadvantage observed with sole administration of a single dose of the long-acting composition. They determined that the first intramuscular administration of a long-acting composition followed by the second intramuscular administration of the long-acting composition, after a lag period of about 6-10 weeks (first aspect of the invention) or about 50-54 weeks (second aspect of the invention), essentially eliminated the undesired period of decreased E2 suppression typically following administration of a single long-acting composition.

[0145] FIG. 12 shows two illustrative dosage regimens of the invention. In accordance with the first embodiment of the first aspect of the invention, a first dose of long-acting composition (1 aLAI), thus initiating a first dosing period (DP1). After a delay period of approximately 6-10 weeks or approximately 8 weeks, a second dose of long-acting composition (2 a LAI), thus beginning a second dosing period (DP2). DP1 and DP2 last approximately 11- 13 months or approximately 12 months. A third dose of long-acting composition (3 a LAI) is administered toward the end of DP2, i.e., from approximately 4 weeks before to approximately 4 weeks after the end of DP2, thus beginning a third dosing period (DP3). Subsequent annual administrations of additional long-acting compounds are contemplated, thus further extending the overall PT.

[0146] According to the second embodiment of the first aspect of the invention (FIG. 12), a first dose of long-acting composition (1a LAI), thus initiating a first dosing period (DP1). After a delay period of approximately 6-10 weeks or approximately 8 weeks, a second dose of long-acting composition (2 a LAI), thus beginning a second dosing period (DP2). DP1 and DP2 last approximately 11-13 months or approximately 12 months. A third dose of long-acting composition (3 a LAI) is administered towards the end of DP1, i.e., within approximately 4 weeks before to approximately 4 weeks after the end of DP1. Subsequent annual administrations of the long-acting composition are contemplated, thus further extending the overall PT.

[0147] According to a first embodiment of the second aspect of the invention (FIG. 12), a first dose of long-acting composition (1 aLAI), thus initiating a first dosing period (DP1-HD). This is the highest dose dosing period. After a delay period of approximately 50-54 weeks or approximately 52 weeks, a second dose of long-acting composition (2 a LAI), thus beginning a second dosing period (DP2-LD). This is the lowest dose dosing period. DP1-HD and DP2-LD each last approximately 11-13 months or approximately 12 months. A third dose of long-acting composition (3 a LAI) is administered towards the end of DP 2-LD, i.e., it is administered within approximately 4 weeks before to approximately 4 weeks after the end of DP2-LD. Subsequent annual administrations of additional long-acting composition are contemplated, thus further extending the overall PT. The dose for the 3 aThe dose of the long-acting composition may be higher, lower, or approximately the same as the dose of the 2nd a long-acting composition dose.

[0148] In accordance with the first aspect of the invention, a first dose of long-acting composition (PLA, DMSO, letrozole) comprising about 100 mg of drug, in particular letrozole, was administered intramuscularly. Approximately 8 weeks after administration of the first dose of the long-acting composition, a second dose of the long-acting composition (PLA, DMSO, letrozole) comprising about 100 mg of drug was administered intramuscularly. The resulting profile for the extent (%) of E2 suppression is depicted in FIG. 11. The period of waning E2 suppression at 112-224 days was essentially eliminated. As a result, patients treated with the drug will receive the full therapeutic benefit of the drug throughout the procedure.

[0149] If used in a dosage regimen, the non-long-acting composition may comprise the same solvent (pharmaceutically acceptable liquid carrier) or a different solvent than that present in the long-acting composition.

[0150] Any composition may additionally comprise one or more pharmaceutically acceptable excipients selected from the group consisting of water-miscible solvent, surfactant, buffer, solubiliser, chelating agent, preservative, antioxidant, adsorbents, acidifying agent, alkalising agent, antifoaming agent, buffering agent, colourant, electrolyte, salt, stabilizer, tonicity modifier or oil. Suitable solvents are listed in the “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance for industry Q3C Impurities: Residual Solvents” (1997), which makes recommendations on what amounts of residual solvents are considered safe in pharmaceutical products.

[0151] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues and without undue toxicity, irritation, allergic response or any other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0152] The invention provides a method for treating a disease, disorder, or condition that is therapeutically responsive to a nonsteroidal aromatase inhibitor. The nonsteroidal aromatase inhibitor may be letrozole, anastrozole, or a metabolite of either of these.Illustrative diseases, disorders, or conditions include, for example: a) adjuvant treatment (treatment after surgery with or without radiation) of postmenopausal women with hormone receptor-positive early breast cancer; b) metastases in pre- and postmenopausal women; c) precocious puberty or children with pubertal gynecomastia; d) reduction of estrogen, including estradiol, in males; e) hormone-sensitive breast cancer after surgery; f) ovarian stimulation; g) promotion of spermatogenesis in male patients suffering from non-obstructive 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 ovary syndrome; k) ovarian cancer; i) breast cancer that is estrogen hormone receptor positive or responsive; m) priming for in vitro maturation cycles; n) preoperative treatment with letrozole in premenopausal women undergoing laparoscopic myomectomy for large uterine fibroids; o) short stature in peripubertal children; p) unexplained infertility or infertility with unknown or uncertain etiology; ) idiopathic central precocious puberty in male children.

[0153] In some embodiments, the long-acting composition is formed by 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, the PLA and drug are in one container and the solvent is in a separate container, and the contents of the containers are mixed to form the composition. In another In one embodiment, the PLA, the drug, and the solvent are in separate containers, and the contents of the containers are mixed to form the composition. In another embodiment, the PLA and the solvent are in one container, and the drug is in a separate container, and the contents of the containers are mixed to form the composition. The container or containers may be part of a pharmaceutical kit. Accordingly, the invention also provides a pharmaceutical kit comprising one or more containers, wherein the contents of the one or more containers are as described herein.

[0154] The method may further comprise the step of forming the injectable composition prior to administration thereof. The method may further comprise the step of providing a kit comprising containers with the ingredients of the injectable composition. The composition may 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 necessary or as many times as necessary to ameliorate the disease, disorder, or condition. Combinations of the dosage 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 after administration of a dose of said composition.

[0155] The injectable composition can be administered to muscle tissue, adipose tissue, the peritoneum, or subcutaneously. 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 muscle site or can be divided into two or more portions and administered to two or more muscle sites of a subject. For example, a first portion of a dose can be administered to a first section of the gluteal muscle and a second portion of the dose can be administered to a second section of the gluteal muscle of a subject. A single-body implant will be formed at each injection site. Such intra-day administration is considered single-dose administration with a single dosing period.Alternatively, administration may be modified such that there is one needle entry point into the subject but more than one injection site beneath the skin, which may be achieved by first penetrating the skin and muscle and delivering a portion of a dose, then partially withdrawing and redirecting the needle to another section of muscle while keeping the needle tip beneath the skin and then injecting. another portion of the dose into this other section of the muscle. Such a mode of administration is still considered the administration of a single dose within a single dosing period.

[0156] A typical injectable composition dose comprises about 30 to about 90 mg of letrozole, about 50-100 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 75 mg of letrozole, about 100 mg of letrozole, about 200 mg of letrozole, or about 400 mg of letrozole. Anastrozole may be used instead of letrozole.

[0157] Following administration to a subject, the preferred long-acting composition will form one or more implants (preferably a single implant) in said subject.

[0158] Single dose administration is typically considered the 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 minutes, up to 15 minutes, or up to 5 minutes.

[0159] In another embodiment, the injectable composition is sterile as a finished product. In another embodiment, the incompatible polymer is sterilized prior to its aseptic filling process, preferably by irradiation (such as beta irradiation) or by another method, e.g., filtration.

[0160] The implant of the invention can provide substantially improved plasma levels of drug compared to another injectable formulation (not according to the invention) containing the same drug when administered on an equivalent dose basis.

[0161] The invention also provides a sustained-release implant comprising PLA and a drug (which is letrozole, anastrozole, or a salt thereof, or a metabolite of any thereof), wherein a) the weight ratio of PLA to drug is from about 0.6:1 to about 2.8:1, from about 1.0 to 2.0, from about 1.1:1 to 1.6:1, from about 1.1:1 to about 1.4:1, from about 1.1:1 to about 1.35:1, from about 1.1:1 to about 1.3:1, from about 1.2:1 to about 1.3:1, or about 1.25:1; b) the implant has been prepared from a long-acting composition comprising i) 15-35% by weight of letrozole, 25-35% by weight of PLA and 30-60% by weight of DMSO; ii) 18-28% by weight of letrozole, 30-35% by weight of PLA and 37-52% by weight of DMSO;iii) about 23 to about 27% by weight of letrozole, about 28 to about 34% by weight of PLA, and about 41 to about 47% by weight of DMSO; or iv) about 24 to about 26% by weight of letrozole, about 29 to about 33% by weight of PLA, and about 42 to about 47% by weight of DMSO, wherein the; Weight percentages are relative to the total weight of the composition prior to 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 in the range of about 1.5-40 ng / ml or about 2-40 ng / ml from about 2 days after administration and continuously over 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 prior to being included in the composition. The implant may be used in a method of administration or a method of treatment as defined herein.

[0162] The invention also provides a method for forming an implant, the method comprising a) mixing DMSO, PLA, and drug to form a long-acting composition; and b) administering the 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 formation of the implant, is as defined herein. The in vivo and in vitro behavior of the implant is as defined herein.

[0163] All values ​​disclosed herein may have a conventional technical measurement error (standard deviation) of ±10%. The term "approximately" is intended to represent ±10%, ±5%, ±2.5%, or ±1% of a specified value; i.e., "approximately 20%" means 20±2%, 20±1%, 20±0.5%, or 20±0.25%.

[0164] In view of the foregoing description and the following examples, one skilled in the art will be able to practice the claimed invention without undue experimentation. The foregoing will be better understood with reference to the following examples, which detail certain procedures for preparing embodiments of the present invention. All references to these examples are for illustrative purposes only. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many embodiments contemplated by the present invention. Example 1 Long-acting compositions

[0165] The following formulations are prepared.

[0166] A ready-to-use formulation can be prepared, for example, and included in a ready-to-use syringe for intramuscular injection. The same formulation can be part of, for example, a kit with two syringes, one male and one female, or two male syringes joined by a connector, in which the PLA solution in DMSO is in one syringe and the letrozole is in solid form in a second syringe. Similarly, the final composition can be obtained, for example, by maintaining one syringe with the PLA and letrozole in solid form and the solvent (DMSO) in a second syringe. Formulation 1:

[0167] The weight ratio of DMSO to PLA is approximately 1.5:1. The weight ratio of DMSO to drug is approximately 5.11:1. The weight ratio of polymer solution to drug is approximately 8.52:1. The weight ratio of PLA to drug is approximately 3.41:1. Formulation 2: formulation with letrozole in suspension

[0168] The particle size of letrozole in formulation 2 was characterized by the laser diffraction technique (Malvern Mastersizer 2000, suspended in water until 9.41% obscuration) and had the following distribution (in % by volume): d(0.1) = 38.21 pm, d(0.5) = 141.35 pm and d(0.9) = 312.13 pm.

[0169] The weight ratio of DMSO to PLA is approximately 1.5:1. The weight ratio of DMSO to drug is approximately 1.8:1. The weight ratio of polymer solution to drug is approximately 3:1. The weight ratio of PLA to drug is approximately 1.2:1. Formulation 3:

[0170] The weight ratio of DMSO to PLA is approximately 1.5:1. The weight ratio of DMSO to drug is approximately 1.8:1. The weight ratio of solution polymeric to drug ratio is approximately 3:1. The weight ratio of PLA to drug is approximately 1.2:1. Formulation 4:

[0171] The weight ratio of DMSO to PLA is approximately 1.5:1. The weight ratio of DMSO to drug is approximately 1.8:1. The weight ratio of polymer solution to drug is approximately 3:1. The weight ratio of PLA to drug is approximately 1.2:1. Formulation 5:

[0172] The weight ratio of DMSO to PLA is approximately 1.41:1. The weight ratio of DMSO to drug is approximately 1.75:1. The weight ratio of polymer solution to drug is approximately 3:1. The weight ratio of PLA to drug is approximately 1.25:1. Formulation 6:

[0173] The weight ratio of DMSO to PLA is approximately 1.41:1. The weight ratio of DMSO to drug is approximately 1.75:1. The weight ratio of solution polymer to drug is approximately 3:1. The weight ratio of PLA to drug is approximately 1.25:1. Formulations 7 to 12:

[0174] For some preferred compositions, the % w / w in the active agent composition was between 20.0 and 27.0%. The % w / w in the PLA composition was between 20.0 and 50.0%. The % w / w in the solvent composition was between 23.0 and 60.0%. The compositions were mixed in a syringe to form suitable implants.

[0175] Different types of PLA were used for these compositions: 1. PLA with a particle size mass distribution where more than 10% of the particles had a particle size of 300 microns or larger when measured by analytical sieving according to USP <786> ; 2. PLA with particle size volume distribution with D90 greater than 330 microns when measured by laser diffraction analysis; 3. PLA with particle size mass distribution, where no more than 10% of the particles had a particle size greater than 300 microns and no more than 80% of the particles had a particle size less than 125 microns when measured by analytical sieving according to USP <786> ; 4. PLA with particle size volume distribution with D90 not greater than 330 microns and D80 not less than 135 microns when measured by laser diffraction analysis; 5. PLA with particle size mass distribution where more than 80% of the particles had a particle size less than 125 microns, when measured by analytical sieving according to USP <786> ; 6. PLA with particle size volume distribution with D80 less than 135 microns when measured by laser diffraction analysis.

[0176] The compositions of the invention are prepared by first dry-blending the active agent with the PLA and then adding the solvent, preferably DMSO, to dissolve the PLA and obtain a suspension of the active agent. The reconstitution procedure should be carried out immediately prior to injection, and the preparation time should not exceed 15 minutes, preferably 10 minutes, more preferably 5 minutes, before administering the composition IM.

[0177] The implants prepared in this manner were used for the following dissolution test: horizontal orbital motion at 50 rpm; medium: PBS pH 7.4; temperature: 37 ± 0.5 Q C; HPLC / UV analytical technique; wavelength 230 nm.

[0178] It was observed that for PLAs 1 and 2, the release was not as satisfactorily sustained as desired when the preferred preparation time was applied (FIG. 3). However, for PLAs 3 and 4, the sustained release was satisfactory (FIG. 4).

[0179] When PLAs 5 and 6 were used, large, hard agglomerates formed, and the composition could not be prepared within the preferred time of no more than 15 minutes. Therefore, this composition was not considered clinically suitable. In any case, the implant was analyzed, and sustained release was satisfactory (FIG. 5). Example 2 Determination of particle size Analytical screening according to USP <786>

[0180] The mass distribution of PLA particle size 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 stirring time was 5 minutes. Laser light diffraction

[0181] The particle size distribution of PLA is expressed as volume distribution and was determined using laser diffraction using the wet dispersion method. No pretreatment was applied to the sample. The sample was added directly to the dispersion medium (water). The dispersion mechanism was agitated at 3000 rpm, and the sample was stabilized for 30 seconds before measurement. Example 3 Clinical data Preliminary results of Phase I

[0182] Preliminary results indicate that long-term sustained hormone suppression therapy (HT) may achieve a superior clinical outcome in breast cancer compared with once-daily oral dosing.

[0183] Early discontinuation and non-adherence to HT are common and are associated with increased mortality: improved adherence to letrozole ISM® treatment has the potential to improve treatment.

[0184] Sustained lower effective doses (compared to oral treatment) may reduce adverse side effects (bone loss, bone / joint / muscle pain, dyslipidemia) due to lower drug exposure.

[0185] A better safety profile has the potential to have a positive impact on adherence to treatment duration. Phase I Results

[0186] 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 healthy postmenopausal female volunteers. The study has four arms: Experiment: Cohort 1: Letrozol ISM 50 mg:14 oral doses of 2.5 mg FEMARA® (once daily) + single IM injection of 50 mg Letrozol ISM. Experiment: Cohort 2: Letrozole ISM 100 mg:14 oral doses of 2.5 mg FEMARA® (once daily) + single IM injection of 100 mg Letrozole ISM. Experiment: Cohort 3: Letrozole ISM 200 mg:14 oral doses of 2.5 mg FEMARA® (once daily) + single IM injection of 200 mg Letrozole ISM. Experiment: Cohort 4: Letrozole ISM 400 mg:14 oral doses of 2.5 mg FEMARA® (once daily) + single IM injection of 400 mg Letrozole ISM.

[0187] The objective of this study is to evaluate the pharmacokinetic profile of single ascending doses of Letrozole ISM and, secondarily, to evaluate the safety and tolerability of single ascending doses of Letrozole ISM, measure estrogen levels and characterize the oral pharmacokinetic profile of letrozole to be used in subsequent comparison with Letrozole ISM.

[0188] The study is being conducted in healthy postmenopausal women who meet the inclusion and exclusion criteria. The study design includes a screening period and two treatment periods. Treatment Period 1 comprises 14 oral doses of 2.5 mg of Femara®. Treatment Period 2 comprises single IM doses of 50, 100, 200, and 400 mg of Letrozole ISM. The total expected duration of the study is approximately 71 weeks. Inclusion criteria:

[0189] The inclusion / exclusion criteria for the 120 participants are as follows: • Healthy postmenopausal women, aged 18 to 75 years, who have reached complete menopause, either natural or surgical, and amenorrhea, and have not been on hormone replacement therapy in the last 3 months. • Postmenopausal subjects must have had no menstruation for 1 year, and oophorectomized subjects must have had no menstruation 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. • Basal plasma levels of follicle-stimulating hormone (FSH) and 17p-estradiol should be compatible with the subject's postmenopausal status (FSH > 40 mIU / ml; 17(3- estradiol < 31 pg / ml), confirmed at least 48 hours prior to dosing. • Weight 50 kg and GMI > 19 and 39 kg / m2. • Subjects must be in good health, as determined by medical history, physical examination, vital sign assessments (pulse rate, systolic and diastolic blood pressure, and temperature), clinical laboratory evaluations, and a 12-lead ECG. Minor deviations outside the reference ranges will be acceptable if the Investigator deems them not clinically significant. • Subjects who have not had a mammogram in the past 12 months (documentation is required) must be willing to have one. • Subjects with an intact uterus and cervix who have not had a Pap smear within the past 6 months (documentation required) should be willing to have one. • Subjects will have given their written informed consent to participate in the study and comply with the study restrictions. • Subjects must be able to communicate with clinic staff. Exclusion criteria: • Patients who have a history of allergy or hypersensitivity to letrozole or any of the inactive ingredients within the last 3 months. • Patients who have a history of galactose intolerance, severe hereditary lactase deficiency, glucose-galactose malabsorption. • Patients who have used estrogen or progesterone hormone replacement therapy, thyroid replacement therapy, oral contraceptives, androgens, luteinizing hormone (LH) releasing hormone analogues, prolactin inhibitors or antiandrogens within 3 months prior to Screening. • Patients who have regularly consumed foods or dietary supplements containing high levels of isoflavinoids, including soy, soy milk, soybeans, 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 whether a subject who ingests foods or dietary supplements containing isoflavinoids is eligible to participate in the study. • Patients who have used: o Any medications, including St. John’s wort, known to be strong or moderate inducers of CYP P450 3A4 within 3 weeks prior to dosing (Treatment Period 1). o Any medications or products known to be strong or moderate inhibitors of CYP P450 3A4 (e.g., grapefruit juice) within 7 days prior to dosing in Treatment Period 1. o Any preparation prescribed 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. o Any systemic or topical medication not prescribed 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 are permitted, including the use of calcium and / or vitamin D for the prevention of osteoporosis. • Patients who have been diagnosed with osteoporosis (previously or as a result of DEXA scanning for this study with a T-score < -2.5). Subjects with osteopenia (with a T-score between -1 and -2.5) will be eligible to participate in this study. • Patients who are not on a stable dose of long- or short-acting bisphosphonate therapy for at least 3 months prior to Screening. • Patients who are on raloxifene therapy. • Patients who have an abnormality in heart rate, blood pressure, or temperature at Screening and prior to the 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. • Patients who have a 12-lead ECG abnormality at Screening and prior to the first dose (Treatment Period 1) that, in the opinion of the Investigator, increases the risk of participating in the study. • Patients who have any clinically significant abnormal findings on physical examination. • Patients who have clinically significant abnormal laboratory safety findings at the time of Screening or Registration, upon repeat testing, as determined by the investigator (1 repeat assessment is acceptable). • Patients who have ALT or AST >1.5 x ULN. For subjects with elevated total bilirubin, direct and indirect bilirubin will be assessed. • Subjects with elevated cholesterol or triglyceride levels above the ULN should be determined by the investigator as not clinically significant. • Patients who have relevant diseases or clinically significant abnormal findings on Screening, as determined by medical history, physical examination, laboratory tests, ECG, DEXA, and breast and pelvic examination. • Patients with a 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 or treatment, diabetes or any other endocrine disease, estrogen-dependent neoplasia, postmenopausal uterine bleeding, or endometrial hyperplasia. Subjects who have undergone cholecystectomy will be admitted if there are no medical sequelae following surgery. • Patients who have a history of cancer in the last 5 years with the exception of non-melanoma skin cancer. • Patients who have a history of drug dependence and a recent history of alcoholism or alcohol abuse. • Patients who have a positive result for hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis C antibody, or human immunodeficiency virus (HIV) antibody. • Patients with a positive drug of abuse screen or breath alcohol test at Screening (urine will be tested for the presence of the following: amphetamine, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, phencyclidine, and methadone). • Patients with a history of or difficulty accessing veins for venipuncture. • Patients who have donated blood in the 30 days prior to the first dose (Treatment Period 1). • Patients who have received blood products within 2 months prior to Screening. • Patients who have received an investigational drug or participated in other clinical trials within 30 days, or 5 half-lives (whichever is longer) prior to dosing (Treatment Period 1). • Patients who have previously participated in or withdrawn from this study. (Subjects who have been screened but not included in a cohort, or subjects who dropped out of screening in a previous cohort for non-medical reasons, may be eligible for inclusion in subsequent cohorts.) • Any other unspecified reason that, in the opinion of the investigator (or designee) or Sponsor, makes the subject unsuitable for enrollment. PK Results

[0190] Plasma concentrations of letrozole were analyzed up to Day 897 and Day 729 following a single intramuscular (IM) injection of 50 mg and 100 mg letrozole ISM, respectively. Furthermore, plasma levels of letrozole were also analyzed for up to 897 and 729 days. Most subjects had maintained quantifiable plasma concentrations of letrozole up to the last reported sampling time points in both groups (FIG. 8). The dose-normalized peak exposure (Cmax / D) is comparable between both dose strengths of letrozole ISM. Accordingly, the implant or sustained-release composition of the invention provides mediocre and therapeutic levels of plasma concentrations 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.

[0191] Example 4 Comparison of dosing regimens

[0192] Two long-acting compositions were provided, each containing letrozole (approximately 100 mg potency), PLA, and DMSO. The compositions were administered as follows. Single administration of long-acting composition

[0193] Subjects were administered the long-acting compositions according to the following schedule: Day 1: A quantity (0.4 ml) of long-acting composition comprising a 100 mg dose of letrozole was administered intramuscularly. The plasma concentration of letrozole (ng / mL; FIG. 9) and the degree of E2 suppression (%; FIG. 10) were determined daily or periodically. Sequential dosing regimen of the long-acting composition

[0194] Subjects were administered the compositions according to the following schedule: First day: a first amount ([0.4] mL) of long-acting composition comprising a 100 mg dose of letrozole was administered intramuscularly; and at the end of eight weeks from said first day, a second amount ([0.4] mL) of the long-acting composition comprising a 100 mg dose of letrozole was administered intramuscularly. After each administration, the degree of E2 suppression (%; FIG. 11 ) was determined on a daily or periodic basis. Example 5 Additional long-acting compositions

[0195] The following formulations are prepared: Formulation 13. Formulation 14. Formulation 15. Formulation 16. Formulation 17. Formulation 18. Example 6 Dosage regimen of the second aspect

[0196] The long-acting compositions are prepared as described above and administered as follows. Subjects meeting the selection criteria of Example 3 are administered at least two sequential doses of long-acting composition: a first higher dose of LAI-HD (containing 200-400 mg of letrozole or anastrozole) and, after a delay period, a subsequent lower dose of LAI-LD (containing 75-100 mg of letrozole or anastrozole, respectively). Each long-acting composition has a dosing period of approximately 50-54 weeks.

[0197] Each subject is administered a daily dose of the long-acting compound (LAI-LD) intramuscularly. After approximately 50-54 weeks or approximately 52 weeks, each subject is administered a daily dose of LAI-LD intramuscularly.

[0198] Optionally, as needed, a subject is administered another dose of the long-acting composition approximately 50-54 weeks or approximately 52 weeks after the long-acting composition-LD administration. The subject may continue receiving annual doses of the long-acting composition for as many years as clinically necessary to provide the desired clinical benefit or therapeutic outcome.

Claims

CLAIMS 1) A long-acting injectable composition comprising polylactic acid (PLA), DMSO and at least one aromatase inhibitor drug selected from the group consisting of letrozole, anastrozole and combinations thereof, characterized in that the particle size distribution of the PLA is as follows: - a mass particle size distribution with no more than 10% of particles above 300 microns and no more than 80% of particles below 125 microns, as measured by analytical sieving according to USP <786> ; and - a volume particle size distribution where less than 10% of particles are smaller than 20 microns, less than 10% of particles are larger than 350 microns, D50 is between 70-200 microns, D80 is not less than 135 microns, and D90 is not greater than 330 microns, as measured by laser diffraction analysis. 2) The composition according to claim 1, characterized in that the particle size distribution of the PLA is as follows: - a mass particle size distribution with no more than 10% of particles above 250 microns when measured by analytical sieving according to USP <786> ; and - a particle size distribution by volume with a D90 not exceeding 280 microns when measured by laser diffraction analysis. 3) The composition according to claims 1 or 2, characterized in that it comprises 15-35% by weight of drug, 25-35% by weight of PLA and 30-60% by weight of DMSO, where the weight percentages are with respect to the total weight of said composition. 4) The composition according to any of claims 1-3, characterized in that it comprises 18-28% by weight of drug, 30-35% by weight of PLA and 37-52% by weight of DMSO, where the weight percentages are with respect to the total weight of said composition. 5) The composition according to any of claims 1-4, characterized in that it comprises 23-27% by weight of the drug, 28-34% by weight of PLA and 41-47% by weight of DMSO, where the weight percentages are with respect to the total weight of said composition. 6) The composition according to any one of claims 1 to 5, characterized in that the particle size distribution of said aromatase inhibitor drug is approximately the same as the particle size distribution of said PLA. 7) The composition according to any one of claims 1 to 6, characterized in that the drug is present in said composition as a suspension, and the PLA is dissolved in the solvent in said composition. 8) The composition according to any one of claims 1 to 7, characterized in that the PLA is terminated with ester terminal groups. 9) The composition according to any one of claims 1 to 8, characterized in that the weight ratio of DMSO to PLA is from 1.3:1 to 1.5:1, or is approximately 1.4:

1. 10) The composition according to claim 9, characterized in that the weight ratio of DMSO to drug is in the range of 1.5:1 to 2:1, 1.7:1 to 1.8:1, or is approximately 1.75:

1. 11) The composition according to any of the preceding claims 1-10, wherein the amount of drug in said composition is selected from the group consisting of 10-450 mg, 30-90 mg, about 50 mg, 50-100 mg, 80-150 mg, 75-125 mg, about 75 mg, about 100 mg, 150-250 mg, about 200 mg, about 350-450 mg, and about 400 mg. 12) The composition according to any of the preceding claims 1-11, for use in the treatment of a subject in need of such treatment. 13) The composition for use according to claim 12 in the treatment of a disease, condition or disorder responsive to an aromatase inhibitor in a subject, comprising administering to the subject the composition of any one of claims 1 to 11. 14) The composition for use of claim 12 or 13, comprising a) intramuscularly administering to a subject an amount of long-acting injectable composition according to any of the preceding claims 1 to 11 comprising a first dose of aromatase inhibitor; and b) subsequently, after a period of delay, administer intramuscularly an amount of long-acting injectable composition comprising a second dose of aromatase inhibitor. 15) The composition for use according to claim 14, wherein the delay period is about 6 weeks or more after administering said first dose of composition. 16) The composition for use according to claim 15, wherein the delay period is selected from: about 6-10 weeks, about 48-60 weeks or about 50-54 weeks. 17) The composition for use of any of claims 12 to 16, further comprising administering a third dose of said composition approximately 1 year after said first dose or said second dose. 18) The composition for use of any of claims 12 to 17, comprising administering an additional dose of said composition annually for a total treatment period of about three years or more, about 5 years or more, about 7 years or more, or about 10 years. 19) The composition for use of any of claims 12 to 18, wherein the amount of drug in said first dose is greater than the amount of drug in said second dose. 20) The composition for use according to any of claims 12 to 18, wherein the amount of drug in said first dose is approximately equal to or less than the amount of drug in said second dose. 21) The composition for use according to any of claims 12 to 19, wherein the first dose comprises about 200-400 mg of drug, and the second dose comprises about 75-100 mg of drug. 22) The composition for use according to any of claims 12 to 21, wherein said disease, disorder or condition is selected from the group consisting of a) adjuvant treatment (treatment after surgery with or without radiation) of women Postmenopausal women with hormone receptor-positive early breast cancer; b) metastases in pre- and postmenopausal women; c) precocious puberty or children with pubertal gynecomastia; d) reducing estrogens, including estradiol, in men; e) hormone-sensitive breast cancer after surgery; f) ovarian stimulation; g) promoting spermatogenesis in male patients suffering from non-obstructive 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 ovary syndrome; k) ovarian cancer; i) breast cancer that is estrogen hormone receptor-positive or sensitive; m) priming for in vitro maturation cycles; n) preoperative treatment with letrozole in premenopausal women undergoing laparoscopic myomectomy for large uterine fibroids; o) short stature in peripubertal children;p) unexplained infertility or infertility with unknown or uncertain etiology; q) idiopathic central precocious puberty in children; r) gynecomastia; s) endometriosis; t) ER-negative disease in subjects who did not respond to prior tamoxifen therapy; u) early breast cancer in postmenopausal women who have received prior standard adjuvant tamoxifen therapy; and v) advanced breast cancer in postmenopausal women with disease progression after tamoxifen treatment. 23) In situ intramuscular implant comprising the composition according to any one of claims 1 to 11. 24) The intramuscular implant of claim 23, wherein the drug is letrozole and the implant releases 0.1 to 2 mg of letrozole daily after administration to a subject in need thereof.