Triptorelin composition and application thereof

Abstract

Injectable triptorelin phospholipid-based phase separation gel (PPSG) pharmaceutical compositions, methods of making the same, and methods of treatment using the same are described.

Description

Technical Field

[0001] This article describes the triptorelin pharmaceutical composition and its uses. Background Technology

[0002] Triptorelin is a synthetic decapeptide agonist analog of gonadotropin-releasing hormone (GnRH) and reversibly inhibits luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Triptorelin can be used to treat hormone-responsive cancers, such as breast or prostate cancer; manage endometriosis, female infertility, and uterine fibroids; and treat precocious puberty.

[0003] Triptorelin formulations in biodegradable polymeric microparticles (containing poly-d,l-lactide-co-glycolic acid, PLGA) (reconstituted with sterile water prior to use) are approved for the treatment of prostate cancer. Verity Pharmaceuticals and central precocious puberty ( This product is used by Arbor Pharmaceuticals, LLC. U.S. Patent 10,166,181 describes an injectable pharmaceutical composition prepared using a mixture of triptorelin PLGA microparticles, wherein each type of triptorelin microparticle contains triptorelin dihydroxynaphthyl acetate in a different lactic and glycolic acid copolymer (PLGA), such as a PLGA containing about 85% lactide and 15% glycolide or a PLGA containing about 75% lactide and 25% glycolide, wherein the mixture of microparticles allegedly provides prolonged triptorelin release after injection. U.S. Patent No. 7,252,842 discloses microparticles containing a hydrophilic active agent, including triptorelin-loaded microparticles containing a PLGA containing about 85% lactide and 15% glycolide. However, the microparticles prepared according to Example 28 of U.S. Patent No. 7,252,842 have a low core loading (about 2%) and poor encapsulation efficiency (about 17%), as well as an average particle size of <20 μm.

[0004] In China, the only long-acting injectable triptorelin product for the treatment of central precocious puberty in children is a PLGA microparticle product, which must be prepared into a suspension (e.g., reconstituted) prior to use and requires a specific package consisting of two syringes, one containing the API powder (e.g., comprising triptorelin PLGA microparticles) and the other containing a diluent. In clinical use, the healthcare professional must prepare the suspension and complete the administration (injection) within one minute of suspension preparation, otherwise the PLGA microparticles will settle, resulting in inaccurate injection dose. In 2023, there were over a hundred adverse events reported in China related to the administration of injectable triptorelin microparticle products. In addition, the incidence of sterile abscess (SA) formation with PLGA microparticles can be as high as 0.6%, attributed to the formation of antibodies against the biodegradable PLGA polymer.

[0005] Injectable peptide formulations in phospholipid-based phase separation gel (PPSG) systems are described in Zhang et al., Biomaterials 45: 1-9 (2015), which reports formulations of octreotide acetate (as a model drug) with egg phosphatidylcholine (E80) phospholipid and ethanol (with or without medium-chain triglyceride oil) and tested in rats.

[0006] Accordingly, there remains a need for injectable triptorelin pharmaceutical compositions, particularly injectable triptorelin pharmaceutical compositions that can be provided in an injectable form (e.g., without the need for reconstitution prior to use). There is also a need for injectable triptorelin pharmaceutical compositions having one or more improved properties (e.g., reduced incidence of adverse events, reduced post-injection pain, and increased bioavailability of triptorelin). SUMMARY

[0007] Provided herein are triptorelin phospholipid-based phase separation gel (PPSG) pharmaceutical compositions.

[0008] Provided herein are injectable triptorelin pharmaceutical compositions, the composition comprising:

[0009] (a) triptorelin or a pharmaceutically acceptable salt thereof;

[0010] (b) a phospholipid;

[0011] (c) a pharmaceutically acceptable oil;

[0012] (d) ethanol, and

[0013] (e) a cosolvent.

[0014] According to some aspects, the triptorelin is triptorelin acetate. According to some aspects, the triptorelin is triptorelin pamoate. According to some aspects, the composition comprises about 0.1% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof.

[0015] According to any aspect, the phospholipid comprises one or more selected from the group consisting of soy phosphatidylcholine (SPC), distearoyl phosphatidyl ethanolamine (DSPE), distearoyl phosphatidyl choline (DSPC), hydrogenated soy phosphatidyl choline (HSPC), egg sphingomyelin (ESM), dimyristoyl phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), dioleoyl phosphatidyl choline (DOPC), distearoyl phosphatidyl choline (DSPC), dimyristoyl phosphatidyl glycerol (DMPG), dipalmitoyl phosphatidyl glycerol (DPPG), dioleoyl phosphatidyl glycerol (DOPG), distearoyl phosphatidyl glycerol (DSPG), dimyristoyl phosphatidyl ethanolamine (DMPE), dipalmitoyl phosphatidyl ethanolamine (DPPE) 60, dioleoyl phosphatidyl ethanolamine (DOPE), dimyristoyl phosphatidyl serine (DMPS), dipalmitoyl phosphatidyl serine (DPPS), and dioleoyl phosphatidyl serine (DOPS). According to a particular aspect, the phospholipid comprises SPC. According to a particular aspect, the composition does not comprise egg phosphatidyl choline (EPC).

[0016] According to any aspect, the pharmaceutically acceptable oil comprises one or more selected from the group consisting of pharmaceutically acceptable medium chain triglyceride oil (MCT oil) and pharmaceutically acceptable vegetable oil. According to some aspects, the pharmaceutically acceptable oil comprises MCT oil. According to some aspects, the pharmaceutically acceptable oil comprises a pharmaceutically acceptable vegetable oil selected from the group consisting of soybean oil, sesame oil, olive oil, and peanut oil. According to a particular aspect, the pharmaceutically acceptable oil comprises soybean oil.

[0017] According to any aspect, the co-solvent comprises one or more selected from the group consisting of N-methyl-2-pyrrolidone (NMP), propylene glycol (PG), dimethyl sulfoxide (DMSO). According to some aspects, the co-solvent comprises NMP. According to some aspects, the composition comprises ethanol and NMP in a mass ratio of 1 :2 to 2: 1, optionally a mass ratio of 2: 1.

[0018] According to any aspect, the composition comprises a therapeutically effective dose of triptorelin in a volume of about 0.2 mL to about 1 mL, optionally a volume of about 0.45 mL.

[0019] According to any aspect, the composition comprises about 5 mg to about 10 mg of triptorelin (based on free base) in a volume of about 0.2 mL to about 1 mL, optionally a volume of about 0.45 mL. According to some aspects, the composition comprises about 3.75 mg of triptorelin (based on free base) in a volume of about 0.45 mL.

[0020] According to any aspect, the composition comprises about 20% w / w to about 90% w / w phospholipid, based on the total weight of the composition, optionally wherein the composition comprises about 65% w / w to about 85% w / w phospholipid.

[0021] According to any aspect, the mass ratio of phospholipid to pharmaceutically acceptable oil in the composition is about 25:60 to about 83:2. According to some aspects, the mass ratio of phospholipid to pharmaceutically acceptable oil in the composition is about 70:15.

[0022] According to any aspect, the mass ratio of phospholipid to ethanol and co-solvent combination in the composition is about 25:60 to about 83:2. According to some aspects, the mass ratio of phospholipid to ethanol and co-solvent combination in the composition is about 70:15.

[0023] According to any aspect, the mass ratio of pharmaceutically acceptable oil to ethanol and co-solvent combination in the composition is about 1:10 to about 10:1. According to some aspects, the mass ratio of pharmaceutically acceptable oil to ethanol and co-solvent combination in the composition is about 1:1. According to some aspects, the mass ratio of ethanol to co-solvent in the composition is about 2:1.

[0024] According to some aspects, the composition comprises, based on the total weight of the composition:

[0025] (i) about 0.01% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof;

[0026] (ii) about 20% w / w to about 90% w / w phospholipid;

[0027] (iii) about 5% w / w to about 95% w / w pharmaceutically acceptable oil; and

[0028] (iv) about 1% w / w to about 30% w / w ethanol and co-solvent combination.

[0029] According to some aspects, the composition comprises, based on the total weight of the composition:

[0030] (i) about 0.1% w / w to about 10% w / w triptorelin acetate;

[0031] (ii) about 65% w / w to about 85% w / w soy phosphatidylcholine;

[0032] (iii) about 15% w / w to about 30% w / w MCT oil;

[0033] (iv) about 5% w / w to about 29% w / w 95% ethanol; and

[0034] (v) about 1% w / w to about 25% w / w NMP.

[0035] According to some aspects, the composition comprises, based on the total weight of the composition:

[0036] (i) about 0.1% w / w to about 10% w / w triptorelin acetate;

[0037] (ii) about 65% w / w to about 85% w / w soy lecithin;

[0038] (iii) about 15% w / w to about 30% w / w soybean oil;

[0039] (iv) about 5% w / w to about 29% w / w of 95% ethanol; and

[0040] (v) about 1% w / w to about 25% w / w NMP.

[0041] According to particular aspects, the composition comprises, based on the total weight of the composition:

[0042] (i) about 1% w / w triptorelin acetate;

[0043] (ii) about 69% w / w soy lecithin;

[0044] (iii) about 15% w / w MCT oil;

[0045] (iv) about 10% w / w of 95% ethanol; and

[0046] (v) about 5% w / w NMP.

[0047] According to particular aspects, the composition comprises, based on the total weight of the composition:

[0048] (i) about 1% w / w triptorelin acetate;

[0049] (ii) about 69% w / w soy lecithin;

[0050] (iii) about 15% w / w soybean oil;

[0051] (iv) about 10% w / w of 95% ethanol; and

[0052] (v) about 5% w / w NMP.

[0053] According to any aspect, wherein upon administration by injection, the composition forms a gel depot in situ.

[0054] In other aspects, methods of administering triptorelin to a subject in need thereof are provided, the method comprising administering to a subject in need thereof any of the compositions described herein.

[0055] In other aspects, provided are methods of treating one or more disorders selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof, the method comprising administering any of the compositions disclosed herein.

[0056] In other aspects, provided are triptorelin pharmaceutical compositions for use in treating one or more disorders selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof.

[0057] In other aspects, provided is the use of triptorelin in the manufacture of a medicament for treating one or more disorders selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof, wherein the medicament comprises any of the triptorelin pharmaceutical compositions described herein.

[0058] According to any aspect, the composition is administered by injection, optionally by intramuscular injection or subcutaneous injection.

[0059] In other aspects, provided are methods of preparing an injectable triptorelin pharmaceutical composition, the method comprising:

[0060] (a) mixing triptorelin or a pharmaceutically acceptable salt thereof with ethanol and a cosolvent to obtain a solution of triptorelin;

[0061] (b) adding a phospholipid to the solution obtained in step (a) and mixing to obtain a solution of triptorelin and phospholipid; and

[0062] (c) adding a pharmaceutically acceptable oil to the solution obtained in step (b) and mixing to obtain a homogenous solution.

[0063] According to any aspect, the method further comprises sterilizing the homogenous solution obtained in step (c). According to a particular aspect, the sterilizing comprises filter sterilization. BRIEF DESCRIPTION OF DRAWINGS

[0064] Figure 1 Normalized triptorelin content of triptorelin formulations over three months at accelerated storage conditions (25°C ± 2°C / 60% ± 5% RH) is shown.

[0065] Figure 2 Injectability of tested triptorelin compositions formulated with different phospholipids is demonstrated.

[0066] Figure 3AProvided are plots of testosterone plasma concentration (ng / ml) versus time following administration of triptorelin compositions prepared from different phospholipids to rats compared to a reference triptorelin formulation.

[0067] Figure 3B Provided are plots of testosterone plasma concentration (ng / ml) versus time following administration of triptorelin compositions prepared from different phospholipids to rats compared to a reference triptorelin formulation.

[0068] Figure 4A Provided are plots of testosterone plasma concentration (ng / ml) versus time following administration of triptorelin compositions prepared from different pharmaceutically acceptable oils and cosolvents to rats compared to a reference triptorelin formulation.

[0069] Figure 4B Provided are plots of testosterone plasma concentration (ng / ml) versus time following administration of triptorelin compositions described herein prepared from different pharmaceutically acceptable oils and cosolvents to rats compared to a reference triptorelin formulation.

[0070] Figure 5A Relative pain threshold following injection of rats with a reference triptorelin formulation is reported.

[0071] Figure 5B Relative pain threshold following injection of rats with a triptorelin composition formulated with MCT is reported.

[0072] Figure 5C Relative pain threshold following injection of rats with a triptorelin composition formulated with MCT and NMP is reported.

[0073] Figure 5D Relative pain threshold following injection of rats with a triptorelin composition formulated with MCT and PG is reported.

[0074] Figure 5E Relative pain threshold following injection of rats with a triptorelin composition formulated with MCT and DMSO is reported. DETAILED DESCRIPTION

[0075] The present disclosure provides triptorelin pharmaceutical compositions that can be provided in an injectable form (e.g., a liquid form that does not require reconstitution prior to use). These compositions are generally referred to as triptorelin phospholipid-based phase separation gel (PPSG) pharmaceutical compositions, and are more conveniently referred to herein as “triptorelin PPSG compositions” or simply “compositions.” The triptorelin PPSG compositions described herein can be formulated to be suitable for administration by injection, e.g., subcutaneous injection or intramuscular injection. The triptorelin PPSG compositions described herein can exhibit one or more advantageous properties relative to available triptorelin PLGA microparticle products, such as easier to manufacture, easier to administer, associated with reduced incidence of adverse reactions and / or reduced post-injection pain, higher bioavailability of triptorelin, and / or delivery of a greater dose of triptorelin. The triptorelin PPSG compositions described herein can be used in methods of treatment, e.g., methods of treating one or more conditions such as a hormone-responsive cancer (e.g., breast cancer or prostate cancer), endometriosis, female infertility, uterine fibroids, or precocious puberty.

[0076] Definitions

[0077] Unless otherwise defined, the technical and scientific terms used herein have the meanings that are commonly understood by one of ordinary skill in the art to which this application belongs. Any suitable materials and / or methods known to those of ordinary skill in the art can be used in the practice of the application, as provided herein; however, particular materials and methods are described for purposes of illustration. Materials, reagents and the like to which reference are made in the following description and examples are obtainable from commercial sources, unless otherwise mentioned.

[0078] As used herein, the singular forms “a,” “an,” and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0079] As used herein, the term “about” when used in reference to a numerical value means that number and plus or minus 10% of that number. For example, “about 10” is to be understood as both “10” and “9-11.”

[0080] As used herein, the phrase in the alternative or in the form of A / B or in the form of A and / or B means (A), (B), or (A and B); the phrase at least one of A, B and C means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0081] As used herein, the terms“comprising,”“including,” and“containing” are used broadly and encompass both the stated components and additional components, as well as embodiments that do not claim the stated components. The phrase“consisting essentially of’ is used to include those elements specifically recited and additional elements that do not materially affect the essential and novel characteristics of the claimed invention, e.g., ingredients that do not materially affect the stability or bioavailability of triptorelin in a composition.

[0082] As used herein,“subject” and“patient” are used interchangeably and refer to any mammal, including humans. In the context of the present disclosure, the subject is typically a mammal, particularly a human, e.g., an adult human undergoing treatment for a hormone-responsive cancer, e.g., breast cancer or prostate cancer, a female undergoing treatment for endometriosis, uterine fibroids, or female infertility, or a child undergoing treatment for precocious puberty.

[0083] As used herein, the terms“administer,”“administration,” and“administering” refer to, e.g., providing, giving, dosing, and / or prescribing, e.g., by a health care professional or an authorized agent or under the direction of a health care professional, as well as, e.g., by a health care professional or a subject, to take or inject.

[0084] As used herein, the terms“treat,”“treating,” and“treatment” generally refer to any therapeutic or prophylactic regimen to which triptorelin can be applied, regardless of whether the treatment is considered“successful.”

[0085] As used herein, the phrases“therapeutically effective amount” and“therapeutically effective dose” refer to an amount or dose of a drug that provides a specified pharmacological effect when administered to a subject in need of such treatment. It is emphasized that a therapeutically effective amount is not always effective in treating the target condition or achieving the intended effect or outcome, even though a person of skill in the art considers such an amount or dose to be therapeutically effective. Exemplary doses and therapeutically effective amounts are provided below with reference to adult subjects for convenience. Such amounts can be adjusted by a person of skill in the art according to standard practices required to treat a particular subject and / or condition / disease.

[0086] The disclosure of particular compounds under a particular class (e.g.,“antioxidants,”“antimicrobial agents,” etc.) is not necessarily limiting. A person of skill in the art will appreciate that a given compound can exhibit more than one function or can exhibit different functions depending on the composition in which the compound is used.

[0087] Triptorelin

[0088] Triptorelin is a decapeptide having the following formula: pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2. The systematic (IUPAC) name is L-pyroglutamoyl-L-histidyl-L-tryptophyl-L- serinyl-L-tyrosyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolyl-glycinamide or [D- Trp6]GnRH. Triptorelin has a molecular formula of C 64 H 82 N 18 O 13 and a molecular weight of 1311.5 g / mol. It is registered with CAS Registry Number 57773-63-4. As used herein, “triptorelin” refers to the triptorelin decapeptide and pharmaceutically acceptable salts thereof, including water-soluble salts thereof, such as triptorelin acetate.

[0089] Triptorelin is an agonist analog of gonadotropin-releasing hormone (GnRH) and reversibly suppresses luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Triptorelin can be used to treat hormone-responsive cancers, such as breast or prostate cancer; manage endometriosis, female infertility, and uterine fibroids; and treat precocious puberty.

[0090] Triptorelin PPSG Pharmaceutical Compositions

[0091] The pharmaceutical compositions described herein comprise triptorelin or a pharmaceutically acceptable salt thereof formulated in a phospholipid-based phase separation gel (PPSG) composition. The PPSG composition is an injectable composition that readily forms a gel depot in situ after injection. In particular embodiments, the triptorelin PPSG compositions as described herein comprise triptorelin or a pharmaceutically acceptable salt thereof, a phospholipid, a pharmaceutically acceptable oil, ethanol, and a cosolvent. Without being bound by theory, it is believed that upon administration in a liquid form (e.g., by injection), the PPSG composition undergoes phase separation, forming a solid or semi-solid gel (e.g., a depot) in the body at or near the injection site due to an in situ water-ethanol / cosolvent exchange between the surrounding body tissue and the PPSG composition. As the gel depot degrades, triptorelin is released from the depot for systemic delivery.

[0092] As described above, the compositions described herein comprise triptorelin or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions described herein comprise triptorelin acetate. In some embodiments, the compositions described herein comprise triptorelin pamoate.

[0093] As also described above, the compositions described herein include a phospholipid. Suitable phospholipids include natural and synthetic phospholipids, including glycerophospholipids and sphingomyelins. Non-limiting examples of suitable phospholipids include one or more of: soy phosphatidylcholine (SPC), distearoylphosphatidyl ethanolamine (DSPE), distearoylphosphatidylcholine (DSPC), hydrogenated soy phosphatidylcholine (HSPC), egg sphingomyelin (ESM), dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylglycerol (DOPG), distearoylphosphatidylglycerol (DSPG), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE)60, dioleoylphosphatidylethanolamine (DOPE), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), and dioleoylphosphatidylserine (DOPS). In particular embodiments, the phospholipid includes SPC.

[0094] In particular embodiments, the phospholipid is or includes soy phosphatidylcholine (SPC). In further particular embodiments, the phospholipid is or includes soy phosphatidylcholine having a phosphatidylcholine content greater than or equal to 94.0%, such as SPC S100 phospholipid product.

[0095] In particular embodiments, the compositions described herein do not include egg phosphatidylcholine (EPC). For example, in particular embodiments, the compositions described herein do not include a phospholipid consisting of 80% egg phosphatidylcholine, such as E 80. As shown in the examples, triptorelin compositions as described herein formulated with soy phosphatidylcholine (e.g., SPC S100 and SPC S75) exhibited higher stability than triptorelin compositions formulated with egg phosphatidylcholine (e.g., E 80).

[0096] As also described above, the compositions described herein include a pharmaceutically acceptable oil. The pharmaceutically acceptable oil can include one or more selected from pharmaceutically acceptable medium-chain triglyceride oil (“MCT oil”) and pharmaceutically acceptable vegetable oil.

[0097] In some embodiments, the oil is or includes MCT oil. As described in the United States Pharmacopeia (“USP”) and the European Pharmacopoeia (“Ph. Eur.”), “MCT” refers to a mixture of triglycerides of saturated fatty acids, primarily caprylic acid (C8H 16 O2) and capric acid (C 10 H 20MCT oil, USP / Ph. Eur. grade, contains not less than 95% saturated fatty acids having 8 and 10 carbon atoms, a specific gravity of 0.93-0.96 at 20 °C, and a viscosity of 25-33 cP at 20 °C. Thus, in some embodiments, the MCT oil used in the compositions described herein contains not less than 95% saturated fatty acids having 8 and 10 carbon atoms, and optionally has a specific gravity of 0.93-0.96 at 20 °C, and further optionally has a viscosity of 25-33 cP at 20 °C (or a viscosity of about 25-35 cP at 20 °C, as discussed in more detail below).

[0098] In some embodiments, the oil is or includes a vegetable oil. In some embodiments, the vegetable oil comprises long chain fatty acids (e.g., having 13-21 carbon atoms), such as sesame oil, soybean oil, peanut oil, olive oil, or castor oil. In some embodiments, the oil is or includes soybean oil (e.g., pharmaceutical grade soybean oil).

[0099] As described above, the triptorelin compositions described herein comprise ethanol (e.g., 95% ethanol) and a cosolvent. The cosolvent can include one or more selected from N-methyl-2-pyrrolidone (NMP), propylene glycol (PG), dimethyl sulfoxide (DMSO). In particular embodiments, the cosolvent includes NMP. In some embodiments, the composition comprises ethanol (e.g., 95% ethanol) and N-methyl-2-pyrrolidone (NMP) in a mass ratio of about 1:2 to about 2:1. In some embodiments, the composition comprises ethanol (e.g., 95% ethanol) and N-methyl-2-pyrrolidone (NMP) in a mass ratio of about 2:1. As shown in the examples, compositions formulated with 95% ethanol and NMP exhibit faster triptorelin dissolution rates, improved composition stability, and reduced post-injection pain compared to compositions formulated with 95% ethanol as the only cosolvent.

[0100] In particular embodiments, the mass ratio of phospholipid (e.g., soybean phosphatidylcholine) to oil (e.g., MCT oil or soybean oil) in the compositions described herein can be about 25:60 to about 83:2, such as about 45:55 to about 85:15. In further particular embodiments, the mass ratio of phospholipid to oil is about 55:30, or about 70:15. In further particular embodiments, the mass ratio of phospholipid to oil is about 70:15.

[0101] Additionally or alternatively, in particular embodiments, the mass ratio of phospholipid to ethanol and cosolvent in combination in the compositions described herein can be about 25:60 to about 83:2, for example about 45:55 to about 85: 15. In some embodiments, the mass ratio of phospholipid to ethanol (e.g., 95% ethanol) and cosolvent in combination is about 70: 15, optionally wherein the mass ratio of ethanol (e.g., 95% ethanol) to cosolvent is about 2: 1.

[0102] Additionally or alternatively, in particular embodiments, the mass ratio of oil to ethanol and cosolvent in combination in the compositions described herein can be about 1:10 to about 10: 1, for example about 1:5 to about 5: 1. In some embodiments, the mass ratio of oil to ethanol (e.g., 95% ethanol) and cosolvent in combination is about 1: 1, optionally wherein the mass ratio of ethanol (e.g., 95% ethanol) to cosolvent is about 2: 1.

[0103] In some embodiments, the compositions described herein comprise a therapeutically effective amount of triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate) in a volume suitable for administration by injection (e.g., by subcutaneous injection or intramuscular injection). In some embodiments, the compositions described herein can have a higher drug loading of triptorelin than available triptorelin PLGA microparticle formulations, allowing for a reduction in injection volume, increased patient comfort, and reduced post-injection pain. For example, the triptorelin PPSG compositions described herein can be formulated with triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate) at a concentration of about 10 mg / mL. This enables a therapeutically effective amount to be dosed in a relatively small volume.

[0104] In some embodiments, the compositions described herein comprise a therapeutically effective amount of triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate) in a volume of about 1 mL or less, including about 0.5 mL or less, about 0.4 mL or less, or about 0.2 mL or less. In particular embodiments, the compositions described herein comprise a therapeutically effective amount of triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate) in a volume of about 0.4 mL, for example a volume of 0.4 mL. Thus, in particular embodiments, the compositions described herein comprise about 5 mg to about 20 mg of triptorelin (on a free base basis) in a volume of about 0.2 mL to about 1 mL, for example about 10 mg of triptorelin acetate in a volume of about 1 mL. In particular embodiments, the compositions described herein can comprise about 3.75 mg of triptorelin (on a free base basis) in a volume of about 0.45 mL, including 3.75 mg of triptorelin (on a free base basis) in a volume of 0.45 mL.

[0105] The compositions described herein can comprise about 0.01% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate), including about 0.1% w / w to about 5% w / w, based on the total weight of the composition. In particular embodiments, the compositions can comprise about 1% w / w triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate), including 1% w / w triptorelin or a pharmaceutically acceptable salt thereof (e.g., triptorelin acetate), based on the total weight of the composition.

[0106] The compositions described herein can comprise about 20% w / w to about 90% w / w phospholipid, including about 65% w / w to about 85% w / w phospholipid, e.g., soy phosphatidylcholine, e.g., SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 69% w / w phospholipid, e.g., about 69% w / w soy phosphatidylcholine, including 60% w / w soy phosphatidylcholine, e.g., about 69% w / w SPC S100, including 69% w / w SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 70% w / w phospholipid, e.g., about 70% w / w soy phosphatidylcholine, including 70% w / w soy phosphatidylcholine, e.g., about 70% w / w SPC S100, including 70% w / w SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 75% w / w phospholipid, e.g., about 75% w / w soy phosphatidylcholine, including 75% w / w soy phosphatidylcholine, e.g., about 75% w / w SPC S100, including 75% w / w SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 80% w / w phospholipid, e.g., about 80% w / w soy phosphatidylcholine, including 80% w / w soy phosphatidylcholine, e.g., about 80% w / w SPC S100, including 80% w / w SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 83% w / w phospholipid, e.g., about 83% w / w soy phosphatidylcholine, including 83% w / w soy phosphatidylcholine, e.g., about 83% w / w SPC S100, including 83% w / w SPC S100, based on the total weight of the composition. In particular embodiments, the compositions as described herein can comprise about 85% w / w phospholipid, e.g., about 85% w / w soy phosphatidylcholine, including 85% w / w soy phosphatidylcholine, e.g., about 85% w / w SPC S100, including 85% w / w SPC S100, based on the total weight of the composition.

[0107] The compositions described herein can comprise about 5% w / w to about 95% w / w of a pharmaceutically acceptable oil (e.g., MCT oil and / or a vegetable oil, such as soybean oil), for example, about 15% w / w to about 30% w / w of a pharmaceutically acceptable oil, based on the total weight of the composition.

[0108] The triptorelin compositions described herein can comprise about 1% w / w to about 30% w / w of ethanol (e.g., 95% ethanol) and a cosolvent combination, for example, about 5% w / w to about 15% w / w of ethanol and a cosolvent combination, based on the total weight of the composition, optionally wherein the mass ratio of ethanol (e.g., 95% ethanol) to cosolvent is about 2: 1.

[0109] In some embodiments, the compositions as described herein comprise:

[0110] (i) about 0.01% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof;

[0111] (ii) about 20% w / w to about 90% w / w phospholipid;

[0112] (iii) about 5% w / w to about 95% w / w pharmaceutically acceptable oil; and

[0113] (iv) about 5% w / w to about 30% w / w of a combination of ethanol and a cosolvent, each based on the total weight of the composition.

[0114] In some embodiments, the compositions as described herein comprise, based on the total weight of the composition:

[0115] (i) about 0.1% w / w to about 5% w / w triptorelin acetate;

[0116] (ii) about 65% w / w to about 85% w / w soy phosphatidylcholine;

[0117] (iii) about 15% w / w to about 30% w / w MCT oil;

[0118] (iv) about 5% w / w to about 29% w / w 95% ethanol; and

[0119] (v) about 1% w / w to about 25% w / w NMP.

[0120] In some embodiments, the compositions as described herein comprise, based on the total weight of the composition:

[0121] (i) about 0.1% w / w to about 5% w / w triptorelin acetate;

[0122] (ii) about 65% w / w to about 85% w / w soy phosphatidylcholine;

[0123] (iii) about 15% w / w to about 30% w / w MCT oil;

[0124] (iv) about 5% w / w to about 29% w / w 95% ethanol; and

[0125] (v) about 1% w / w to about 25% w / w NMP.

[0126] In some embodiments, a composition as described herein comprises, based on the total weight of the composition:

[0127] (i) about 1% w / w triptorelin acetate;

[0128] (ii) about 69% w / w soy phosphatidylcholine;

[0129] (iii) about 15% w / w MCT oil;

[0130] (iv) about 10% w / w 95% ethanol; and

[0131] (v) about 5% w / w NMP.

[0132] In some embodiments, a composition as described herein comprises, based on the total weight of the composition:

[0133] (i) about 1% w / w triptorelin acetate;

[0134] (ii) about 69% w / w soy phosphatidylcholine;

[0135] (iii) about 15% w / w soy oil;

[0136] (iv) about 10% w / w 95% ethanol; and

[0137] (v) about 5% w / w NMP.

[0138] Other Optional Components

[0139] In any embodiment, a triptorelin PPSG pharmaceutical composition as described herein optionally can comprise one or more additional pharmaceutically acceptable ingredients, such as one or more antioxidants, antimicrobials, emulsifiers, solvents, and the like.

[0140] In some embodiments of any of the embodiments disclosed herein, the triptorelin PPSG composition does not comprise diacylglycerol (DAG), e.g., is not formulated with diacylglycerol.

[0141] Ready-to-Use Compositions

[0142] As described above, the triptorelin PPSG pharmaceutical compositions described herein can be formulated as an injectable composition and provided in a ready-to-use form. As used herein, a ready-to-use form can include a triptorelin PPSG pharmaceutical composition as described herein formulated for administration by intramuscular injection and / or subcutaneous injection. In some embodiments, the injectable triptorelin PPSG pharmaceutical compositions as described herein are provided in a ready-to-use form in a pre-filled syringe, e.g., a pre-filled syringe suitable for intramuscular injection or a pre-filled syringe suitable for subcutaneous injection. In other embodiments, the pharmaceutical compositions are provided in a ready-to-use form in a vial.

[0143] In particular embodiments, the injectable triptorelin PPSG pharmaceutical compositions as described herein are provided in a ready-to-use form in a pre-filled syringe with a fine needle (e.g., for improved patient comfort) and do not require any reconstitution or mixing prior to administration. The ability to administer a therapeutically effective dose of triptorelin in a relatively small injection volume and / or via a fine injection needle brings benefits to the patient, e.g., reduced pain at the injection site, and improved convenience and compliance of use.

[0144] Preparation methods

[0145] The compositions described herein can be prepared by any suitable method. The compositions described herein can be prepared by a simple and economical method compared to the methods required to prepare PLGA microparticle formulations. For example, triptorelin or a pharmaceutically acceptable salt thereof can be mixed with ethanol and a cosolvent until the triptorelin or pharmaceutically acceptable salt thereof dissolves. Then, a phospholipid can be added and mixed (e.g., by stirring) until the phospholipid dissolves. Thereafter, a pharmaceutically acceptable oil can be added and mixed (e.g., by stirring) until a uniform solution is obtained. While not necessarily limiting, it was found that the order of adding the components described above facilitated dissolution of the active agent and obtaining a uniform solution.

[0146] The compositions described herein (e.g., prepared as described above) can be sterilized, e.g., by filtration sterilization. For example, the compositions can be sterilized by filtration sterilization using a membrane filter (e.g., made of cellulose ester, polyvinylidene fluoride (PVDF), polytetrafluoroethylene (PTFE), polyethersulfone (PES), or nylon) having a pore size suitable for sterilization (e.g., 2 microns) under suitable conditions (e.g., room temperature and / or atmospheric pressure).

[0147] These preparation methods provide a high level of sterility assurance and are much simpler than the methods required to prepare commercially available injectable triptorelin microparticle formulations (e.g., PLGA microparticle formulations), thereby significantly reducing production costs and saving related economic costs.

[0148] Example compositions

[0149] The following is disclosed as particular illustrative embodiments of compositions as described herein.

[0150] The compositions described in the following table were prepared using the components shown in the following table.

[0151]

[0152] The above compositions can be prepared by mixing triptorelin acetate with ethanol and NMP with stirring until the triptorelin acetate is dissolved; adding the phospholipid and stirring until the phospholipid is dissolved; and adding the pharmaceutically acceptable oil with stirring until a homogeneous solution is obtained. The obtained compositions can be sterilized by filtration sterilization.

[0153] Methods of treatment / uses

[0154] The present disclosure also provides uses of the triptorelin PPSG pharmaceutical compositions described herein in methods of treatment, including administering a triptorelin PPSG pharmaceutical composition as described herein to a subject in need thereof.

[0155] The uses and treatments described herein can include administering a triptorelin pharmaceutical composition as described herein to a subject who can have and / or need treatment for one or more conditions selected from a hormone-responsive cancer (such as breast cancer or prostate cancer), endometriosis, female infertility, uterine fibroids, or precocious puberty. In particular embodiments, the subject treated with a triptorelin pharmaceutical composition as disclosed herein has hormone-sensitive prostate cancer or hormone-sensitive breast cancer. In particular embodiments, the subject treated with a triptorelin pharmaceutical composition as disclosed herein has endometriosis, female infertility, or uterine fibroids. In particular embodiments, the subject treated with a triptorelin pharmaceutical composition as disclosed herein has precocious puberty.

[0156] The compositions can be administered by injection, for example by intramuscular injection or subcutaneous injection. In some embodiments, a therapeutically effective dose is administered in a single injection (e.g., a single intramuscular injection or a single subcutaneous injection). In other embodiments, the dose is administered in divided doses (e.g., in two or more divided doses, such as two or more divided doses administered by intramuscular injection or subcutaneous injection).

[0157] The compositions can be administered in any therapeutically effective dose by any suitable dosing regimen (e.g., once daily, once weekly, once every two weeks, once every three weeks, once every four weeks, etc.). In particular embodiments, the compositions are administered once every four weeks. In further particular embodiments, the compositions are administered once every four weeks in a therapeutically effective dose contained in a volume of about 0.45 mL. In further particular embodiments, the compositions are administered once every four weeks in a therapeutically effective dose contained in about 3.75 mg. In further particular embodiments, the compositions are administered once every four weeks in a therapeutically effective dose contained in about 3.75 mg in a volume of about 0.45 mL.

[0158] As described above, the triptorelin PPSG pharmaceutical compositions described herein can form a phospholipid-based phase separation gel (PPSG) in situ as a depot. For example, upon injection into the body, the composition can gradually semi-solidify via exchange of ethanol in the composition with body fluids, forming a gel that can adhere to tissue and degrade slowly in the body, releasing triptorelin from the depot formed at or near the injection site.

[0159] Preclinical studies of the PPSG compositions described herein indicate that they have at least similar or significantly higher bioavailability of triptorelin than a commercially available injectable triptorelin microparticle formulation (PLGA microparticle formulation). As reported in the examples below, the depot formed by the triptorelin PPSG pharmaceutical compositions described herein can degrade in the body faster than the currently available injectable triptorelin PLGA microparticle formulation, but still maintain effective plasma drug levels for at least 28 days and testosterone concentrations below castration levels. Without being bound by theory, this can be because the phospholipid component in the PPSG compositions degrades faster than the polymer used in the microparticle formulation (e.g., PGLA polymer). Thus, at the end of the target period (e.g., about 30 days, including about 28 days), the depot formed subcutaneously after injection of a triptorelin PPSG pharmaceutical composition as described herein can degrade more completely than the depot formed after injection of the available microparticle formulation (e.g., PLGA microparticle formulation), which reflects more complete release of triptorelin from the depot at the end of the target period. The compositions described herein also have a reduced incidence of adverse reactions compared to the available microparticle formulation (e.g., PLGA microparticle formulation). Without being bound by theory, it is believed that the components of the compositions (e.g., the phospholipid component) have better biocompatibility than the components used in the PLGA microparticle formulation.

[0160] Overall, the triptorelin PPSG pharmaceutical compositions described herein exhibit good expected stability characteristics and desirable pK / pD profiles, and are associated with reduced post-injection pain.

[0161] Examples

[0162] The following specific examples are included as illustrative examples of the compositions described herein. These examples are in no way intended to limit the scope of the present disclosure. Other aspects of the present disclosure will be apparent to those skilled in the art.

[0163] Example 1: Stability Study

[0164] The stability of triptorelin in PPSG compositions formulated with either egg phosphatidylcholine (E 80) or soy phosphatidylcholine (S100 or S 75) phospholipids was evaluated over a 3-month period under accelerated storage conditions (25°C ± 2°C / 60% ± 5% RH). The non-triptorelin components of the formulations tested are listed in the table below:

[0165] Formulation Phospholipid MCT oil 95% ethanol S100 70:15 13.95g 2.99g 2.93g S100 55:30 10.98g 6.04g 2.94g E80 70:15 13.93g 2.96g 2.96g E80 55:30 11.01g 5.95g 2.94g S75 70:15 13.9g 2.96g 2.96g S75 55:30 11.03g 6.01 3.01

[0166] The triptorelin concentration in each formulation was about 1% w / w.

[0167] Figure 1 The normalized triptorelin content of the triptorelin formulation compositions tested over time is shown. The order of stability based on phospholipid was SPC S100 > SPC S 75 > E 80 in terms of triptorelin content as an evaluation metric. In particular, the S100 70: 15 formulation appeared to have the highest stability as evaluated in this study. In contrast, the formulation prepared with E 80 (egg phosphatidylcholine) exhibited the poorest stability.

[0168] The stability of triptorelin PPSG compositions formulated with different pharmaceutically acceptable oils and different cosolvents was evaluated over a 3-month period under accelerated storage conditions (25°C ± 2°C / 60% ± 5% RH). Impurities were evaluated by HPLC analysis based on relative retention time (RRT) compared to triptorelin. The non-triptorelin components of the formulations tested are listed in the table below:

[0169] Formulation Phospholipid Oil 95% ethanol Co-solvent Soybean oil + PG 13.98g 3.01g 2.00g 0.99 g PG Soybean oil + NMP 13.98g 3.02g 1.99g 1.01 g NMP Soybean oil + DMSO 13.98g 3.02g 2.01g 1.01 g DMSO Soybean oil 13.96g 3.03g 3.01 -- MCT oil + PG 16.54g 9.00g 1.49g 3.00 g PG MCT oil + NMP 16.49g 9.16g 1.62g 3.15 NMP MCT oil + DMSO 16.52g 9.00g 1.49g 3.31 g DMSO

[0170] PG: propylene glycol; NMP: N-methyl-2-pyrrolidone; DMSO: dimethyl sulfoxide. The triptorelin concentration in each formulation was about 1% w / w.

[0171] The results are shown in the table below. As shown by the data reported in the table, the formulations prepared with either soybean oil or MCT oil as the pharmaceutically acceptable oil and NMP as the cosolvent exhibited the highest stability, as reflected by the lowest total impurity content. That is, the data suggest that the addition of NMP is associated with a reduction in impurity formation.

[0172]

[0173] Example 2: In vitro injectability study

[0174] Injectability of triptorelin PPSG compositions formulated with either egg phosphatidylcholine (E 80) or soy phosphatidylcholine (S100) phospholipids was evaluated in vitro. A software-controlled texture analyzer was used to measure injection force in compression mode. The syringe was placed in the force gauge holder with the needle facing down. The trigger force was 5.0 g. The test was run at a test speed of 1 mm / sec, which is representative of the speed at which a manual syringe is delivered to a patient. The load force (g) required to move the plunger was measured as a function of plunger displacement (mm). An injection force greater than 1200 g was considered difficult to inject.

[0175] The non-triptorelin components of the formulations tested are listed in the table below:

[0176] Formulation Phospholipid MCT 95% ethanol 70％S100 7.0g 1.5g 1.5g 55％S100 5.5g 3.0g 1.5g 70％E80 7.0g 1.5g 1.5g 55％E80 5.5g 3.0g 1.5g

[0177] The triptorelin concentration in the formulations was about 1% w / w.

[0178] Figure 2 Injectability results are shown. As shown in the figure, the formulations prepared with S100 were easier to inject than formulations prepared with the same amount of E 80.

[0179] Example 3: Rat pharmacokinetic and pharmacodynamic studies

[0180] The in vivo pharmacokinetics (pK) and pharmacodynamics (pD) of triptorelin PPSG pharmaceutical compositions formulated without cosolvent were evaluated in male rats. The study included eight groups, each receiving one of the formulations listed below.

[0181] The non-triptorelin components of the eight formulations tested (one for each study group) are listed in the table below:

[0182]

[0183] The triptorelin concentration in each formulation was about 1% w / w.

[0184] Dosing: Each rat was administered a quantity of the composition providing 1 mg of triptorelin subcutaneously, except for the 70% S100+MCT half-dose group. For the 70% S100+MCT half-dose group, a quantity of the composition providing 0.5 mg of triptorelin was administered.

[0185] Figure 3A Plasma concentrations of triptorelin (ng / ml) versus time are shown for the results, Figure 3B Plasma concentrations of testosterone (ng / ml) versus time are shown for the results. As Figure 3AThe pharmacokinetic profiles of the triptorelin for the formulations prepared with S100 and E 80 were similar, but the AUC was higher for the formulation prepared with S100 (1710 vs 1500 ng*h / mL). As shown, the formulation prepared with 70% phospholipid (about 69% w / w based on the entire composition) exhibited the target duration of release of about 28 days. Based on these results, the formulation prepared with 70% S100 phospholipid (about 69% w / w based on the entire composition) was selected for further study. As shown in Figure 3B The formulations prepared with S100 and E 80 achieved similar reductions in testosterone levels. In this study, all of the PPSG formulations exhibited higher bioavailability than the reference microgranule formulation.

[0186] The following table provides the basis data for Figure 3A

[0187]

[0188]

[0189] "Mean" is measured in ng / mL.

[0190] Figure 3B The basis data for

[0191]

[0192]

[0193] The in vivo pharmacokinetics (pK) and pharmacodynamics (pD) of triptorelin PPSG pharmaceutical compositions formulated with different cosolvents were evaluated in male rats. The study included nine groups, each receiving one of the formulations listed below.

[0194] The non-triptorelin components of the nine formulations tested (one for each study group) are listed in the following table:

[0195]

[0196] The concentration of triptorelin in each formulation was about 1% w / w.

[0197] Dosing: For all groups, each rat was administered a quantity of the composition providing 1 mg of triptorelin subcutaneously.

[0198] Figure 4A The resulting triptorelin plasma concentration (ng / ml) versus time curves are shown, while Figure 4B ​The resulting testosterone plasma concentration (ng / ml) versus time curves are shown. As shown, the co-solvents did not have a significant effect on the pharmacokinetic profile of triptorelin or the resulting testosterone levels, i.e., the PK / PD behavior was similar in the different co-solvents tested. In this study, the bioavailability of the PPSG formulation was approximately the same as the bioavailability of the reference microparticle formulation. Figure 3A-3B Summary of reported studies Figure 4A-4B The difference in the relative bioavailability results shown in the reported studies can be due to the fact that the observed bioavailability fluctuations were greater for the reference microparticle formulation, particularly compared to the observed bioavailability fluctuations for the PPSG formulation (which were smaller) (e.g., the same PPSG formulation produced similar pK curves in the two studies).

[0199] The following table provides the underlying data for Figure 4A Example 1.

[0200]

[0201]

[0202] The "mean" is measured in ng / mL.

[0203] The following table provides the underlying data for Figure 4B Example 2.

[0204]

[0205]

[0206] The "mean" is measured in ng / mL.

[0207] Example 4: In vivo pain assessment study in rats

[0208] An in vivo pain assessment was performed in male rats with triptorelin PPSG pharmaceutical compositions formulated with or without different co-solvents. Prior to administration of the PPSG compositions, rats with similar pain thresholds were sought and divided into groups of 6 rats each by a pinprick test. The PPSG compositions were injected subcutaneously into the back of the rats and the pain threshold was measured prior to injection and 1 minute, 1 hour and 24 hours after injection. The relative pain threshold was assessed as the post-injection pain threshold / pre-injection pain threshold; the coefficient of variation (CV) was calculated as 100% x SD / mean.

[0209] An increase in relative pain threshold post-injection indicates the presence of a numbing effect, which can be due to physical shielding after injection and / or the numbing effect of ethanol. Neither numbing nor pain is desirable; thus, an ideal relative pain threshold post-injection is 1.0. The coefficient of variation represents the deviation from the ideal relative pain threshold post-injection, where a greater value indicates a greater degree of deviation. Thus, a lower coefficient of variation indicates a good result for the assessment.

[0210] The non-triptorelin components of the formulations tested and the coefficient of variation of the relative pain threshold post-injection for each formulation are listed in the table below:

[0211]

[0212] The concentration of triptorelin in each formulation was about 1% w / w.

[0213] Figure 5A The relative pain threshold post-injection is shown for the reference microparticle formulation, while Figure 5B-5E The relative pain threshold post-injection is shown for triptorelin PPSG compositions formulated with MCT, MCT + NMP, MCT + PG, or MCT + DMSO, respectively. As reported in the table above, the PPSG formulation prepared with NMP as a cosolvent had the lowest coefficient of variation, indicating the least pain at the injection site.

Claims

1. An injectable triptorelin pharmaceutical composition, the composition comprising: (a) triptorelin or a pharmaceutically acceptable salt thereof; (b) a phospholipid; (c) a pharmaceutically acceptable oil; (d) ethanol, and (e) a co-solvent.

2. The composition of claim 1, wherein the triptorelin is triptorelin acetate.

3. The composition of claim 1, wherein the composition comprises about 0.1% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof.

4. The composition of any one of the preceding claims, wherein the phospholipid comprises one or more selected from the group consisting of: soy phosphatidylcholine (SPC), distearoyl phosphatidyl ethanolamine (DSPE), distearoyl phosphatidyl choline (DSPC), hydrogenated soy phosphatidyl choline (HSPC), egg sphingomyelin (ESM), dimyristoyl phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), dioleoyl phosphatidyl choline (DOPC), distearoyl phosphatidyl choline (DSPC), dimyristoyl phosphatidyl glycerol (DMPG), dipalmitoyl phosphatidyl glycerol (DPPG), dioleoyl phosphatidyl glycerol (DOPG), distearoyl phosphatidyl glycerol (DSPG), dimyristoyl phosphatidyl ethanolamine (DMPE), dipalmitoyl phosphatidyl ethanolamine (DPPE) 60, dioleoyl phosphatidyl ethanolamine (DOPE), dimyristoyl phosphatidyl serine (DMPS), dipalmitoyl phosphatidyl serine (DPPS), and dioleoyl phosphatidyl serine (DOPS).

5. The composition of any one of the preceding claims, wherein the phospholipid comprises SPC.

6. The composition of any one of the preceding claims, wherein the composition does not comprise egg phosphatidyl choline (EPC).

7. The composition of any one of the preceding claims, wherein the pharmaceutically acceptable oil comprises one or more selected from the group consisting of pharmaceutically acceptable medium chain triglyceride oil (MCT oil) and pharmaceutically acceptable vegetable oil.

8. The composition of claim 7, wherein the pharmaceutically acceptable oil comprises MCT oil.

9. The composition of any one of claims 7-8, wherein the pharmaceutically acceptable oil comprises a pharmaceutically acceptable vegetable oil selected from the group consisting of soybean oil, sesame oil, olive oil, and peanut oil.

10. The composition of claim 9, wherein the pharmaceutically acceptable oil comprises soybean oil.

11. The composition of any one of the preceding claims, wherein the co-solvent comprises one or more selected from the group consisting of N-methyl-2-pyrrolidone (NMP), propylene glycol (PG), dimethyl sulfoxide (DMSO).

12. The composition of claim 11, wherein the co-solvent comprises NMP.

13. The composition of claim 12, wherein the composition comprises ethanol and NMP in a mass ratio of 1:2 to 2:1, optionally a mass ratio of 2:

1.

14. The composition of any one of the preceding claims, wherein the composition comprises a therapeutically effective dose of triptorelin in a volume of about 0.2 mL to about 1 mL, optionally about 0.45 mL.

15. The composition of any one of the preceding claims, wherein the composition comprises about 5 mg to about 10 mg of triptorelin (on a free base basis) in a volume of about 0.2 mL to about 1 mL, optionally about 0.45 mL.

16. The composition of any one of the preceding claims, wherein the composition comprises about 3.75 mg of triptorelin (on a free base basis) in a volume of about 0.45 mL.

17. The composition of any one of the preceding claims, wherein the composition comprises about 20% w / w to about 90% w / w phospholipid, based on the total weight of the composition, optionally wherein the composition comprises about 65% w / w to about 85% w / w phospholipid.

18. The composition of any one of the preceding claims, wherein the mass ratio of phospholipid to pharmaceutically acceptable oil in the composition is about 25:60 to about 83:

2.

19. The composition of claim 18, wherein the mass ratio of phospholipid to pharmaceutically acceptable oil in the composition is about 70:

15.

20. The composition of any one of the preceding claims, wherein the mass ratio of phospholipid to ethanol and cosolvent combination in the composition is about 25:60 to about 83:

2.

21. The composition of claim 20, wherein the mass ratio of phospholipid to ethanol and cosolvent combination in the composition is about 70:

15.

22. The composition of any one of the preceding claims, wherein the mass ratio of pharmaceutically acceptable oil to ethanol and cosolvent combination in the composition is about 1:10 to about 10:

1.

23. The composition of any one of the preceding claims, wherein the mass ratio of pharmaceutically acceptable oil to ethanol and cosolvent combination in the composition is about 1:

1.

24. The composition of any one of the preceding claims, wherein the mass ratio of ethanol to cosolvent in the composition is about 2:

1.

25. The composition of any one of the preceding claims, comprising, based on the total weight of the composition: (i) about 0.01% w / w to about 10% w / w triptorelin or a pharmaceutically acceptable salt thereof; (ii) about 20% w / w to about 90% w / w phospholipid; (iii) about 5% w / w to about 95% w / w pharmaceutically acceptable oil; and (iv) about 1% w / w to about 30% w / w ethanol and cosolvent combination.

26. The composition of claim 25, comprising, based on the total weight of the composition: (i) about 0.1% w / w to about 10% w / w triptorelin acetate; (ii) about 65% w / w to about 85% w / w soy phosphatidylcholine; (iii) about 15% w / w to about 30% w / w MCT oil; (iv) about 5% w / w to about 29% w / w 95% ethanol; and (v) about 1% w / w to about 25% w / w NMP.

27. The composition of claim 25, comprising, based on the total weight of the composition: (i) about 0.1% w / w to about 10% w / w triptorelin acetate; (ii) about 65% w / w to about 85% w / w soy phosphatidylcholine; (iii) about 15% w / w to about 30% w / w soybean oil; (iv) about 5% w / w to about 29% w / w of 95% ethanol; and (v) about 1% w / w to about 25% w / w NMP.

28. The composition of claim 25, comprising, based on the total weight of the composition: (i) about 1% w / w triptorelin acetate; (ii) about 69% w / w soy phosphatidylcholine; (iii) about 15% w / w MCT oil; (iv) about 10% w / w of 95% ethanol; and (v) about 5% w / w NMP.

29. The composition of claim 25, comprising, based on the total weight of the composition: (i) about 1% w / w triptorelin acetate; (ii) about 69% w / w soy phosphatidylcholine; (iii) about 15% w / w soybean oil; (iv) about 10% w / w of 95% ethanol; and (v) about 5% w / w NMP.

30. The composition of any one of the preceding claims, wherein upon administration by injection, the composition forms a gel depot in situ.

31. A method of administering triptorelin to a subject in need thereof, the method comprising administering to a subject in need thereof the composition of any one of claims 1-30.

32. A method of treating one or more conditions selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof, the method comprising administering to a subject in need thereof the composition of any one of claims 1-30.

33. The triptorelin pharmaceutical composition of any one of claims 1-30 for use in treating one or more conditions selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof.

34. Use of triptorelin in the manufacture of a medicament for treating one or more conditions selected from central precocious puberty, hormone-responsive cancer, endometriosis, female infertility, or uterine fibroids in a subject in need thereof, wherein the medicament comprises the triptorelin pharmaceutical composition of any one of claims 1-30.

35. The method, composition for use, or use of any one of claims 31-34, wherein the composition is administered by injection, optionally by intramuscular injection or subcutaneous injection.

36. A method of making an injectable triptorelin pharmaceutical composition, the method comprising: (a) mixing triptorelin or a pharmaceutically acceptable salt thereof with ethanol and a cosolvent to obtain a solution of triptorelin; (b) adding a phospholipid to the solution obtained in step (a) and mixing to obtain a solution of triptorelin and phospholipid; and and (c) adding a pharmaceutically acceptable oil to the solution obtained in step (b) and mixing to obtain a homogenous solution.

37. The method of claim 36, further comprising sterilizing the homogenous solution obtained in step (c).

38. The method of claim 37, wherein the sterilizing comprises filter sterilization.

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