Novel compositions

Abstract

Provided herein are pharmaceutical compositions comprising biodegradable polymeric microspheres comprising triptorelin or a pharmaceutically acceptable salt form thereof and a lactic acid polymer.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising biodegradable polymeric microspheres, including triptorelin or a pharmaceutically acceptable salt thereof, and lactic acid polymers. The invention further relates to methods of using the pharmaceutical compositions described herein. Background Technology

[0002] Triptorelin is a gonadotropin-releasing hormone (GnRH) agonist, a potent inhibitor of testosterone in men and estrogen in women. Triptorelin or its pharmaceutically acceptable salt forms are used for a variety of therapeutic applications, including the treatment of prostate cancer, prostate cancer symptoms, central precocious puberty, endometrial stromal sarcoma, uterine fibroids, breast cancer, and endometriosis. Treatment of these conditions often requires long-term therapy with triptorelin or its pharmaceutically acceptable salts.

[0003] Sustained-release compositions can be used to reduce the number of doses required over a long period. However, formulating sustained-release drug compositions with an acceptable triptorelin release profile for specific therapeutic applications is challenging, especially if the desired sustained-release profile exceeds 6 months, such as 10 months or longer.

[0004] Therefore, there is a need for new sustained-release pharmaceutical compositions that can provide sustained release of triptorelin or its pharmaceutically acceptable salts, especially over longer periods, such as 10 months or longer. In particular, there is a need for sustained-release triptorelin compositions with acceptable release profiles. Furthermore, there is a need for pharmaceutical compositions that are convenient and easy to use, have an acceptable shelf life, are safe and well-tolerated by patients, and minimize patient discomfort, such as discomfort caused by repeated dosing and / or injectability and injectability issues associated with long-term treatment. Patient discomfort is particularly concerning for children with central precocious puberty. Summary of the Invention

[0005] This invention relates to pharmaceutical compositions comprising biodegradable polymeric microspheres comprising (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof, and (b) a single lactic acid polymer having a lactide content of 80% or higher, a molecular weight (Mw) of about 30,000 g / mol to about 80,000 g / mol, and a polydispersity of about 1.4 to about 2.0 as determined by gel permeation chromatography, wherein the pharmaceutical composition provides sustained release of the triptorelin for at least 10 months, at least 11 months, or at least 12 months.

[0006] The present invention further relates to the use of the pharmaceutical compositions described herein for the treatment of diseases or ailments in which triptorelin or a pharmaceutically acceptable soluble salt thereof has a therapeutic effect.

[0007] The present invention also relates to the use of the pharmaceutical compositions described herein in treating a disease or ailment of a subject, wherein said disease or ailment is prostate cancer, prostate cancer symptoms, central precocious puberty, endometrial stromal sarcoma, uterine fibroids, breast cancer, or endometriosis.

[0008] Methods for treating diseases or ailments using the pharmaceutical compositions described herein are also provided.

[0009] This invention further relates to a method for preparing triptorelin biodegradable polymer microspheres, wherein the method comprises... (a1) The organic phase is prepared by dissolving the triptorelin or a pharmaceutically acceptable soluble salt thereof, and a single lactic acid polymer or a pharmaceutically acceptable salt thereof having a lactide content of 80% or higher and an initial intrinsic viscosity of about 0.4 to about 0.8 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C, in one or more organic solvents at room temperature; (a2) An aqueous phase is prepared by dissolving polyvinyl alcohol and a salting-out agent in water and cooling the aqueous phase to about 2 to about 8°C to produce a cooled aqueous phase; (a3) The organic phase and the cooled aqueous phase are mixed to form the microspheres, and (a4) Filter, wash and dry the microspheres.

[0010] This article also discloses biodegradable polymer microspheres prepared by the above method, and pharmaceutical compositions comprising such microspheres.

[0011] The present invention also relates to a reagent kit, the reagent kit comprising: a) The pharmaceutical compositions described herein; b) The support material optionally used for resolution, and c) A vial or syringe optionally pre-filled with the pharmaceutical composition described in a). Attached Figure Description

[0012] Figure 1 The mean plasma concentrations (ng / mL) of triptorelin in rats after administration of composition M suspended in an aqueous or lipid-supported medium are provided.

[0013] Figure 2 Mean plasma concentrations (ng / mL) of each posttriptorelin in the AD formulation for rats are provided.

[0014] Figure 3 Mean plasma concentrations (ng / mL) of each posttriptorelin in rats in the EH formulation are provided.

[0015] Figure 4 Mean plasma concentrations (ng / mL) of each posttriptorelin in the administration composition IL in rats are provided.

[0016] Figure 5 The mean plasma concentrations (ng / mL) of triptorelin in rats after administration of compositions 1 and 2 are provided.

[0017] Figure 6 The mean plasma concentrations (ng / mL) of triptorelin in rats after administration of composition 3 and 4 are provided. Detailed Implementation

[0018] definition To facilitate understanding of this disclosure, certain terms are first defined. Unless otherwise expressly specified herein, each of the following terms shall have the following meanings as used herein. Additional definitions are set forth throughout the application.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0020] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural indicators. The terms “a” (or “an”) and “one or more” and “at least one” are used interchangeably herein. In some respects, the terms “a” or “an” mean “a single”. In other respects, the terms “a” or “an” include “two or more” or “a plurality”.

[0021] Furthermore, when used herein, “and / or” should be considered as a specific disclosure of each of the two specified features or components in the presence or absence of the other. Thus, the term “and / or” as used in phrases such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0022] The term "about" is used herein to mean approximately, roughly, about, or within a range. When the term "about" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the listed numerical value. Typically, the term "about" can modify a range of variation in numerical values ​​that are higher or lower than the stated value by a certain amount, for example, above or below (higher or lower) by 10%. In some aspects of this disclosure, the term "about" covers deviations of 0.001% to 10% relative to the listed value, including the endpoints. In some aspects, the term "about" covers increases of 0.001% to 10% relative to the listed value, including the endpoints. In some aspects, the term "about" covers decreases of 0.001% to 10% relative to the listed value, including the endpoints.

[0023] Units, prefixes, and symbols are represented in their internationally recognized form (SI).

[0024] A numerical range includes the numbers that define that range. In the case of enumerating a range of values, it should be understood that each intermediate integer value between the upper and lower limits of the enumeration of the range and each of its fractions, along with each subrange between such values, is also specifically disclosed.

[0025] The upper and lower limits of any range may be independently included in or excluded from the range, and every range that includes any limit, excludes any limit, or includes both limits is also covered within this disclosure. Therefore, the ranges listed herein should be understood as abbreviations of all values ​​within that range, including the listed endpoints. For example, the range 1 to 10 is understood to include any number, combination of numbers, or subrange of numbers in the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0026] Any numerical value inherently contains some error that necessarily arises from the standard deviation found in their respective measurements. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the statement of the range “1 to 10” should be considered to include any and all subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10; that is, all subranges that begin with a minimum value of 1 or greater (such as 1 to 6.1) and terminate with a maximum value of 10 or less (such as 5.5 to 10).

[0027] Where values ​​are explicitly listed, it should be understood that values ​​having approximately the same quantity or amount as the listed values ​​are also within the scope of this disclosure. Where combinations are disclosed, each sub-combination of the elements of that combination is also specifically disclosed and within the scope of this disclosure. Conversely, where different elements or groups of elements are disclosed individually, their combinations are also disclosed. Where any disclosed element is disclosed to have multiple alternatives, examples of that disclosure are also disclosed herein, wherein each alternative is excluded individually or in any combination with other alternatives; more than one element may be disclosed with such exclusions, and all combinations of elements having such exclusions are disclosed herein.

[0028] As used herein, the term "triptorelin" is also referred to as (2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(2-amino-2-oxoylethyl)carbamoyl]pyrrolidine-1-yl]-5-(diaminomethylimino)-1-oxoylpentane-2-yl]amino]-4-methyl-1-oxoyl Triptorelin has the following structure:

[0029] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic and organic acid addition salt. These salts can be prepared in situ during the manufacture of a drug delivery system or dosage form, or by reacting a purified compound of the invention, in its free base form, with a suitable organic or inorganic acid, and then separating the resulting salt during subsequent purification. Representative salts include those derived from: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, ascorbic acid, lactic acid, citric acid, fumaric acid, malonic acid, maleic acid, hydrobromic acid, nitric acid, tartaric acid, tosylic acid, methanesulfonic acid, aspartic acid, benzoic acid, succinic acid, oleic acid, lauric acid, glucohepanoic acid, lactobionic acid, laurylsulfonic acid, palmitic acid, pamoic acid, stearic acid, and valeric acid. Acid addition salts can be monovalent or divalent. These salts can be water-soluble or water-insoluble. Pharmaceutically acceptable water-soluble salts include acetates, lactates, maleates, ascorbic acid salts, succinates, benzoates, toluenesulfonates, hydrochlorides, hydrobromic acids, sulfates, hydrogen sulfates, phosphates, citrates, methanesulfonates, tartrates, nitrates, oleates, laurates, glucono-heptates, lactobionates, laurylsulfonates, etc. In some cases, acid addition salts are acetates.

[0030] As used herein, the term "biodegradable polymer" refers to a polymer or copolymer, or a mixture of polymers or copolymers, that undergoes enzymatic and / or non-enzymatic degradation in vivo to produce biocompatible degradation products that can be further metabolized by humans and animals. Biodegradation can be triggered in response to contact with bodily fluids, for example, after injection into a patient. Examples of biodegradable polymers include, but are not limited to, lactic acid polymers. In some aspects, biodegradable polymers (such as lactic acid polymers) can degrade via hydrolysis in response to contact with bodily fluids after injection into a patient.

[0031] As used herein, the term "biodegradable polymer microparticles" refers to monolithic microparticles formed from one or more biodegradable polymers or copolymers. The microparticles have an internally continuous biodegradable polymer matrix. The microparticles can have any shape, including spherical or irregular shapes. The term encompasses both microspheres and microparticles.

[0032] As used herein, the term "biodegradable polymer microparticles" refers to monolithic microparticles of a non-spherical, irregular shape formed from one or more biodegradable polymers or copolymers. Microparticles may have an internally continuous biodegradable polymer matrix (e.g., lactic acid polymer).

[0033] As used herein, the term "biodegradable polymer microspheres" refers to monolithic microparticles of a spherical or substantially spherical regular shape formed from one or more biodegradable polymers or copolymers. Microspheres may have an internal continuous biodegradable polymer matrix (e.g., lactic acid polymers).

[0034] For example, biodegradable polymer microparticles can be produced by dry processes (e.g., extrusion and milling). For example, biodegradable polymer microspheres can be produced by wet processes (e.g., emulsion and precipitation).

[0035] As used herein, in relation to wet processes, the term "salting-out agent" refers to a component that attracts water molecules and thereby reduces the number of water molecules available to interact with biodegradable forms such as lactic acid polymers and / or triptorelin or pharmaceutically acceptable soluble salts.

[0036] As used herein, the term "biodegradable polymer implant" refers to a cylindrical rod with a diameter of 0.2 to 10 mm and a length of 1 to 50 mm or even longer, formed from one or more biodegradable polymers (e.g., a single lactic acid polymer), which can be obtained by extrusion and cut to the desired length using a granulator.

[0037] As used herein, the term "lactic acid polymer" refers to a polymer containing only lactic acid, or a copolymer of lactic acid with other monomers (e.g., glycolic acid). Lactic acid polymers include polylactic acid (also known as polylactide or PLA). Lactic acid polymers can be poly-DL-lactic acid (also known as poly-DL-lactide). Lactic acid polymers can be linear or branched.

[0038] The copolymer of lactic acid and other monomers used in the sustained-release compositions described herein may be a copolymer having the composition of lactic acid and glycolic acid (PLGA). The ratio of lactic acid to glycolic acid may be in the range of about 80:20 to 99.9:0.1, for example about 85:15 to 99:1, about 90:10 to 99:1, or about 95:5 to 99:1. The PLGA may be a poly(D,L-lactide-co-glycolic acid) copolymer. The PLGA may be linear or branched.

[0039] As used herein, the term "drug loading" refers to the weight ratio (expressed as a percentage) of the total mass of the free base of triptorelin to the biodegradable polymer particles, i.e., as represented by the following equation: Drug loading (DL%) = m(triptorelin) / m(BPM) × 100 Where m(triptorelin) represents the mass of triptorelin, and m(BPM) represents the mass of the biodegradable polymer microparticles. Similar calculations can be performed to determine the drug loading of the implant.

[0040] DvX means that X% of the volume of a biodegradable polymer microparticle sample is smaller than the indicated diameter value. For example, Dv50 of 80 µm means that 50% of the volume of a biodegradable polymer microparticle sample has a diameter less than 80 µm, such as diameters of 20 µm, 30 µm, 40 µm, 50 µm, 60 µm, or 70 µm. DvX (e.g., Dv50) is determined by wet laser diffraction, for example, as described in Chapter 2.9.31 of the European Pharmacopoeia V.10.8. Particle size measurement can be performed by wet laser diffraction, for example, using a Malvern Mastersizer 3000 equipped with a Hydro medium volumetric (MV) dispersion unit. For example, biodegradable polymer microparticles can be suspended (at room temperature, e.g., 20-25°C) in an aqueous-based medium containing a surfactant (e.g., polysorbate 80 (0.1%)). The sample can then be dispersed in purified water in a hydro MV dispersion unit (stirring speed 2000 rpm) until 10% to 20% opacity is achieved. The sample is then sonicated for 2 min (Hydro MV dispersion unit set to medium (50%)) and analyzed using a Malvern Mastersizer 3000. Results are calculated based on Mie theory (real part of particle refractive index 1.52, imaginary part of particle refractive index 0.001). A "general analytical model" can be used.

[0041] As used herein, the “intrinsic viscosity” of a biodegradable polymer (e.g., lactic acid polymer) is based on the flow time of the biodegradable polymer in solution (where the polymer is dissolved in a given solvent) through the same narrow capillary relative to the flow time through the same pure solvent. According to IUPAC, intrinsic viscosity is defined as the ratio of the natural logarithm of the relative viscosity to the mass concentration of the polymer. The intrinsic viscosity of a biodegradable polymer (e.g., lactic acid polymer) can be measured using conventional methods, such as the capillary viscometer method as described in Chapter 2.2.9 of the European Pharmacopoeia 10.0. For example, the intrinsic viscosity of a polymer can be measured at 30°C at a concentration of 0.5 g / dL in chloroform, for example using a Cannon-Fenske Routine size 25 viscometer.

[0042] As used herein, the “initial intrinsic viscosity” of a biodegradable polymer (e.g., a lactic acid polymer) refers to the intrinsic viscosity of the biodegradable polymer as a starting material (i.e., before it enters the preparation process of microparticles or implants).

[0043] As used herein, “polydispersity” or “polydispersity index (IP)” refers to the Mw / Mn ratio of a biodegradable polymer, where Mw is the weight-average molecular weight (g / mol) and Mn is the number-average molecular weight (g / mol). It can be determined by gel permeation chromatography (GPC).

[0044] The term "subject" refers to an animal, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In this document, the term "subject" and "patient" are used interchangeably, for example, referring to a mammalian subject, such as a human subject.

[0045] As used herein, the terms “treat,” “treated,” and “treating” refer to both therapeutic treatment and preventative or preventive measures, wherein the goal is to prevent or alleviate (reduce) an undesirable physical symptom, ailment, or disease, or to achieve a beneficial or desired clinical outcome. Therefore, those requiring treatment include those already diagnosed with or suspected of having the symptom. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms; reduction in the severity of the symptom, ailment, or disease; stabilization of the condition (i.e., no worsening); delay or slowing of the onset of the progression of the symptom, ailment, or disease; improvement or relief of the condition (whether partial or complete), whether detectable or undetectable; improvement in at least one measurable physical parameter, which may not be perceptible to the patient; or enhancement or improvement of the symptom, ailment, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to expected survival without treatment. As used herein, the term "administration" means any manner in which a therapeutic agent is transferred, delivered, introduced, or transported to a subject who requires treatment with such an agent. Such administration methods include, but are not limited to, oral, topical, intramuscular, intradermal, intranasal, subcutaneous, intraocular, or intra-articular administration. In some aspects, administration may be parenteral, such as by injection, for example, intramuscular or subcutaneous injection. For instance, administration may be by intramuscular injection.

[0046] The term "therapeutic effective amount" refers to the amount of free triptorelin that provides a beneficial or desired therapeutic and / or preventive outcome. Where the actual formulation contains triptorelin in its pharmaceutically acceptable water-soluble salt form, the therapeutic effective amount is expressed as an "equivalent free base," or corresponds to an amount of free triptorelin. For prophylactic use, beneficial or desired outcomes may include, for example, one or more of the following: such as elimination or reduction of risk, reduction of severity, or delay of disease onset, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes occurring during disease development. For therapeutic use, beneficial or desired outcomes may include, for example, one or more of the following clinical outcomes: such as reduction of one or more symptoms and pathological conditions caused by or related to the disease, improvement of the quality of life of patients with the disease, reduction of the dosage of other medications required to treat the disease, enhancement of the effects of other medications (such as through targeting), delay of disease progression, and / or prolongation of survival. For example, an effective amount may be an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. An effective amount of triptorelin can be administered as a single dose or divided into multiple doses, the sum of which is the effective amount. For example, an effective amount can be provided in two separate doses over a period of time, providing the total effective amount of the formulation. For example, an effective amount can be provided in a single dose every 10, 11, or 12 months.

[0047] I. Pharmaceutical Composition A. Biodegradable polymer microspheres This article describes pharmaceutical compositions comprising biodegradable polymeric microspheres comprising (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof, and (b) a single lactic acid polymer having a lactic acid content of 80% or higher, a molecular weight (Mw) of about 30,000 g / mol to about 80,000 g / mol, and a polydispersity of about 1.4 to about 2.0 as determined by gel permeation chromatography (“GPC”), wherein the pharmaceutical compositions provide a sustained release of triptorelin for at least 10 months.

[0048] In some aspects, based on the free base of triptorelin, the pharmaceutical compositions described herein have a drug loading of triptorelin or a pharmaceutically acceptable soluble salt thereof (e.g., triptorelin acetate) of about 10% to about 20% (w / w), preferably about 10% to about 15% (w / w), and more preferably about 12% (w / w). In some aspects, based on the free base of triptorelin, the drug loading of triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate) is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0049] Drug loading can be measured using conventional methods, such as high performance liquid chromatography (HPLC).

[0050] In some respects, triptorelin is present in the pharmaceutical compositions included herein as a pharmaceutically acceptable salt form. In some respects, triptorelin is present in the pharmaceutical compositions included herein as a pharmaceutically acceptable water-soluble salt form. In some respects, the pharmaceutically acceptable water-soluble salt form of the pharmaceutical compositions described herein is triptorelin acetate.

[0051] In some aspects, based on the free base of triptorelin, the pharmaceutical compositions described herein have a drug loading of triptorelin acetate of about 10% to about 20% (w / w), preferably about 10% to about 15% (w / w), and more preferably about 12% (w / w). In some aspects, based on the free base of triptorelin, the drug loading of triptorelin acetate is about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%.

[0052] In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein have a Dv50 of about 20 µm to about 80 µm, about 25 µm to about 80 µm, about 30 µm to about 80 µm, about 35 µm to about 80 µm, about 40 µm to about 80 µm, about 45 µm to about 80 µm, about 50 µm to about 80 µm, about 55 µm to about 80 µm, about 60 µm to about 80 µm, about 65 µm to about 80 µm, about 70 µm to about 80 µm, about 20 µm to about 75 µm, about 25 µm to about 75 µm, about 30 µm to about 75 µm, about 35 µm to about 75 µm, about 40 µm to about 75 µm, about 45 µm to about 75 µm, about 50 µm to about 75 µm, about 55 µm to about 75 µm, about 60 µm to about 75 µm, about 65 ... µm to about 75 µm, about 20 µm to about 70 µm, about 25 µm to about 70 µm, about 30 µm to about 70 µm, about 35 µm to about 70 µm, about 40 µm to about 70 µm, about 45 µm to about 70 µm, about 50 µm to about 70 µm, about 55 µm to about 70 µm, about 60 µm to about 70 µm, about 20 µm to about 65 µm, about 25 µm to about 65 µm, about 30 µm to about 65 µm, about 35 µm to about 65 µm, about 40 µm to about 65 µm, about 45 µm to about 65 µm, about 50 µm to about 65 µm, about 55 µm to about 65 µm, about 20 µm to about 60 µm, about 25 µm to about 60 µm, about 30 µm to about 60 µm, about 35 µm to about 60 µm, about 40 ... µm to about 60 µm, about 45 µm to about 60 µm, about 50 µm to about 60 µm, about 20 µm to about 55 µm, about 25 µm to about 55 µm, about 30 µm to about 55 µm, about 35 µm to about 55 µm, about 40 µm to about 55 µm, about 45 µm to about 55 µm, about 20 µm to about 50 µm, about 25 µm to about 50 µm, about 30 µm to about 50 µm, about 35 µm to about 50 µm, about 40 µm to about 50 µm, about 20 µm to about 45 µm, about 25 µm to about 45 µm, about 30 µm to about 45 µm, about 35 µm to about 45 µm, about 20 µm to about 40 µm, about 25 µm to about 40 µm, about 30 µm to about 40 µm, about 20 µm to about 35 µm, about 25 µm to about 40 ... µm to about 35 µm, or about 20 µm to about 30 µm.In some aspects, the biodegradable polymer microspheres of the pharmaceutical compositions described herein have a Dv50 of about 20 µm to about 80 µm or about 40 µm to about 60 µm. In some aspects, the biodegradable polymer microspheres of the pharmaceutical compositions described herein have a Dv50 of about 20 µm to about 80 µm. In some aspects, the biodegradable polymer microspheres of the pharmaceutical compositions described herein have a Dv50 of about 40 µm to about 60 µm.

[0053] In some respects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a molecular weight of about 30,000 g / mol to about 80,000 g / mol and a polydispersity of about 1.4 to about 2.0. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having molecular weights of about 30,000 g / mol to about 80,000 g / mol, about 30,000 g / mol to about 75,000 g / mol, about 30,000 g / mol to about 70,000 g / mol, about 30,000 g / mol to about 65,000 g / mol, about 30,000 g / mol to about 60,000 g / mol, about 30,000 g / mol to about 55,000 g / mol, about 30,000 g / mol to about 50,000 g / mol, about 30,000 g / mol to about 45,000 g / mol, about 30,000 g / mol to about 40,000 g / mol, about 35,000 g / mol to about 80,000 g / mol, and about 35,000 g / mol. g / mol to about 75,000 g / mol, about 35,000 g / mol to about 70,000 g / mol, about 35,000 g / mol to about 65,000 g / mol, about 35,000 g / mol to about 60,000 g / mol, about 35,000 g / mol to about 55,000 g / mol, about 35,000 g / mol to about 50,000 g / mol, about 35,000 g / mol to about 45,000 g / mol, about 40,000 g / mol to about 80,000 g / mol, about 40,000 g / mol to about 75,000 g / mol, about 40,000 to about 70,000 g / mol, about 40,000 to about 65,000 g / mol, about 40,000 to about 60,000 g / mol g / mol, about 40,000 g / mol to about 55,000 g / mol, about 40,000 g / mol to about 50,000 g / mol, about 45,000 g / mol to about 80,000 g / mol, about 45,000 g / mol to about 75,000 g / mol, about 45,000 g / mol to about 70,000 g / mol, about 45,000 g / mol to about 65,000 g / mol, about 45,000 g / mol to about 60,000 g / mol, about 45,000 g / mol to about 55,000 g / mol, about 50,000 g / mol to about 80,000 g / mol, about 50,000 g / mol to about 75,000 g / mol, about 50,000 g / mol to about 70,000 g / mol, about 50,000 g / mol to about 65,000 g / mol, about 50,000 g / mol to about 60,000 g / mol, about 55,000 g / mol to about 80,000 g / mol, about 55,000 g / mol to about 75,000 g / mol, about 55,000 g / mol to about 70,000 g / mol, about 55,000 g / mol to about 65,000 g / mol, about 60,000 g / mol to about 80,000 g / mol, about 60,000 g / mol to about 75,000 g / mol, about 60,000 g / mol to about 70,000 g / mol, about 65,000 g / mol to about 80,000 g / mol, about 65,000 g / mol to about 80,000 g / mol, about 65,000 g / mol to about 7 ... The molecular weight of the biodegradable polymeric microspheres of the pharmaceutical compositions described herein is from about 30,000 g / mol to about 85,000 g / mol, or from about 40,000 g / mol to about 65,000 g / mol, or from about 45,000 g / mol to about 65,000 g / mol. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a molecular weight of about 30,000 g / mol to about 80,000 g / mol. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a molecular weight of about 40,000 g / mol to about 65,000 g / mol. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a molecular weight of about 45,000 g / mol to about 65,000 g / mol.

[0054] In some respects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a molecular weight of about 30,000 g / mol to about 80,000 g / mol and a polydispersity of about 1.4 to about 2.0. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a polydispersity of about 1.4 to about 2.0, about 1.4 to about 1.9, about 1.4 to about 1.8, about 1.4 to about 1.7, about 1.4 to about 1.6, about 1.4 to about 1.5, about 1.5 to about 2.0, about 1.5 to about 1.9, about 1.5 to about 1.8, about 1.5 to about 1.7, about 1.5 to about 1.6, about 1.6 to about 2.0, about 1.6 to about 1.9, about 1.6 to about 1.8, about 1.6 to about 1.7, about 1.7 to about 2.0, about 1.7 to about 1.9, about 1.7 to about 1.8, about 1.8 to about 2.0, about 1.8 to about 1.9, or about 1.9 to about 2.0. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a polydispersity of about 1.4 to 2.0 or about 1.5 to about 1.9. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a polydispersity of about 1.4 to about 2.0. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a polydispersity of 1.5 to about 1.9.

[0055] In some respects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having a polydispersity of about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0.

[0056] In some respects, the molecular weight and polydispersity of the polymer are measured in the formed microspheres (rather than, for example, in the polymer starting material). Depending on the end product under consideration, the molecular weight and polydispersity of the polymer may be measured in the microspheres or microsphere formulations within a pharmaceutical composition, depending on manufacturing limitations. For example, the molecular weight and polydispersity of the polymer in the microspheres may be measured after irradiation.

[0057] In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise a lactic acid polymer having an initial intrinsic viscosity of about 0.4 dL / g to about 0.8 dL / g. In some aspects, the initial intrinsic viscosity of the polymer is measured at 30°C at a concentration of 0.5 g / dL in chloroform. In some aspects, the initial intrinsic viscosity of the polymer is measured using a Cannon-Fenske Routinesize 25 viscometer. In some aspects, the initial intrinsic viscosity of the polymer is measured at 30°C at a concentration of 0.5 g / dL in chloroform using a Cannon-Fenske Routinesize 25 viscometer. In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having an initial intrinsic viscosity of about 0.4 dL / g to about 0.8 dL / g, about 0.4 dL / g to about 0.7 dL / g, about 0.4 dL / g to about 0.6 dL / g, about 0.4 dL to about 0.5 dL / g, about 0.5 dL / g to about 0.8 dL / g, about 0.5 dL / g to about 0.7 dL / g, about 0.5 dL / g to about 0.6 dL / g, about 0.6 dL / g to about 0.8 dL / g, about 0.6 dL / g to about 0.7 dL / g, or about 0.7 dL / g to about 0.8 dL / g. In some respects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having an initial intrinsic viscosity of about 0.4 dL / g to about 0.8 dL / g or about 0.55 dL / g to about 0.75 dL / g.

[0058] In some aspects, the biodegradable polymeric microspheres of the pharmaceutical compositions described herein comprise lactic acid polymers having an initial intrinsic viscosity of about 0.4 dL / g, about 0.45 dL / g, about 0.5 dL / g, about 0.55 dL / g, about 0.6 dL / g, about 0.65 dL / g, about 0.7 dL / g, about 0.75 dL / g, or about 0.8 dL / g.

[0059] In some aspects, the lactic acid polymer is a single lactic acid polymer having a lactic acid content of 80% or higher. In other aspects, the lactic acid polymer is a single lactic acid polymer having a lactic acid content of approximately 80%, approximately 81%, approximately 82%, approximately 83%, approximately 84%, approximately 85%, approximately 86%, approximately 87%, approximately 88%, approximately 89%, approximately 90%, approximately 91%, approximately 92%, approximately 93%, approximately 94%, approximately 95%, approximately 96%, approximately 97%, approximately 98%, approximately 99%, or approximately 100%. In some aspects, the lactic acid polymer is a single lactic acid polymer (i.e., polylactide or PLA) having a lactic acid content of approximately 100%.

[0060] In some respects, the lactic acid polymer is a PLGA copolymer containing a lactide to glycolide molar ratio greater than 80:20. In other respects, the lactic acid polymer is a PLGA copolymer containing lactide to glycolide molar ratios of 80:20, 85:15, 90:10, or 95:5.

[0061] There are no restrictions on the end groups of lactic acid polymers. Examples of possible end groups include hydroxyl groups, ester groups (e.g., stearyl or lauryl groups), acidic groups (e.g., carboxyl groups), etc. In some respects, the end groups of lactic acid polymers are ester groups.

[0062] In some respects, lactic acid polymers are monolactic acid polymers that have a lactic acid content of about 100% and are linear.

[0063] In some respects, the pharmaceutical composition contains only a single group of biodegradable microspheres as defined herein.

[0064] B. Components of the pharmaceutical composition In some respects, the pharmaceutical compositions described herein include triptorelin in the form of a water-soluble acetate. In some aspects, the pharmaceutical compositions described herein include about 40 mg to about 90 mg, about 40 mg to about 85 mg, about 40 mg to about 80 mg, about 40 mg to about 75 mg, about 40 mg to about 70 mg, about 40 mg to about 65 mg, about 40 mg to about 60 mg, about 40 mg to about 55 mg, about 40 mg to about 50 mg, about 45 mg to about 90 mg, about 45 mg to about 85 mg, about 45 mg to about 80 mg, about 45 mg to about 75 mg, about 45 mg to about 70 mg, about 45 mg to about 65 mg, about 45 mg to about 60 mg, about 45 mg to about 55 mg, about 50 mg to about 90 mg, about 50 mg to about 85 mg, about 50 mg to about 80 mg, about 50 mg to about 75 mg, about 50 mg to about 70 mg, about 50 mg to about 65 mg, about 50 mg to about 60 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 85 mg, about 55 mg to about 90 mg, about 55 mg to about 85 mg, about 55 mg to about 9 ... Triptorelin as a free base in amounts of about 40 mg to about 90 mg. In some aspects, the pharmaceutical compositions described herein comprise triptorelin as a free base in amounts of about 40 mg to about 90 mg. Where triptorelin is present in the form of its acetate, the amount is expressed as an "equivalent free base". Therefore, it should be understood that, due to the weight of the acetate, the actual amount of triptoreline acetate is higher than the amount of "triptoreline as a free base".

[0065] In some aspects, the pharmaceutical compositions described herein comprise about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, or about 90 mg of triptorelin as a free base. In some aspects, the pharmaceutical compositions described herein comprise about 70 mg of triptorelin as a free base.

[0066] In addition to biodegradable polymer microspheres, the pharmaceutical compositions described herein may further include one or more other pharmaceutical excipients, such as those typically included in the formulation types discussed, such as diluents, surfactants, stabilizers, release modifiers, preservatives, antioxidants, buffers, anti-agglomeration agents, etc.

[0067] Non-limiting examples of other pharmaceutical excipients that may be included in the pharmaceutical compositions described herein include polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose (CMC-Na), dextrin, polyethylene glycol, and suitable surfactants such as poloxamer, also known as poly(ethylene oxide-block-propylene oxide), under the trade name TWEEN® (e.g., Tween 20, Tween 40, Tween 60, Tween 80, Tween 65, Tween 85, Tween 21, Tween 61, Tween 81) Known and commercially available poly(oxyethylene)-sorbitan-fatty acid esters, such as those known and commercially available under the trade name SPAN, lecithin, inorganic salts such as zinc carbonate, magnesium hydroxide, magnesium carbonate, or protamine, such as human protamine or salmon protamine, or natural or synthetic polymers carrying amine residues, such as polylysine, hydroxyethyl cellulose (HEC) and / or hydroxypropyl cellulose (HPC), polyvinylpyrrolidone, and gelatin, such as porcine gelatin or fish gelatin. Suitable anti-agglomeration agents include, for example, mannitol, glucose, dextrose, sucrose, sodium chloride, or water-soluble polymers such as polyvinyl alcohol, polyvinylpyrrolidone, or polyethylene glycol.

[0068] In some aspects, the pharmaceutical compositions described herein may be compositions of dried, biodegradable polymeric microspheres prepared for suspension in a liquid support prior to injection. In other aspects, the pharmaceutical compositions described herein may be ready-to-use suspensions comprising a liquid support and biodegradable polymeric microspheres as described herein. The liquid support in the pharmaceutical compositions described herein may be an aqueous (water-based) support or a non-aqueous support.

[0069] In some respects, the aqueous (water-based) support is primarily water. In other respects, the aqueous (water-based) support comprises more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100% water. These percentages are indicated as (w / v) percentages.

[0070] In some respects, aqueous (water-based) supports may contain additional drug excipients. These additional excipients can be used to ensure isotonicity and improve the wettability and non-settling properties of the microspheres. Examples of drug excipients include, but are not limited to, mannitol, sodium chloride, glucose, dextrose, sucrose or glycerol, nonionic surfactants such as poloxamer, poly(oxyethylene)-sorbitol-fatty acid ester, sodium carboxymethyl cellulose (CMC-Na), sorbitol, poly(vinylpyrrolidone) or aluminum monostearate, and polyethylene glycol (PEG), such as PEG 4000.

[0071] In some respects, the non-aqueous support is anhydrous or substantially anhydrous, for example, a pharmaceutically acceptable liquid comprising 0.25% (w / v) or less water, 0.1% or less water, or 0.05% (w / v) or less water. In some respects, the non-aqueous liquid is inert or substantially inert to the biodegradable polymer microspheres described herein and to triptorelin or its pharmaceutically acceptable soluble salt form.

[0072] The water content of non-aqueous supports can be measured using conventional methods, such as the microdetermination method described in Chapter 2.5.32 of the European Pharmacopoeia 10.0.

[0073] In some respects, the non-aqueous support may be a pharmaceutically acceptable oil. In some respects, the oil is a viscous liquid at ambient temperature (20°C–30°C) or slightly warmer, and is both hydrophobic (immiscible with water) and lipophilic (miscible with other oils). Non-limiting examples of suitable oils include vegetable oils, such as coconut oil, palm oil, palm kernel oil, sesame oil, soybean oil, almond oil, rapeseed oil, corn oil, sunflower oil, peanut oil, olive oil, castor oil, soybean oil, safflower oil, cottonseed oil, ethyl oleate, and any combination thereof.

[0074] In some respects, non-aqueous supports are pharmaceutically acceptable oils. In some respects, pharmaceutically acceptable oils may include medium-chain triglycerides (MCTs). In some respects, an MCT is a glycerol ester formed from glycerol and three medium-chain fatty acids; each of these three medium-chain fatty acids is a C6 to C12 fatty acid, i.e., a carboxylic acid with a fatty chain having 6 to 12 carbon atoms, such as C6 (caproic acid), C8 (octanoic acid), C10 (decanoic acid), and C12 (dodecanoic acid). The three medium-chain fatty acids forming the triglyceride may all be the same; for example, all three may be medium-chain fatty acids with a fatty chain having, for example, 8 or 10 carbon atoms, or one or all of these medium-chain fatty acids may be different from the others. The fatty chain of the MCT may be saturated or unsaturated.

[0075] In some respects, if a pharmaceutically acceptable oil comprises more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, or 100% of one or more medium-chain triglycerides, then the pharmaceutically acceptable oil is considered to consist essentially of one or more MCTs.

[0076] On the one hand, the non-aqueous liquid is an oil that is essentially composed of C8 and / or C10 medium-chain triglycerides, for example, essentially composed of C8 and C10 medium-chain triglycerides, such as 50% to 80% C8 MCT and 20% to 50% C10 MCT, such as 58% C8 MCT and 41% C10 MCT present in MIGLYOL® 812, as mentioned below. As stated above, the MCT content in the oil is measured by GC according to the method described in Ph. Eur. 2.4.22, without further conversion.

[0077] In some respects, the pharmaceutical composition includes MCT, which is saturated at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.

[0078] Pharmaceutically acceptable MCT oils are commercially available. Non-limiting examples of commercially available MCT oils include MIGLYOL® 810, 812, and 818 (Sasol Germany GmbH, Witten, Germany). In some respects, the MCT oil may be MIGLYOL® 812.

[0079] In some aspects, the pharmaceutical composition is a suspension comprising biodegradable polymeric microspheres at concentrations of: about 100 mg / mL to about 500 mg / mL, about 100 mg / mL to about 450 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 350 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 250 mg / mL, about 100 mg / mL to about 200 mg / mL, about 150 mg / mL to about 500 mg / mL, about 150 mg / mL to about 450 mg / mL, about 150 mg / mL to about 400 mg / mL, about 150 mg / mL to about 350 mg / mL, about 150 mg / mL to about 300 mg / mL, about 150 mg / mL to about 250 mg / mL, about 200 mg / mL to about 500 mg / mL, about 200 mg / mL to about 450 mg / mL. mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 350 mg / mL, about 200 mg / mL to about 300 mg / mL, about 250 mg / mL to about 500 mg / mL, about 250 mg / mL to about 450 mg / mL, about 250 mg / mL to about 400 mg / mL, about 250 mg / mL to about 350 mg / mL, about 300 mg / mL to about 500 mg / mL, about 300 mg / mL to about 450 mg / mL, about 300 mg / mL to about 400 mg / mL, about 350 mg / mL to about 500 mg / mL, about 350 mg / mL to about 450 mg / mL, or about 400 mg / mL to about 500 mg / mL. In some aspects, the pharmaceutical composition is a suspension comprising biodegradable polymeric microspheres at concentrations of about 100 mg / mL to about 500 mg / mL, about 200 mg / mL to about 400 mg / mL, or about 250 mg / mL to about 350 mg / mL. In some aspects, the pharmaceutical composition is a suspension comprising biodegradable polymeric microspheres at concentrations of about 100 mg / mL to about 500 mg / mL. In some aspects, the pharmaceutical composition is a suspension comprising biodegradable polymeric microspheres at concentrations of about 200 mg / mL to about 400 mg / mL. In some aspects, the pharmaceutical composition is a suspension comprising biodegradable polymeric microspheres at concentrations of about 250 mg / mL to about 350 mg / mL.

[0080] In some respects, the pharmaceutical compositions described herein, including biodegradable polymer microspheres, or liquid load suspensions comprising biodegradable polymer microspheres, may be provided in an injection device (e.g., a syringe), ready for injection.

[0081] In some aspects, the pharmaceutical compositions described herein can be manufactured aseptically or non-sterilely. In some aspects, the pharmaceutical compositions described herein, such as liquid-loaded suspensions comprising biodegradable polymeric microspheres or compositions comprising dried biodegradable polymeric microspheres, are sterilized. In some aspects, the pharmaceutical compositions described herein are sterilized by irradiation (e.g., by X-ray or gamma irradiation). In some aspects, the pharmaceutical compositions described herein are sterilized by X-ray irradiation at doses of about 25 to about 40 kGy.

[0082] In some respects, the pharmaceutical compositions described herein, in the form of a liquid-loaded suspension comprising biodegradable polymer microspheres, exhibit the following in vitro release profiles: release of less than 10% triptorelin within 21 hours, less than 15% triptorelin after approximately 165 hours, and more than 75% triptorelin after approximately 330 hours, wherein said release can be measured using a USP II device, including: - An MCT oil suspension was introduced, the suspension comprising the biodegradable polymer microspheres equivalent to 70 mg of triptorelin in 900 mL of 100 mM acetate buffer. - Apply the following temperature gradient: Incubate at approximately 37°C for about 21 hours. A temperature gradient was applied, increasing by approximately 0.5°C per hour for about 46 hours. o Maintain at 60°C for up to 330 hours. The sample is taken out from the device at a specific time point, and the dissolved drug is quantified by HPLC.

[0083] In some respects, in vitro release was measured using a USP II device, for example, with the following parameters: a liquid carrier suspension, such as an MCT oil suspension comprising biodegradable polymer microspheres equivalent to 70 mg of triptorelin, was introduced into 900 mL of 100 mM acetate buffer at pH 4, and the mixture was paddle-rotated at approximately 75 rpm at approximately 37°C for approximately 21 hours, followed by an application of a temperature gradient increasing at approximately 0.5°C per hour for approximately 46 hours, and then maintained at 60°C for the remaining time, with the rotational speed remaining constant throughout the experiment. Samples removed from the device were filtered through a 0.2 µm filter and the dissolved drug was quantified using the same HPLC method as described herein for drug loading determination.

[0084] II. Medical Use In some respects, the pharmaceutical compositions described herein are provided for use as a medicine. For diseases and / or ailments, the medicine may be used for long-term treatment, such as long-term maintenance therapy (e.g., at least 10, 11, or 12 months).

[0085] In some respects, the use of the pharmaceutical compositions described herein in the prevention and / or treatment of diseases and / or ailments is provided.

[0086] In some respects, the pharmaceutical compositions described herein can be used for the prevention and / or treatment of any disease and / or disorder in which triptorelin or a pharmaceutically acceptable soluble salt form thereof (e.g., triptorelin acetate) has therapeutic effects. In some respects, the disease or disorder is selected from prostate cancer, prostate cancer symptoms, central precocious puberty (“CPP”), endometrial stromal sarcoma, uterine fibroids, breast cancer, or endometriosis. In some respects, the disease or disorder is central precocious puberty.

[0087] Methods for treating any disease or ailment specified herein (e.g., CPP) are also envisioned, which include the step of administering the pharmaceutical composition described herein to a subject (e.g., a person) in need of such treatment.

[0088] In some respects, the pharmaceutical compositions described herein are administered to a subject (e.g., a person) who has not previously received treatment for the disease or condition (e.g., CPP), and who is a treatment-naïve patient.

[0089] In some aspects, the pharmaceutical compositions described herein are administered to a subject (e.g., a person) who has previously received treatment for the disease or condition (e.g., CPP). In some aspects, the subject (e.g., a person) who has previously received treatment for the disease or condition (e.g., CPP) has received a pre-loading dose of treatment, and the pharmaceutical compositions are administered for the disease or condition. In some aspects, the subject (e.g., a person) who has previously received treatment for the disease or condition (e.g., CPP) has received treatment for at least one month, at least two months, at least six months, or at least one year, and the pharmaceutical compositions are administered for the disease or condition. Such prior treatment may use triptorelin, or other GnRH agonists, GnRH antagonists, or GnRH analogs.

[0090] In some respects, the pharmaceutical compositions described herein may be administered parenterally to a subject (e.g., a human). In other respects, the pharmaceutical compositions described herein may be administered parenterally to a subject by intramuscular or subcutaneous injection.

[0091] The pharmaceutical compositions described herein can be administered multiple times as needed, for example, depending on the duration of release of the composition. In some respects, the pharmaceutical compositions can be administered annually.

[0092] The pharmaceutical compositions described herein provide sustained release of triptorelin or a pharmaceutically acceptable soluble salt thereof, comprising within biodegradable polymeric microspheres. In some aspects, the sustained release lasts for at least 10 months. In some aspects, the sustained release lasts for at least 1 year. In some aspects, the sustained release lasts for about 1 year.

[0093] In some respects, the pharmaceutical compositions described herein provide sustained hormone suppression for about 10 months, about 11 months, or about 12 months in subjects (e.g., humans).

[0094] In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) every 10, 11, or 12 months. In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) annually. In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) approximately every 52 weeks.

[0095] In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) suffering from central precocious puberty every 10, 11, or 12 months. In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) suffering from central precocious puberty annually. In some aspects, the pharmaceutical composition described herein is administered to a subject (e.g., a person) suffering from central precocious puberty approximately every 52 weeks.

[0096] In some respects, the pharmaceutical composition described herein, when administered in a quantitative dosing regimen, achieves desired hormone suppression compared to subjects who have not received the pharmaceutical composition described herein. Hormone suppression can be assessed in various ways, such as according to the considered therapeutic indication.

[0097] In some aspects, the pharmaceutical composition comprises biodegradable polymeric microspheres, including (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof and (b) a single lactic acid polymer, as a suspension in a liquid medium or in a dried form for suspension in a liquid medium. The inventors have discovered that despite the use of a single lactic acid polymer (i.e., not a mixture) and a water-soluble salt of triptorelin in the microspheres (i.e., not an implant), triptorelin can still be sustained-released over a period of at least 10 months, at least 11 months, or at least 12 months.

[0098] In some respects, the pharmaceutical composition comprises a single set of biodegradable microspheres as defined herein. In this context, "single set" means that all microspheres have substantially the same characteristics, such as regarding particle size distribution, lactic acid polymer properties, etc. The inventors have discovered that triptorelin can still be sustained-released over a period of at least 10 months, at least 11 months, or at least 12 months, despite the use of single set of biodegradable microspheres.

[0099] In patients with central precocious puberty (CPP), hormone suppression can be characterized in some respects by suppressing LH to prepubertal levels (defined as LH ≤ 5 IU / L after stimulation with GnRH or a GnRH agonist). This can be measured in serum, plasma, and / or blood.

[0100] In some respects, pharmaceutical compositions comprising microspheres of a single lactic acid polymer can be used to treat patients with CPP, wherein the microspheres contain about 40 to about 90 mg of triptorelin in the form of acetate, suspended in a mixture of C8 / C10 triglycerides (MIGLYOL® 812).

[0101] It should be understood that in the sentence “about 40 to about 90 mg of triptorelin in acetate form”, there is about 40 to about 90 mg of free triptorelin base, but the actual amount of triptorelin in acetate form is higher.

[0102] In some respects, pharmaceutical compositions comprising microspheres of a single lactic acid polymer can be used to treat patients with CPP, wherein the microspheres contain about 40 to about 90 mg of triptorelin in the form of acetate, suspended in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). As an example, pharmaceutical compositions comprising microspheres of poly-DL-lactic acid (DL PLA, 100:0) can be used to treat patients with CPP, wherein the microspheres contain about 40 to about 90 mg of triptorelin in the form of acetate in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In one example, a pharmaceutical composition comprising microspheres of poly-DL-lactic acid (DL PLA, 100:0) can be used to treat patients with CPP, the poly-DL-lactic acid having ester end groups and an initial intrinsic viscosity of about 0.55 to about 0.75 (as measured in g / dL concentration in chloroform at 30°C), the microspheres comprising about 40 to about 90 mg of triptorelin in the form of acetate in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In one example, a pharmaceutical composition comprising microspheres of poly-DL-lactic acid (DL PLA, 100:0) can be used to treat CPP patients, wherein the poly-DL-lactic acid has ester end groups, a weight-average molecular weight (Mw) of about 45,000 to 65,000 g / mol, and a polydispersity of about 1.5 to about 1.7 (as determined by GPC), and the microspheres contain about 40 to about 90 mg of triptorelin in the form of acetate in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In this context, CPP patients may be those who have previously received different therapies (e.g., other GnRH agonist therapies).

[0103] In some respects, pharmaceutical compositions comprising microspheres of a single lactic acid polymer can be used to treat patients with CPP, wherein the microspheres contain approximately 70 mg of triptorelin in the form of acetate, suspended in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). As an example, pharmaceutical compositions comprising microspheres of poly-DL-lactic acid (DL PLA, 100:0) can be used to treat patients with CPP, wherein the microspheres contain approximately 70 mg of triptorelin in the form of acetate in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In one example, a pharmaceutical composition comprising microspheres of poly-DL-lactic acid (DL PLA, 100:0) can be used to treat patients with CPP, the poly-DL-lactic acid having ester end groups and an initial intrinsic viscosity of about 0.55 to about 0.75 (as measured in g / dL concentration in chloroform at 30°C), the microspheres comprising about 70 mg of triptorelin in the form of acetate in a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In one example, a pharmaceutical composition comprising microspheres of poly-DL-lactic acid (DLPLA, 100:0) can be used to treat CPP patients. The poly-DL-lactic acid has ester-terminal groups, a weight-average molecular weight (Mw) of about 45,000 to 65,000 g / mol, and a polydispersity of about 1.5 to about 1.7 (as determined by GPC). The microspheres contain about 70 mg of triptorelin in the acetate form within a mixture of C8 / C10 triglycerides (MIGLYOL® 812). In this context, CPP patients may be those who have previously received different therapies (e.g., other GnRH agonist therapies).

[0104] In some respects, hormone suppression in prostate cancer patients can be characterized by suppressing testosterone to castration levels (defined as testosterone ≤ 50 ng / dL (i.e. ≤ 1.735 nmol / L)). This can be measured in serum, plasma, and / or blood.

[0105] In some aspects, the pharmaceutical compositions described herein provide sustained release of triptorelin in a subject (e.g., a human) with a limited burst release, such as Cmax ≤ 4 ng / mL. In some aspects, a limited burst release of triptorelin is observed within hours following administration of the pharmaceutical compositions described herein, such as within 48 h, 24 h, or 12 h after administration, with an initial Cmax ≤ 4 ng / mL. In some aspects, the initial Cmax corresponds to the maximum concentration of triptorelin (overall Cmax) observed throughout the entire release period (e.g., at least 10 months, at least 11 months, or at least 12 months). In some aspects, the initial Cmax is lower than the overall Cmax. In some preferred aspects, the overall Cmax in the subject (e.g., a human) is ≤ 4 ng / mL.

[0106] In some respects, the pharmaceutical compositions described herein can provide sustained release of triptorelin above a threshold of 0.0137 ng / mL throughout the maintenance period (e.g., from 48 h or 1 month to 10, 11, or 12 months after administration). This threshold is associated with a 90% probability of adequate hormone suppression (stimulated serum LH ≤ 5 IU / L) throughout the total release period.

[0107] In some respects, the pharmaceutical compositions described herein can provide sustained release of triptorelin above a threshold of 0.0316 ng / mL throughout the maintenance period (e.g., from 48 h or 1 month to 10, 11, or 12 months after administration). This threshold is associated with a 95% probability of adequate hormone suppression (stimulated serum LH ≤ 5 IU / L) throughout the total release period.

[0108] In some respects, the pharmaceutical compositions described herein can provide a sustained release of triptorelin ranging from 0.0137 ng / mL to 4 ng / mL throughout the maintenance period (such as 48 hours or 1 month after administration to 10, 11 or 12 months).

[0109] In some respects, the pharmaceutical compositions described herein can provide a sustained release of triptorelin ranging from 0.0316 ng / mL to 4 ng / mL throughout the maintenance period (such as 48 hours or 1 month after administration to 10, 11 or 12 months).

[0110] In some respects, this article describes kits that include: a) The pharmaceutical composition described herein b) Optional liquid load for suspension, and c) A vial or syringe optionally pre-filled with the pharmaceutical composition described in a).

[0111] III. Methods for manufacturing biodegradable polymer microspheres Methods for preparing biodegradable polymeric microspheres of triptorelin or its pharmaceutically acceptable salts (e.g., triptorelin acetate) are also provided, these methods comprising: (a1) The organic phase is prepared by dissolving triptorelin or a pharmaceutically acceptable soluble salt thereof (e.g., triptorelin acetate) and a single lactic acid polymer (e.g., polylactide) having a lactic acid content of 80% or higher and an initial intrinsic viscosity of about 0.4 to about 0.8 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C in one or more organic solvents at room temperature; (a2) An aqueous phase is prepared by dissolving polyvinyl alcohol and a salting-out agent in water and cooling the aqueous phase to about 2°C to about 8°C to produce a cooled aqueous phase; (a3) The organic phase and the cooled aqueous phase are mixed to form microspheres, and (a4) Filter, wash and dry the microspheres.

[0112] In some respects, room temperature refers to the temperature range of approximately 18°C ​​to approximately 25°C.

[0113] In some aspects, the aqueous phase is cooled to about 2°C to about 7°C, about 2°C to about 6°C, about 2°C to about 5°C, about 2°C to about 4°C, about 3°C ​​to about 8°C, about 3°C ​​to about 7°C, about 3°C ​​to about 6°C, about 3°C ​​to about 5°C, about 3°C ​​to about 4°C, about 4°C to about 8°C, about 4°C to about 7°C, about 4°C to about 6°C, or about 4°C to about 5°C. In some aspects, the aqueous phase is cooled to about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, or about 8°C, preferably to about 4°C.

[0114] The organic phase may contain one or more organic solvents suitable for dissolving biodegradable polymers and / or triptorelin or pharmaceutically acceptable soluble salts (e.g., triptorelin acetate). Non-limiting examples of organic solvents used to prepare the organic phase that can be used to dissolve biodegradable polymers include alcohols (e.g., methanol), ethyl acetate, acetone, dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, or halogenated hydrocarbons (e.g., dichloromethane (DCM), chloroform, hexafluoroisopropanol (HFIP), dimethyl sulfoxide (DMSO)) and any combinations thereof. In some aspects, one or more organic solvents in the organic phase are mixtures of dichloromethane and methanol.

[0115] In some aspects, dichloromethane is present in the mixture in the following amounts: about 50% to about 100% (w / w), about 50% to about 95% (w / w), about 50% to about 90% (w / w), about 50% to about 85% (w / w), about 50% to about 80% (w / w), about 50% to about 75% (w / w), about 50% to about 70% (w / w), about 50% to about 65% (w / w), about 50% to about 60% (w / w), about 55% to about 100% (w / w), about 55% to about 95% (w / w), about 55% to about 90% (w / w), about 55% to about 85% (w / w), about 55% to about 80% (w / w), about 55% to about 75% (w / w), about 55% to about 70% (w / w), about 55% to about 65% (w / w), approximately 60% to approximately 100% (w / w), approximately 60% to approximately 95% (w / w), approximately 60% to approximately 90% (w / w), approximately 60% to approximately 85% (w / w), approximately 60% to approximately 80% (w / w), approximately 60% to approximately 75% (w / w), approximately 60% to approximately 70% (w / w), approximately 65% ​​to approximately 100% (w / w), approximately 65% ​​to approximately 95% (w / w), approximately 65% ​​to approximately 90% (w / w), approximately 65% ​​to approximately 80% (w / w), approximately 65% ​​to approximately 75% (w / w), approximately 70% to approximately 100% (w / w), approximately 70% to approximately 95% (w / w), approximately 70% to approximately 90% (w / w), approximately 70% to approximately 85% (w / w), approximately 70% to approximately 80% (w / w), about 75% to about 100% (w / w), about 75% to about 95% (w / w), about 75% to about 90% (w / w), about 75% to about 85% (w / w), about 80% to about 100% (w / w), about 80% to about 95% (w / w), or about 80% to about 90% (w / w). In some aspects, dichloromethane is present in the mixture in an amount of about 50% to about 100% (w / w).

[0116] In some aspects, dichloromethane is present in the mixture in amounts of about 50%, about 55%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% (w / w). In some aspects, dichloromethane is present in the mixture in amounts of about 75% (w / w).

[0117] In some aspects, methanol is present in the mixture in the following amounts: about 5% to about 50% (w / w), about 5% to about 45% (w / w), about 5% to about 40% (w / w), about 5% to about 35% (w / w), about 5% to about 30% (w / w), about 5% to about 25% (w / w), about 5% to about 20% (w / w), about 5% to about 15% (w / w), about 7.5% to about 50% (w / w), about 7.5% to about 45% (w / w), about 7.5% to about 40% (w / w), about 7.5% to about 35% (w / w), about 7.5% to about 30% (w / w), about 7.5% to about 25% (w / w), about 7.5% to about 20% (w / w), about 10% to about 50% (w / w), and about 10% to about 45%. (w / w), about 10% to about 40% (w / w), about 10% to about 35% (w / w), about 10% to about 30% (w / w), about 10% to about 25% (w / w), about 10% to about 20% (w / w), about 15% to about 50% (w / w), about 15% to about 45% (w / w), about 15% to about 40% (w / w), about 15% to about 35% (w / w), about 15% to about 30% (w / w), about 15% to about 25% (w / w), about 20% to about 50% (w / w), about 20% to about 45% (w / w), about 20% to about 40% (w / w), about 20% to about 35% (w / w), about 20% to about 30% (w / w), about 25% to about 50% (w / w), about 25% to about 45% (w / w), about 25% to about 40% (w / w), about 25% to about 35% (w / w), about 30% to about 50% (w / w), about 30% to about 45% (w / w), about 30% to about 40% (w / w), about 35% to about 50% (w / w), about 35% to about 45% (w / w), or about 40% to about 50% (w / w). In some aspects, methanol is present in the mixture in an amount of about 5% to about 50%.

[0118] In some respects, methanol is present in the mixture in amounts of about 5%, about 7.5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% (w / w). In some respects, methanol is present in the mixture in amounts of about 25% (w / w).

[0119] Non-limiting examples of stabilizers include polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, dextrin, polyethylene glycol, poloxamer, poly(oxyethylene)-sorbitan fatty acid esters, sorbitan fatty acids, lecithin, and mixtures thereof. In one aspect, the stabilizer is polyvinyl alcohol (PVA).

[0120] In some aspects, the polyvinyl alcohol in the aqueous phase is present in amounts of about 0.1% to about 10% (w / w), about 0.1% to about 9% (w / w), about 0.1% to about 8% (w / w), about 0.1% to about 7% (w / w), about 0.1% to about 6% (w / w), about 0.1% to about 5% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 3% (w / w), about 0.1% to about 2% (w / w), or about 0.1% to about 1%. In some aspects, the polyvinyl alcohol in the aqueous phase is present in amounts of about 0.1% to about 10% (w / w).

[0121] In some aspects, the polyvinyl alcohol in the aqueous phase is present in amounts of about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2%, about 2.25%, about 2.5%, about 2.75%, about 3%, about 3.25%, about 3.5%, about 3.75%, about 4%, about 4.25%, about 4.5%, about 4.75%, about 5%, about 5.25%, about 5.5%, about 5.75%, about 6%, about 6.25%, about 6.5%, about 6.75%, about 7%, about 7.25%, about 7.5%, about 7.75%, about 8%, about 8.25%, about 8.5%, about 8.75%, about 9%, about 9.25%, about 9.5%, about 9.75%, or about 10%. In some respects, polyvinyl alcohol in the aqueous phase is present in an amount of about 1% (w / w).

[0122] The salting-out agent in step (a2) of the method described herein can be a salt. In some aspects, the salt can be an alkali metal salt, such as an alkali metal chloride, alkali metal nitrate, or alkali metal sulfate. Non-limiting examples of suitable salts include sodium chloride (NaCl) and potassium chloride (KCl). In some aspects, the salting-out agent in step (a2) of the method described herein is NaCl.

[0123] In some aspects, the salting-out agent (e.g., NaCl) in step (a2) of the method described herein is present in amounts of about 0.1% to about 10% (w / w), about 0.1% to about 9% (w / w), about 0.1% to about 8% (w / w), about 0.1% to about 7% (w / w), about 0.1% to about 6% (w / w), about 0.1% to about 5% (w / w), about 0.1% to about 4% (w / w), about 0.1% to about 3% (w / w), about 0.1% to about 2% (w / w), or about 0.1% to about 1%. In some aspects, the salting-out agent (e.g., NaCl) in step (a2) of the method described herein is present in amounts of about 0.1% to about 10% (w / w).

[0124] In some aspects, the salting-out agent (e.g., NaCl) in step (a2) of the method described herein is present at concentrations of approximately 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.25%, 3.5%, and 3.7%. It is present in amounts of 5%, about 4%, about 4.25%, about 4.5%, about 4.75%, about 5%, about 5.25%, about 5.5%, about 5.75%, about 6%, about 6.25%, about 6.5%, about 6.75%, about 7%, about 7.25%, about 7.5%, about 7.75%, about 8%, about 8.25%, about 8.5%, about 8.75%, about 9%, about 9.25%, about 9.5%, about 9.75%, or about 10%. In some aspects, the salting-out agent (e.g., NaCl) in step (a2) of the method described herein is present in an amount of about 2.5% (w / w).

[0125] In some aspects, the organic phase and aqueous phase of the methods described herein are mixed at a ratio of 1:50 to 1:500, 1:50 to 1:400, 1:50 to 1:300, 1:50 to 1:250, 1:50 to 1:200, 1:50 to 1:150, or 1:50 to 1:100. In some aspects, the organic phase and aqueous phase of the methods described herein are mixed at a ratio of about 1:100.

[0126] In some aspects, the organic phase and aqueous phase of the method described herein are continuously mixed. In other aspects, the organic phase and aqueous phase of the method described herein are simultaneously fed / pumped into a mixing device (e.g., a rotor-stator mixer) and mixed therein.

[0127] In some respects, the organic solvents in the methods described herein can be removed from the emulsion by solvent evaporation or solvent extraction. In some respects, the microspheres prepared by the methods described herein can be dried. In some respects, the microspheres prepared by the methods described herein are dried in an oven.

[0128] According to the present invention, the predetermined level of any residual solvent in the microspheres, especially after drying, can be based on the guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals or Human Use (ICH Q3C). In the case of DCM, the predetermined level of residual solvent can be 10,000 ppm or less, 5,000 ppm or less, 1,000 ppm or less, or 600 ppm or less. In the case of methanol, the predetermined level of residual solvent can be 40,000 ppm or less, 3,000 ppm or less, or 500 ppm or less.

[0129] Sieving can be performed using sieves with aperture sizes that produce the particle sizes specified above and below. In some respects, the sieve is a 106 µm sieve, although smaller or larger aperture sizes can be used, such as 50 µm or 200 µm, or any other value in the range of 75 µm to 180 µm.

[0130] In some aspects, the encapsulation efficiency of triptorelin in the microspheres prepared by the methods described herein is about 80% to about 99%, about 80% to about 95%, about 80% to about 90%, about 85% to about 99%, about 85% to about 95%, or about 90% to about 99%. In other aspects, the encapsulation efficiency of triptorelin in the microspheres prepared by the methods described herein is about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0131] IV. The invention is further characterized by the following provisions: Clause 1. A pharmaceutical composition comprising biodegradable polymeric microspheres, said biodegradable polymeric microspheres comprising (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof, and (b) a single lactic acid polymer having a lactide content of 80% or higher, a molecular weight (Mw) of about 30,000 g / mol to about 80,000 g / mol, and a polydispersity of about 1.4 to about 2.0 as determined by gel permeation chromatography, wherein said pharmaceutical composition provides sustained release of said triptorelin for at least 10 months.

[0132] Clause 2. The pharmaceutical composition according to Clause 1, wherein the pharmaceutical composition provides a sustained release of triptorelin for at least 11 months or at least 12 months.

[0133] Clause 3. The pharmaceutical composition according to Clause 1 or 2, wherein, based on the free base of triptorelin, the biodegradable polymeric microspheres have a drug loading of about 10% to about 20% (w / w), preferably about 10% to about 15% (w / w), and more preferably about 12% (w / w) of triptorelin or its pharmaceutically acceptable water-soluble salt.

[0134] Clause 4. The pharmaceutical composition according to any one of Clauses 1 to 3, wherein the triptorelin is present as triptorelin acetate.

[0135] Clause 5. The pharmaceutical composition according to any one of Clauses 1 to 4, wherein the biodegradable polymer microspheres have a Dv50 of about 20 µm to about 80 µm, preferably about 40 µm to about 60 µm.

[0136] Clause 6. The pharmaceutical composition according to any one of Clauses 1 to 5, wherein the lactic acid polymer has a molecular weight of about 40,000 g / mol to about 65,000 g / mol and a polydispersity of about 1.5 to about 1.9.

[0137] Clause 7. The pharmaceutical composition according to Clause 6, wherein the lactic acid polymer has a molecular weight of about 45,000 to about 65,000 g / mol.

[0138] Clause 8. The pharmaceutical composition according to any one of Clauses 1 to 7, wherein the molecular weight of the lactic acid polymer is measured in the formed microspheres.

[0139] Clause 9. The pharmaceutical composition according to any one of Clauses 1 to 8, wherein the polydispersity of the lactic acid polymer is measured in the formed microspheres.

[0140] Clause 10. The pharmaceutical composition according to any one of Clauses 1 to 9, wherein the lactic acid polymer has an initial intrinsic viscosity of about 0.4 dL / g to about 0.8 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C.

[0141] Clause 11. The pharmaceutical composition according to Clause 10, wherein the lactic acid polymer has an initial intrinsic viscosity of about 0.55 dL / g to about 0.75 dL / g, measured at a concentration of 0.5 g / dL in chloroform at 30°C.

[0142] Clause 12. The pharmaceutical composition according to any one of Clauses 1-11, wherein the biodegradable polymer microspheres have a Dv10 of about 10 µm to about 40 µm, preferably about 15 µm to about 30 µm, a Dv50 of about 40 µm to about 60 µm, and a Dv90 of about 60 µm to about 120 µm, preferably about 80 µm to about 100 µm.

[0143] Clause 13. The pharmaceutical composition according to any one of Clauses 1 to 12, wherein the lactic acid polymer is polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA), particularly PLA.

[0144] Clause 14. The pharmaceutical composition according to any one of Clauses 1 to 13, wherein the lactic acid polymer is selected from PLGA 85:15, PLGA 90:10, PLGA 95:5 or PLA 100:0.

[0145] Clause 15. The pharmaceutical composition according to any one of Clauses 1 to 14, wherein the lactic acid polymer is selected from PLGA 85:15 having an ester end group, PLA 100:0 having a carboxyl end group, or PLA 100:0 having an ester end group.

[0146] Clause 16. The pharmaceutical composition according to any one of Clauses 1 to 15, wherein the lactic acid polymer is DL PLA 100:0 having carboxyl end groups and having an initial intrinsic viscosity of about 0.55 to about 0.75 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C.

[0147] Clause 17. The pharmaceutical composition according to any one of Clauses 1 to 12, wherein the lactic acid polymer has a lactic acid content of about 100%.

[0148] Clause 18. The pharmaceutical composition according to any one of Clauses 1 to 17, wherein the pharmaceutical composition comprises triptorelin as a free base in an amount of about 40 mg to about 90 mg, preferably about 70 mg.

[0149] Clause 19. The pharmaceutical composition according to any one of Clauses 1 to 18, wherein the sustained release lasts for at least one year, preferably about one year.

[0150] Clause 20. A pharmaceutical composition according to any one of Clauses 1 to 19, wherein the pharmaceutical composition is a suspension comprising biodegradable polymer microspheres or a composition of dried biodegradable polymer microspheres for suspension in a liquid medium.

[0151] Clause 21. The pharmaceutical composition according to Clause 20, wherein the pharmaceutical composition is a suspension comprising the biodegradable polymer microspheres at a concentration of about 100 mg / mL to about 500 mg / mL, preferably about 200 mg / mL to about 400 mg / mL, and more preferably about 250 mg / mL to about 350 mg / mL.

[0152] Clause 22. The pharmaceutical composition according to Clause 20 or 21, wherein the suspension or liquid medium comprises a non-aqueous load.

[0153] Clause 23. The pharmaceutical composition according to Clause 22, wherein the non-aqueous support comprises an oil.

[0154] Clause 24. The pharmaceutical composition according to Clause 23, wherein the oil comprises medium-chain triglycerides.

[0155] Clause 25. The pharmaceutical composition according to any one of Clauses 22 to 24, wherein the non-aqueous support is a mixture of medium-chain triglycerides, such as a mixture of C8 / C10 triglycerides.

[0156] Clause 26. The pharmaceutical composition according to Clause 24 or 25, wherein, in vitro, less than 10% of the triptorelin is released within 21 hours, less than 15% of the triptorelin is released after about 165 hours, and more than 75% of the triptorelin is released after about 330 hours.

[0157] Clause 27. The pharmaceutical composition according to Clause 26, wherein in vitro release is measured using a USP II device, comprising: - An MCT oil suspension was introduced, the suspension comprising the biodegradable polymer microspheres equivalent to 70 mg of triptorelin in 900 mL of 100 mM acetate buffer. - Apply the following temperature gradient: Incubate at approximately 37°C for about 21 hours. A temperature gradient was applied, increasing by approximately 0.5°C per hour for about 46 hours. o Maintain at 60°C for up to 330 hours. The sample is taken out from the device at a specific time point, and the dissolved drug is quantified by HPLC.

[0158] Clause 28. The pharmaceutical composition according to Clause 20, wherein the liquid medium for suspension comprises an aqueous carrier.

[0159] Clause 29. A pharmaceutical composition according to any one of Clauses 1 to 28, wherein the pharmaceutical composition comprises biodegradable polymer microspheres comprising (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof and (b) the single lactic acid polymer, as a suspension in a liquid medium or in a dried form for suspension in a liquid medium.

[0160] Clause 30. The pharmaceutical composition according to any one of Clauses 1 to 29, wherein the pharmaceutical composition comprises a single group of biodegradable polymer microspheres.

[0161] Clause 31. The pharmaceutical composition according to any one of Clauses 1 to 30, wherein the pharmaceutical composition is sterilized by irradiation.

[0162] Clause 32. The pharmaceutical composition according to any one of Clauses 1 to 31, for use as a medicament.

[0163] Clause 33. The pharmaceutical composition according to any one of Clauses 1 to 31, for use in treating a disease or ailment in which triptorelin or a pharmaceutically acceptable soluble salt thereof has a therapeutic effect.

[0164] Clause 34. A pharmaceutical composition for the use described in Clause 33, wherein the disease or ailment is selected from prostate cancer, prostate cancer symptoms, central precocious puberty, endometrial stromal sarcoma, uterine fibroids, breast cancer, or endometriosis.

[0165] Clause 35. A pharmaceutical composition for the use described in Clause 34, wherein the disease or ailment is central precocious puberty.

[0166] Clause 36. A pharmaceutical composition for any of the uses described in Clauses 32 to 35, wherein the pharmaceutical composition is administered parenterally to the subject.

[0167] Clause 37. A pharmaceutical composition for the use described in Clause 36, wherein the pharmaceutical composition is administered parenterally via intramuscular or subcutaneous injection.

[0168] Clause 38. A pharmaceutical composition for the use described in Clause 37, wherein the pharmaceutical composition is administered via intramuscular injection or parenteral administration.

[0169] Clause 39. A method of treating a disease or ailment in which triptorelin or a pharmaceutically acceptable water-soluble salt form thereof has a therapeutic effect, said method comprising administering to a subject in need of the pharmaceutical composition according to any one of Clauses 1 to 31.

[0170] Clause 40. The method described in Clause 39, wherein the disease or ailment is selected from prostate cancer, prostate cancer symptoms, central precocious puberty, endometrial stromal sarcoma, uterine fibroids, breast cancer, or endometriosis.

[0171] Clause 41. The method described in accordance with Clause 40, wherein the disease or ailment is central precocious puberty.

[0172] Clause 42. The method according to any one of Clauses 39 to 41, wherein the subject has not previously received treatment for the disease or ailment.

[0173] Clause 43. The method according to any one of Clauses 39 to 41, wherein the subject has previously received treatment for the disease or ailment.

[0174] Clause 44. A pharmaceutical composition for use according to any one of Clauses 36 to 38 or a method according to any one of Clauses 39 to 43, wherein the subject is a human being.

[0175] Clause 45. A method for preparing triptorelin biodegradable polymer microspheres, comprising: (a1) The organic phase is prepared by dissolving the triptorelin or a pharmaceutically acceptable soluble salt thereof, and a single lactic acid polymer or a pharmaceutically acceptable salt thereof having a lactide content of 80% or higher and an initial intrinsic viscosity of about 0.4 to about 0.8 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C, in one or more organic solvents at room temperature; (a2) An aqueous phase is prepared by dissolving polyvinyl alcohol and a salting-out agent in water and cooling the aqueous phase to about 2 to about 8°C to produce a cooled aqueous phase; (a3) The organic phase and the cooled aqueous phase are mixed to form the microspheres, and (a4) Filter, wash and dry the microspheres.

[0176] Clause 46. The method according to Clause 45, wherein one or more organic solvents in the organic phase are a mixture of dichloromethane and methanol.

[0177] Clause 47. The method according to Clause 46, wherein the dichloromethane is present in the mixture in an amount of about 50% to about 90% (w / w).

[0178] Clause 48. The method according to Clause 47, wherein the dichloromethane is present in the mixture in an amount of about 75% (w / w).

[0179] Clause 49. The method according to Clause 46, wherein the methanol is present in the mixture in an amount of about 5% to about 50% (w / w).

[0180] Clause 50. The method according to Clause 49, wherein the methanol is present in the mixture in an amount of about 25% (w / w).

[0181] Clause 51. The method according to any one of Clauses 45 to 50, wherein the polyvinyl alcohol in the aqueous phase is present in an amount of about 0.1% to about 10% (w / w).

[0182] Clause 52. The method according to Clause 51, wherein the polyvinyl alcohol in the aqueous phase is present in an amount of about 1% (w / w).

[0183] Clause 53. The method according to any one of Clauses 45 to 52, wherein the salting-out agent in the aqueous phase is present in an amount of about 0.1% to about 10% (w / w).

[0184] Clause 54. The method according to Clause 53, wherein the salting-out agent in the aqueous phase is present in an amount of about 2.5% (w / w).

[0185] Clause 55. The method according to any one of Clauses 45 to 54, wherein the salting-out agent in the aqueous phase is sodium chloride.

[0186] Clause 56. The method according to any one of Clauses 45 to 55, wherein the organic phase and the aqueous phase are mixed in a ratio of 1:50 to 1:500.

[0187] Clause 57. The method described in accordance with Clause 56, wherein the ratio is approximately 1:100.

[0188] Clause 58. The method according to any one of Clauses 45 to 57, wherein the biodegradable polymer microspheres have a Dv50 of about 20 µm to about 80 µm, preferably about 40 µm to about 60 µm.

[0189] Clause 59. The method according to any one of Clauses 45 to 58, wherein the encapsulation rate of triptorelin in the microspheres is about 80% to about 99%, preferably about 90% to about 99%.

[0190] Clause 60. Biodegradable polymer microspheres prepared by any one of Clauses 45 to 59.

[0191] Clause 61. A pharmaceutical composition comprising biodegradable polymer microspheres as described in Clause 60.

[0192] Clause 62. The pharmaceutical composition according to Clause 61, wherein the biodegradable polymer microspheres are mixed with an aqueous or non-aqueous support to prepare the pharmaceutical composition.

[0193] Clause 63. The pharmaceutical composition according to Clause 61 or 62, wherein the pharmaceutical composition provides a sustained release of triptorelin for at least 10 months, at least 11 months, or at least 12 months.

[0194] Clause 64. The pharmaceutical composition according to any one of Clauses 1 to 38 or 61 to 63, wherein the pharmaceutical composition provides extended release of the triptorelin, wherein the initial Cmax is 4 ng / mL or less within 48 h, 24 h or 12 h after administration to the subject.

[0195] Clause 65. The pharmaceutical composition according to any one of Clauses 1 to 38 or 61 to 64, wherein the pharmaceutical composition provides sustained release of the triptorelin in a subject, wherein the total Cmax is 4 ng / mL or less.

[0196] Clause 66. The pharmaceutical composition according to any one of Clauses 1 to 38 or 61 to 65, wherein the pharmaceutical composition provides a sustained release of triptorelin above the threshold of 0.0137 ng / mL throughout the maintenance period of 1 month to 10, 11 or 12 months after administration to the subject, preferably from 48 hours to 10, 11 or 12 months after administration.

[0197] Clause 67. The pharmaceutical composition according to any one of Clauses 1 to 38 or 61 to 66, wherein the pharmaceutical composition provides a sustained release of triptorelin above the threshold of 0.0316 ng / mL throughout the maintenance period of 1 month to 10, 11 or 12 months after administration to the subject, preferably from 48 hours to 10, 11 or 12 months after administration.

[0198] Clause 68. The pharmaceutical composition according to any one of Clauses 64 to 67, wherein the subject is a human being.

[0199] Clause 69. A reagent kit comprising: a) A pharmaceutical composition according to any one of clauses 1 to 31, 61 or 63-67; b) The support material optionally used for resolution, and c) A vial or syringe optionally pre-filled with the pharmaceutical composition described in a).

[0200] Although the invention has been described and illustrated with respect to illustrative embodiments and practices, it will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the scope and spirit of the invention. Therefore, the invention is not limited to the illustrative embodiments and practices.

[0201] Example Example 1: Characterization Gel permeation chromatography (GPC) can be performed as follows. The sample is dissolved in tetrahydrofuran (THF) and eluted isocratically with THF at 1 mL / min. Analysis is performed on a tandem Styragel® columns (HR 5, HR 4, HR 3, and HR 2) heated at 40 °C and using a refractive index detector. The number-average molecular weight (Mn), weight-average molecular weight (Mw), and polydispersity index (Ip = Mw / Mn) of the polymer are determined based on calibration curves, using narrow molecular weight polystyrene obtained from Sigma Aldrich as a standard, as shown in Table 1. Table 1:

[0202] The lactic acid content of biodegradable polymers can be measured using conventional methods, such as nuclear magnetic resonance (1H NMR).

[0203] Drug loading can be measured using conventional methods, such as high-performance liquid chromatography (HPLC). The HPLC method can be as follows: An appropriate weight (e.g., 20 mg) of biodegradable polymer microparticles can be weighed, dissolved in acetonitrile (ACN) and dichloromethane (DCM), and the sample can be analyzed by gradient elution using a C18 column, a phosphate-buffered saline mobile phase of pH 6.8 / acetonitrile, and UV detection at 280 nm.

[0204] Example 2: Microsphere Preparation The microspheres (composition AM) listed in Table 2 are manufactured using the following method.

[0205] 1. Mix an appropriate amount of dichloromethane and methanol in a glass container to obtain a solution with the appropriate methanol concentration shown in Table 2 (“Methanol Concentration” column). Then, dissolve an appropriate amount of PL(G)A polymer in this solution to obtain the polymer concentration shown in Table 2 (“PL(G)A Concentration” column). Subsequently, under magnetic stirring, weigh an appropriate amount of triptorelin acetate and add it to the solution in an amount equivalent to the theoretical drug loading of subsequently formed microspheres shown in Table 2 (“Theoretical Drug Loading” column). The resulting solution is referred to as the “organic solution”. This organic solution is maintained at room temperature until mixing step 3.

[0206] 2. Dissolve an appropriate amount of polyvinyl alcohol (PVA 4-88) in an appropriate amount of deionized water to form a 1% PVA 4-88 solution. Then, dissolve an appropriate amount of NaCl in this 1% PVA 4-88 solution to obtain a solution with the NaCl concentration shown in Table 2 (“NaCl Concentration” column). The resulting solution is referred to as the “aqueous solution”. This aqueous solution is maintained at 4°C until mixing step 3.

[0207] 3. Mixing steps. The organic solution (at room temperature) and the aqueous solution (at 4°C) are mixed as follows: The organic solution is pumped into the rotor-stator unit at the rates shown in Table 2 (“Organic Solution Rate” column) using a flexible tubular pump, and the aqueous solution is pumped into the same rotor-stator unit at the rates shown in Table 2 (“Aqueous Solution Rate” column) using a peristaltic pump or flow meter. The two solutions are then mixed in the rotor-stator chamber at the rates shown in Table 2 (“Rotor-Stator Rate” column). The microsphere suspension obtained by the O / W emulsion is collected in a glass beaker or stainless steel container.

[0208] 4. Microsphere ripening. The microsphere suspension was kept under magnetic stirring and vacuum for 4 hours to allow dichloromethane to evaporate. The temperature at the end of the solvent evaporation step was below 15°C.

[0209] 5. Microsphere filtration and washing. The microspheres were collected by filtration (20 µm) and then washed several times with an appropriate amount of 10% methanol solution in water (to remove any triptorelin acetate and / or PVA on their surface).

[0210] 6. Microspheres are dried and sterilized. The microspheres were dried overnight (16 h) under vacuum at 30 °C in a filter, followed by a second drying step in an oven at 40 °C under vacuum for 2 to 7 days. The dried microspheres were sieved through a 106 µm sieve and added to glass vials under nitrogen. These microspheres were then sterilized by X-ray irradiation at a dose of 25 kGy.

[0211] 7. After dissolution on a C18 column using a gradient method (in acetonitrile and dichloromethane), the drug loading was quantified by liquid chromatography. The drug loading is shown in Table 2 (“Actual Drug Loading” column). The molecular weight of the polymer in the microspheres was determined by GPC and is shown in Table 2.

[0212] Composition M has the same composition as composition E, but is manufactured on a different scale. The batch size for compositions A through L is approximately 10 g, and the batch size for composition M is approximately 60 g. The manufacturing line varies depending on the batch size, but the equipment used is equivalent.

[0213] Table 2:

[0214] *GPC data = gel permeation chromatography data, i.e., Mw = weight-average molecular weight (g / mol); Mn = number-average molecular weight (g / mol); IP = polydispersity index (ratio Mw / Mn). Example 3: Particle size determination The particle size distribution of compositions A through M was determined using wet laser diffraction with a Malvern Mastersizer 3000. Each sample was resuspended in an aqueous solution of sodium carboxymethyl cellulose (1.5% w / w) and polysorbate 80 (0.1%), and then diluted / dispersed in pure water in a Hydro MV dispersion unit (stirred at 2000 rpm) until a stable laser opacity of 10% to 20% was achieved. The samples were then subjected to sonication for 3 min (MV dispersion unit set to medium (50%)). The volume-weighted size distribution was calculated using Mie theory with the following parameters: dispersant refractive index 1.33; real part of particle refractive index 1.52; imaginary part of particle refractive index 0.001. The results for compositions A through M are shown in Table 3.

[0215] Table 3: Particle Size Distribution

[0216] Example 4: Pharmacokinetic characteristics of compositions A to L in rats Microspheres were suspended in physiologically acceptable lipophilic loading bodies (MCTs) to obtain a drug suspension concentration of 45 mg / mL. The resulting suspension was intramuscularly injected into six male Sprague Dawley rats (5-6 weeks old) at a dose equivalent to a single dose of 39 mg / kg triptorelin. Plasma samples were collected and triptorelin concentrations were analyzed after a defined time period. The results are shown in Table 4 and [Table data missing]. Figure 2-4 middle.

[0217] Compositions B, D, and E are formulations comprising a single lactic acid polymer that exhibit the longest observed release profiles and significant triptorelin plasma concentrations measurable over at least 10 months. Composition E (with the same composition as composition M) provides particularly favorable pharmacokinetic characteristics.

[0218] Table 4a: In vivo results

[0219] Table 4b: In vivo results

[0220] Example 5: Pharmacokinetic characteristics of composition M in rats Microspheres containing the components of composition M were suspended in a physiologically acceptable aqueous carrier (Group 1) of 1.5% (w / w) sodium carboxymethyl cellulose, 4.25% (w / w) mannitol, and 0.1% (w / w) polysorbate 80, and a physiologically acceptable lipophilic carrier of MCT oil (Group 2) to obtain a drug suspension concentration of 45 mg / mL. The resulting suspension was intramuscularly injected into 20 female Wistar rats (5-6 weeks old) at a dose equivalent to a single dose of 39 mg / kg triptorelin. Plasma samples were collected and triptorelin concentrations were analyzed after a defined time period. The results are shown in Table 5 and Figure 1 middle.

[0221] Table 5: In vivo results for composition M

[0222] Composition M in both load cells exhibited particularly favorable pharmacokinetic characteristics.

[0223] Example 6 (Comparative): Microspheres of triptorelin dihydroxynaphthyl acid formulation Microspheres of composition 1 (batch size approximately 10 g) were manufactured using the following method.

[0224] 1. Suspend an appropriate amount of triptorelin dihydroxynaphthyl acid in an appropriate amount of dichloromethane in a glass container. Then, mix the suspension in a mixer at 15,000 rpm for 3 minutes to obtain a complete suspension.

[0225] 2. Then, an appropriate amount of PLA polymer (DL PLA terminal ester intrinsic viscosity 0.5 dL / g) was dissolved in an appropriate amount of dichloromethane to obtain a polymer concentration of 12% in the solution. This solution was then mixed with the previous suspension under magnetic stirring to give a theoretical drug loading of 18.7% for the subsequently formed microspheres. The resulting suspension was referred to as the "organic solution".

[0226] 3. Dissolve an appropriate amount of PVA 4-88 in an appropriate amount of deionized water to form a 1% PVA 4-88 solution. The resulting solution is called an "aqueous solution".

[0227] 4. The organic solution was pumped into the rotor-stator unit at a rate of 5 mL / min using a flexible tubing pump, and the aqueous solution was pumped at a rate of 625 mL / min using a peristaltic pump to mix the organic and aqueous solutions. The two solutions were mixed in the rotor-stator chamber at a rate of 2500 rpm. The microsphere suspension obtained by the O / W emulsion was collected in a glass beaker.

[0228] 5. The microspheres were collected by filtration (1.2 µm) and then washed several times with an appropriate amount of water (to remove any triptorelin dihydroxynaphthyl acid and / or PVA from their surface). The microspheres were then dried overnight (16 h) under vacuum at room temperature. The dried microspheres were sieved through a 106 µm sieve.

[0229] 6. The microspheres were then mixed with an aqueous diluent consisting of 1.5% CMC Na, 4.25% mannitol, and 0.1% polysorbate 80. The suspension was freeze-dried and then sterilized by 25 kGy gamma irradiation.

[0230] 7. The drug loading was quantified as 14.96% (encapsulation rate 80%) by liquid chromatography.

[0231] 8. Particle size was determined by wet laser diffraction, with a Dv50 of 51.3 µm.

[0232] Example 7 (Comparative): Coated microspheres of triptorelin dihydroxynaphthyl acid formulation Using the following method, coated microspheres (composition 2) are manufactured using microspheres of composition 1.

[0233] 1. Add an appropriate amount of acetone to water to obtain a 9% acetone solution. Dissolve an appropriate amount of PLA polymer (DL PLA terminal ester intrinsic viscosity 0.5 dL / g) in an appropriate amount of the previous solution to obtain a 2% polymer solution (“coating solution”).

[0234] 2. An appropriate amount of microspheres of composition 1 are used to coat a fluidized air bed. At room temperature, the fluidized air rate applied to the microspheres is 16 L / min.

[0235] 3. Add coating solution at a rate of 1.4 L / min over 100 min and atomize it onto the microspheres at a rate of 6 L / min.

[0236] 4. Collect the microspheres and sieve them through a 180µm sieve.

[0237] 5. Next, the microspheres were mixed with an aqueous diluent consisting of 1.5% CMC Na, 4.25% mannitol, and 0.1% polysorbate 80. The suspension was freeze-dried and then sterilized by 25 kGy gamma irradiation.

[0238] 6. The drug loading was quantified as 12.22% (encapsulation rate 65%) by liquid chromatography.

[0239] 7. Particle size was determined by wet laser diffraction, with a Dv50 of 75 µm.

[0240] Example 8 (Comparative): Microparticles of triptorelin dihydroxynaphthyl acid formulation Microparticles (composition 3) are manufactured using the following method: 1. Using a planetary ball mill, mix an appropriate amount of triptorelin dihydroxynaphthyl acid with an appropriate amount of PLA polymer (DL PLA terminal ester intrinsic viscosity 0.5 dL / g) for 3 minutes to obtain a free base loading of 18.7% for triptorelin.

[0241] 2. Then, the mixture is manually extruded using a single screw extruder at a temperature of 110°C (12 / 24mm).

[0242] 3. The extrudate was cut into 2 mm pieces using a granulator and then ground into granules using a cryogenic mill (ring mill). The Dv50 of the microparticles was approximately 250 µm. The microparticles were then mixed with an aqueous diluent consisting of 1.5% CMC Na, 4.25% mannitol, and 0.1% polysorbate 80 and freeze-dried.

[0243] 4. Sterilize these microparticles by 25 kGy γ-irradiation.

[0244] Example 9 (Comparative): Implants of Triptorelin Acetate Formulation The implant (composition 4) is manufactured using the following method: 1. Using a planetary ball mill, mix an appropriate amount of triptorelin acetate with an appropriate amount of PLA polymer (DL PLA terminal ester intrinsic viscosity 0.5 dL / g) and an appropriate amount of sodium dihydroxynaphthyl acid or dihydroxynaphthyl acid for 3 minutes to obtain a 30% free base loading of triptorelin.

[0245] 2. Then, the mixture is manually extruded using a single screw extruder at a temperature of 125°C (12 / 24mm).

[0246] 3. Use a scalpel to manually cut the extrudate into appropriate lengths (2.1cm long and 1.44mm in diameter).

[0247] 4. Sterilize the implant by 25 kGy gamma irradiation.

[0248] Example 10 (Comparative): Pharmacokinetic characteristics of compositions 1, 2, 3 and 4 in rats Microspheres and microparticles of compositions 1, 2, and 3 were reconstituted with water for injection. The resulting suspensions were administered intramuscularly to 10 male Sprague Dawley rats at a dose equivalent to a single dose of 39 mg / kg triptorelin. Plasma samples were collected and triptorelin concentrations were analyzed after a defined time period. The results are shown in Tables 6 and 7. Figure 5 and Figure 6 middle.

[0249] The implant of composition 4 was administered intramuscularly to 10 male Sprague Dawley rats at a dose equivalent to a single dose of 39 mg / kg triptorelin. Plasma samples were collected and triptorelin concentrations were analyzed after a defined time period. The results are shown in Table 7 and... Figure 6 middle.

[0250] Table 6:

[0251] Table 7:

[0252] Compositions 1 through 4 did not exhibit acceptable pharmacokinetic characteristics.

[0253] Example 11: Clinical Trial An open-label, single-arm, multicenter phase 3 study is being conducted to assess the efficacy, safety, and pharmacokinetics of the 12-month formulation of triptorelin (composition M, 70 mg triptorelin in acetate form, in MIGLYOL® 812) [investigation formulation] in pediatric participants with central precocious puberty (CPP) receiving gonadotropin-releasing hormone agonist therapy.

[0254] This phase 3 study enrolled pediatric participants with CPP who had been treated with a gonadotropin-releasing hormone agonist (GnRHa) and switched to the study formulation of triptorelin for 12 months. The study consisted of two parts: • Part A assesses efficacy, safety, and pharmacokinetics (PK) within 12 months (52 weeks) following the first injection of the study formulation of triptorelin 12 months later. It also evaluates the absence of the slow-on-acute (AOC) phenomenon following injection of the study formulation in a randomized subset representing approximately half of the study population. Furthermore, the maximum serum concentration (Cmax) of triptorelin was measured in the PK subset.

[0255] • Part B assessed the efficacy, safety, and durability of the PK characteristics within 12 months (52 weeks) following the second injection of the study formulation at 12 months after the first injection. Similar to Part A, the absence of the AOC phenomenon was studied after the second injection of the study formulation in the AOC subset. Part B also assessed the potential accumulation of triptorelin serum concentrations after the second injection of the study formulation, evaluated Cmax in the PK subset, and evaluated triptorelin serum concentrations (C trough) at the end of the dosing interval in all participants.

[0256] End of treatment (EOT) occurred 52 weeks after the last injection of the study formulation.

[0257] Main objectives The primary objective of Part A is to evaluate the efficacy of the study formulation in suppressing serum LH levels to prepubertal levels 52 weeks after the first injection of the study formulation.

[0258] The endpoint was the percentage of participants whose stimulated serum LH was suppressed to ≤5 IU / L at the planned visit 52 weeks after the first injection of the study formulation.

[0259] research group The study included pediatric participants (boys and girls) who were diagnosed with CPP and received GnRHa therapy.

[0260] Inclusion criteria: 1. Diagnosed with central precocious puberty and currently receiving GnRHa therapy. 2. Girls begin developing sexual characteristics before age 8 and boys before age 9 (i.e., according to the Tanner method, girls develop breasts or boys develop testicular enlargement).

[0261] 3. Initially, only participants aged (a) 5 to 8 years (inclusive) (i.e., <9 years old) are eligible. The sponsor will determine whether participants aged (b) 2 to 4 years (inclusive) (i.e., <5 years old) and / or (c) 9 to 10 years (inclusive) (i.e., <11 years old) can be recruited. The sponsor will notify all researchers in writing when enrollment can begin in either or both of the age ranges (b) and (c).

[0262] 4. Candidates will receive GnRHa therapy for at least one year from the start of the study treatment. 5. Initiate initial GnRHa therapy no later than 18 months after the onset of the first symptom of CPP. 6. Based on historical values ​​at the start of GnRHa therapy, the difference (Δ) between bone age (Greulich and Pyle methods) and chronological age is ≥1 year. 7. Based on historical values ​​prior to the initiation of GnRHa therapy, a pubertal LH response (LH ≥ 6 IU / L) after GnRH / GnRHa stimulation testing, or randomized, non-stimulated serum LH > 0.5 IU / L (if local standards of care are considered). 8. Prior to starting GnRHa therapy, clinical evidence for puberty was defined as Tanner staging ≥2 in girls and testicular volume ≥4 mL (cc) in boys.

[0263] 9. Negative urine pregnancy test: Although pregnancy is unlikely in this study population, all girls must have a negative urine pregnancy test at screening and should not be at risk of pregnancy throughout the study. Researchers are responsible for reviewing medical history, menstrual history, and recent sexual activity to reduce the risk of including participants with undetected early pregnancies.

[0264] 10. Informed consent form (ICF) signed by the parents (one or both) or legal guardian (if applicable), in accordance with local regulations.

[0265] 11. If determined by the age of the participants and the requirements of the research centers and countries, a consent form shall be signed where appropriate.

[0266] Exclusion criteria: 1. Gonadotropin-independent (peripheral) precocious puberty: Gonadotropin-independent gonadal or adrenal steroid secretion. 2. Non-progressive, isolated premature breast development prior to initial GnRHa therapy 3. The presence of an unstable intracranial tumor or an intracranial tumor that may require neurosurgery or brain radiation. Participants with hamartomas who do not require surgery are eligible. 4. Evidence of kidney damage (estimated glomerular filtration rate [eGFR] <60 mL / min / 1.73 m2 as assessed by the updated Schwartz formula [CKiD U25]) or liver damage (total bilirubin >1.5 × ULN, alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3 × ULN). 5. Any other condition or chronic illness that may interfere with growth (e.g., kidney failure, diabetes, moderate to severe scoliosis, previously treated intracranial tumors). 6. Any ongoing treatments other than GnRHa therapy that may affect serum gonadotropin or sex steroid levels or may interfere with growth (e.g., long-term use of steroids [except for mild topical steroids], opioids). 7. Previous or current therapy with medroxyprogesterone acetate, growth hormone, or insulin-like growth factor-1 (IGF-1). 8. Participate in any clinical study involving investigational treatment within 4 weeks prior to enrollment or within 5 half-lives of the investigational product (whichever is longer). 9. Major medical or mental illnesses that could interfere with research visits. 10. Diagnosed with short stature, defined as being more than 2.25 standard deviations (SD) below the average height for the age group. 11. History of known seizures, epilepsy, and / or central nervous system disorders that may be associated with seizures or convulsions. 12. Previous (within 2 months of the start of study treatment) or current use of medications associated with seizures or convulsions. 13.(a) Use of other drugs known to prolong the QT interval (b) A mean QT interval (QTcF) >440 ms based on the Fridricia formula-corrected heart rate (HR), a history of congenital heart disease, arrhythmia, long QT syndrome, or symptoms suggestive of long QT syndrome (including syncope). (c) Family history of long QT syndrome or sudden cardiac death before age 50 14. Known hypersensitivity to triptorelin, leuprolide, or any excipients or related compounds in the formulation. 15. Use anticoagulants (heparin or coumarin derivatives). 16. At the researcher's discretion, any other medical condition that may exclude a participant from the clinical study due to safety concerns or adherence to clinical study procedures.

[0267] Study formulations, dosages, and routes of administration. The study formulation is in the form of a extended-release suspension for injection of biodegradable polymer microspheres of composition M, comprising 70 mg of triptorelin in the acetate form of MIGLYOL® 812, administered every 12 months (52 weeks) for a total of 24 months (104 weeks).

[0268] Participants received two intramuscular (im) injections of the study formulation, the first on day 1 of the study (i.e., visit [V]1) and the second at week 52 (V12).

[0269] Treatment duration The treatment duration (treatment period) for each participant will be approximately 104 weeks. It begins with the first injection and will continue until 52 weeks after the second injection.

[0270] Study duration For each participant, the study will last up to 120 weeks, including a 4-week screening period, a 104-week (2-year) study treatment period, and a 12-week post-treatment period.

[0271] Example 12: Early results from two clinical trial participants In the clinical trial according to Example 11, the first two participants to receive the dose were an 8.9-year-old girl (Patient A) and a 7.5-year-old girl (Patient B), both of whom had previously been treated with a 3-month formulation of commercial triptorelin.

[0272] One month (4 weeks) after the first dose of the study formulation, the serum LH levels stimulated in patients A and B were suppressed to ≤ 5 IU / L, and even to ≤ 4 IU / L.

[0273] Patients A and B belong to the PK subset, and the following time points are defined in the protocol for measuring triptorelin serum concentrations (and other parameters): 0.5, 1, 2, 4, 8, 12, 24, and 48 hours after dosing the study formulation (after dose), and 4 weeks (1 month), 8 weeks (2 months), 12 weeks, 20 weeks, 26 weeks, 36 weeks, 48 ​​weeks, and 52 weeks after dose (for part A, i.e., after the first dose of the study formulation).

[0274] For patients A and B: • Within the first 48 hours after quantitative administration, serum triptorelin levels remained below 4 ng / mL, and even below 2 ng / mL; • Initial Cmax of triptorelin was observed within 8 hours after quantitative administration.

[0275] In both patients A and B, serum triptorelin levels were at least four times the threshold of 0.0316 ng / mL one month after dose administration, and in patient A, serum triptorelin levels were at least two months after dose administration. This was associated with a 95% probability of adequate hormone suppression (stimulated serum LH ≤ 5 IU / L) and was below 4 ng / mL, and even below 2 ng / mL. Values ​​for patient B, who received dose administration several weeks later, were not available at two months.

[0276] The initial administration of the study drug was safe and well-tolerated in both patients A and B.

Claims

1. A pharmaceutical composition comprising biodegradable polymeric microspheres, said biodegradable polymeric microspheres comprising (a) triptorelin or a pharmaceutically acceptable water-soluble salt thereof, and (b) a single lactic acid polymer having a lactide content of 80% or higher, a molecular weight (Mw) of about 30,000 g / mol to about 80,000 g / mol, and a polydispersity of about 1.4 to about 2.0 as determined by gel permeation chromatography, wherein, The pharmaceutical composition provides triptorelin sustained release for at least 10 months, at least 11 months, or at least 12 months.

2. The pharmaceutical composition according to claim 1, wherein, Based on the free base of triptorelin, the biodegradable polymer microspheres have a drug loading of about 10% to about 20% (w / w), preferably about 10% to about 15% (w / w), and more preferably about 12% (w / w) of triptorelin or its pharmaceutically acceptable water-soluble salt.

3. The pharmaceutical composition according to claim 1 or 2, wherein, The triptorelin exists as triptorelin acetate.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein, The biodegradable polymer microspheres have a Dv50 of about 20 µm to about 80 µm, preferably about 40 µm to about 60 µm.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein, The lactic acid polymer has a molecular weight of about 40,000 g / mol to about 65,000 g / mol, preferably about 45,000 to about 65,000 g / mol, and a polydispersity of about 1.5 to about 1.

9.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein, The lactic acid polymer has an initial intrinsic viscosity of about 0.4 dL / g to about 0.8 dL / g, preferably about 0.55 dL / g to about 0.75 dL / g, as measured at 30°C at a concentration of 0.5 g / dL in chloroform.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein, The lactic acid polymer is polylactic acid (PLA) or poly(lactic-co-glycolic acid) (PLGA), especially PLA.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein, The pharmaceutical composition comprises triptorelin as a free base in an amount of about 40 mg to about 90 mg, preferably about 70 mg.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein, The pharmaceutical composition is a suspension comprising biodegradable polymer microspheres or a composition of dried biodegradable polymer microspheres suspended in a liquid medium, preferably wherein the suspension and / or liquid medium comprises a non-aqueous support, wherein the non-aqueous support particularly comprises an oil containing medium-chain triglycerides.

10. The pharmaceutical composition according to any one of claims 1 to 9, for use in treating a disease or ailment in which triptorelin or a pharmaceutically acceptable soluble salt form thereof has a therapeutic effect.

11. The pharmaceutical composition according to any one of claims 1 to 9, for use in treating a disease or ailment of a subject, wherein, The disease or ailment mentioned is prostate cancer, prostate cancer symptoms, central precocious puberty, endometrial stromal sarcoma, uterine fibroids, breast cancer, or endometriosis.

12. The pharmaceutical composition for use according to claim 10 or 11, wherein, The pharmaceutical composition is administered to the subject parenterally, such as by intramuscular or subcutaneous injection.

13. The pharmaceutical composition for use according to any one of claims 10 to 12, wherein, The subject had previously received treatment for the disease or ailment.

14. A method for preparing triptorelin biodegradable polymer microspheres, comprising: (a1) The organic phase is prepared by dissolving the triptorelin or a pharmaceutically acceptable soluble salt thereof, and a single lactic acid polymer or a pharmaceutically acceptable salt thereof having a lactide content of 80% or higher and an initial intrinsic viscosity of about 0.4 to about 0.8 dL / g as measured at a concentration of 0.5 g / dL in chloroform at 30°C, in one or more organic solvents at room temperature; (a2) An aqueous phase is prepared by dissolving polyvinyl alcohol and a salting-out agent in water and cooling the aqueous phase to about 2 to about 8°C to produce a cooled aqueous phase; (a3) The organic phase and the cooled aqueous phase are mixed to form the microspheres, and (a4) Filter, wash and dry the microspheres.

15. Biodegradable polymer microspheres prepared by the method according to claim 14.

16. A pharmaceutical composition comprising the biodegradable microspheres according to claim 15.

17. A reagent kit comprising: a) A pharmaceutical composition according to any one of claims 1 to 9 or 16; b) The support material optionally used for resolution, and c) A vial or syringe optionally pre-filled with the pharmaceutical composition described in a).

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