Atosiban compositions and uses thereof

Abstract

Described herein are injectable, oil-based atosiban pharmaceutical compositions and therapeutic methods using them.

Description

Atty. Docket No. 052209-0673 P3125ATOSIBAN COMPOSITIONS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Chinese Patent Application for Invention No. 202411062591.5, filed August 5, 2024, the entire contents of which are incorporated herein by reference.FIELD

[0002] Described herein are pharmaceutical compositions of atosiban and uses thereof, such as in conjunction with in vitro fertilization embryo transfer (IVF-ET).BACKGROUND

[0003] Atosiban is a synthetic peptide that acts as an inhibitor of oxytocin and vasopressin. Atosiban is described in the literature as having a number of therapeutic uses, including as a tocolytic agent (e.g. to delay preterm birth and / or prevent premature labor). An aqueous formulation of atosiban (formulated as atosiban acetate) has been approved in Europe under the brand name TRACTOCILE® (F erring Pharmaceuticals A / S) to delay imminent pre-term birth in pregnant adult women experiencing uterine contractions. The TRACTOCILE® formulation includes atosiban acetate, mannitol, hydrochloric acid, and water for injection. Each vial of 5 ml solution contains 37.5 mg atosiban (as acetate); after dilution for administration, the concentration of atosiban is 0.75 mg / ml. TRACTOCILE® is a short-acting product with an initial half-life of 0.21 hours and a terminal half-life of 1.7 hours. TRACTOCILE® is administered by infusion over a maximum of 48 hours: an initial intravenous injection (6.75 mg), followed by a high-dose intravenous infusion (18 mg per hour) over three hours, then a lower dose infusion (6 mg per hour) lasting up to 45 hours.

[0004] Atosiban also has been proposed for use to decrease uterine contractions and promote uterine receptivity in patients undergoing embryo transfer, e.g., after in vitro fertilization (also referred to as IVF-ET). See, e.g., Schwarze et al., JBRA Assist Reprod. 2020 24(4): 421-27. Clinical trials have assessed various protocols for the use of atosiban in IFV-ET, including administering atosiban (e.g., TRACTOCILE®) (i) at a single bolus dose of 6.75 mg intravenously14904-2534-7671.1Atty. Docket No. 052209-0673 P3125 with an infusion time of more than 1 minute, or (ii) at a bolus dose of 6.75 mg intravenously followed by continuous infusion at 18 mg / hour for 1 hour, followed by continuous infusion at 6 mg / hour for 2 hours, or (iii) at a bolus dose of 6.75 mg intravenously followed by continuous infusion at 18 mg / hour for 3 hours. Id.

[0005] Thus, there remains a need for atosiban pharmaceutical compositions, including atosiban pharmaceutical compositions that do not require administration by intravenous injection or infusion. In particular, there remains a need for atosiban pharmaceutical compositions suitable for administration by injection, such as by intramuscular injection.SUMMARY

[0006] Provided herein are atosiban pharmaceutical compositions comprising atosiban particles (e.g., spray-dried particles of atosiban) in a pharmaceutically acceptable oil carrier. The atosiban pharmaceutical compositions described herein are suitable for administration by injection, such as by intramuscular injection.

[0007] In accordance with some aspects, provided is a pharmaceutical composition of atosiban (e.g., atosiban free base or a pharmaceutically acceptable salt thereof), comprising atosiban particles in a pharmaceutically acceptable oil carrier. The atosiban may be a hydrophobic salt of atosiban. The atosiban may be in the form of spray-dried particles of a hydrophobic salt of atosiban.

[0008] In accordance with specific aspects, the atosiban is atosiban pamoate. The atosiban pamoate may be a hemi salt having a molar ratio of atosiban to pamoate of about 2: 1. The atosiban pamoate may be in the form of spray-dried particles of atosiban pamoate, such as spray-dried particles of atosiban pamoate hemi salt. The spray-dried atosiban pamoate particles may be dispersed in the oil carrier. The spray-dried atosiban pamoate particles may have a substantially spherical or near-spherical shape, and a longest diameter of from about 0.1 pm to about 50 pm (microns). The spray-dried particles of atosiban pamoate may have an atosiban pamoate content selected from at least 90% w / w, at least 95% w / w, and at least 99% w / w.24904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0009] In accordance with any aspects, the pharmaceutically acceptable oil may comprise one or more selected from a pharmaceutically acceptable medium chain triglyceride oil (MCT oil) and a pharmaceutically acceptable vegetable oil. The pharmaceutically acceptable oil may comprise MCT oil having a viscosity of about 25-35 cP at 20°C. The pharmaceutically acceptable oil may comprise a pharmaceutically acceptable vegetable oil selected from soybean oil, sesame oil, olive oil, and peanut oil. The pharmaceutically acceptable oil may have a viscosity lower than 50 cP at 20°C.

[0010] In accordance with any aspects, the composition may further comprise one or more additional pharmaceutically acceptable carrier ingredients, optionally where the one or more additional pharmaceutically acceptable carrier ingredients are selected from antioxidants, antimicrobial agents, emulsifiers and solvents.

[0011] In accordance with any aspects, the composition may be prepared as a sterile composition.

[0012] In accordance with any aspects, the composition may comprise from about 1 % w / w to about 50% w / w of the atosiban particles, such as from about 5% w / w to about 20% w / w the atosiban particles. The composition may comprise from about 50% w / w to about 99% w / w of the oil carrier. The composition may comprise a therapeutically effective dose of atosiban in a volume of from about 1 mL to about 5 mL. The composition may comprise from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL. The composition may comprise from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of about 2 mL. The composition may comprise about 330.75 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL. The composition may comprise about 330.75 mg atosiban (on a free base basis) in a volume of about 2 mL.

[0013] In accordance with any aspects, the composition may exhibit an injection force from a 25- guage needle selected of less than 1200g, such as an injection force from a 25-guage needle selected from 1000g or less, 750g or less, and 500g or less, such as an injection force from a 25- guage needle of from about 300g to about 500g.34904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0014] In accordance with other aspects, there is provided a kit for preparation of a composition as described herein comprising (i) a first container containing the atosiban particles and (ii) a second container containing the pharmaceutically acceptable oil. In some embodiments, the first container contains dry atosiban particles in powder form. In some embodiments, (i) the first container contains atosiban particles in a first oil carrier comprising the pharmaceutically acceptable oil, and (ii) the second container contains a second oil carrier comprising the pharmaceutically acceptable oil.

[0015] In accordance with other aspects, there is provided a method of administering atosiban to a subject in need thereof, comprising administering a composition as described herein to a subject in need thereof.

[0016] Provided in other aspects are methods of inhibiting uterine contractions, comprising administering to a subject in need thereof an atosiban pharmaceutical composition as described herein. In some aspects, the atosiban pharmaceutical composition is administered by injection. In some aspects, the atosiban pharmaceutical composition is administered by intramuscular injection. In some aspects, the atosiban pharmaceutical composition is administered by a single bolus intramuscular injection, optionally wherein the single bolus injection provides a dose of atosiban of from 100 mg to 500 mg (on a free base basis), such as a dose of atosiban of about 330.75 mg (on a free base basis). In some aspects, the method is for inhibiting uterine contractions for IVF- ET. In some aspects, the method is for inhibiting uterine contractions for IVF-ET in a subject who has experienced repeated embryo implantation failure. Also provided herein are atosiban pharmaceutical compositions as described herein, for use in inhibiting uterine contractions, optionally for use in inhibiting uterine contractions for IFV-FT. Also provided herein are uses of atosiban in the preparation of a medicament for inhibiting uterine contractions, optionally for inhibiting uterine contractions for IVF-FT.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 illustrates the injectability of atosiban compositions formulated in different oil carriers.44904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0018] FIG. 2 provides atosiban plasma concentration (ng / ml) vs. time profiles for the first pharmacokinetic canine study reported in Example 2 (A: Reference drug by IV bolus + IV infusion; ▼ : atosiban acetate solution by single IM injection; ♦: atosiban pamoate suspension by single IM injection).

[0019] FIG. 3 provides atosiban plasma concentration (ng / ml) vs. time profiles for the second pharmacokinetic canine study reported in Example 2 (•: atosiban pamoate suspension (83 mg / ml) by single IM injection; ■: atosiban pamoate suspension (171 mg / ml) by single IM injection).

[0020] FIG. 4 illustrates uterine contractions before and after treatment with atosiban in the canine study reported in Example 3 (•: Reference drug by IV bolus + IV infusion; ■: atosiban pamoate suspension by single IM injection).DETAILED DESCRIPTION

[0021] The present disclosure provides atosiban pharmaceutical compositions that are suitable for administration by injection, such as by intramuscular injection. As described in more detail below, the compositions include atosiban particles (e.g., spray-dried particles of atosiban) in a pharmaceutically acceptable oil carrier. Kits for preparing the compositions also are described. As also described herein, the atosiban pharmaceutical compositions described herein can be used in methods for inhibiting uterine contractions, and may be particularly suitable for use in methods for inhibiting uterine contractions for in vitro fertilization embryo transfer (IVF-ET).Definitions

[0022] Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which the present invention pertains, unless otherwise defined. Any suitable materials and / or methods known to those of ordinary skill in the art can be utilized in carrying out the present invention in view of the guidance provided herein; however, specific materials and methods are described for illustrative purposes. Materials, reagents and the like to which reference is made in the following description and examples are obtainable from commercial sources, unless otherwise noted.54904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0023] As used herein, the singular forms “a,” “an,” and “the” designate both the singular and the plural, unless expressly stated to designate the singular only.

[0024] As used herein, “about” when used with a numerical value means the numerical value stated as well as plus or minus 10% of the numerical value. For example, “about 10” should be understood as both “10” and “9-11.”

[0025] As used herein, a phrase in the form “A / B” or in the form “A and / or B” means (A), (B), or (A and B); a phrase in the form “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).

[0026] As used herein, the terms “comprising,” “including,” and “containing” are used expansively to mean that the described compositions, methods, or kits include at least the stated elements, and may include other elements that are not specified. The phrase “consisting essentially of’ is used to include those elements specifically recited and additional elements that do not materially affect the basic and novel characteristics of the claimed invention, such as ingredients that do not materially undermine the solubility of atosiban in the composition or the palatability of the composition.

[0027] As used herein, “subject” denotes any mammal, including humans. In the context of the present disclosure, the subject typically is a female mammal, in particular a female human, such as a female human undergoing in vitro fertilization or otherwise in need of inhibiting uterine contractions.

[0028] The terms “administer,” “administration,” and “administering” as used herein refer to providing, giving, dosing and / or prescribing, such as by a health professional or his or her authorized agent or under his or her direction, and putting into or injecting, such as by a health professional or the subject.

[0029] The terms “treat,” “treating,” and “treatment” as used herein are used generally to refer to any therapeutic or prophylactic regimen for which atosiban may be indicated, including in vitro64904-2534-7671.1Atty. Docket No. 052209-0673 P3125 fertilization and inhibition of uterine contractions, whether or not the treatment is considered to be “successful”.

[0030] As used herein, the phrases “therapeutically effective amount” and “therapeutically effective dose” refer to an amount or dose that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. It is emphasized that a therapeutically effective amount will not always be effective in treating the targeted condition or achieving the intended effect or result, even though such amount or dose is deemed to be a therapeutically effective amount or dose by those of skill in the art. For convenience only, exemplary doses and therapeutically effective amounts are provided below with reference to adult human subjects. Those skilled in the art can adjust such amounts in accordance with standard practices as needed to treat a specific subject and / or condition / disease.

[0031] The disclosure of specific compounds under specific categories (e.g., “antioxidant,” “antimicrobial agent,” etc.) is not necessarily limiting. Those skilled in the art will understand that a given compound may exhibit more than one function in a given composition, or may exhibit a different function depending on the composition in which it is used.Atosiban

[0032] Atosiban (atosiban free base) has the chemical name l-(3-Mercaptopropanoic acid)-2-(O- ethyl-D-tyrosine)-4-L-threonine-8-L-ornithine-oxytocin and the following chemical structure:74904-2534-7671.1Atty. Docket No. 052209-0673 P3125Its molecular formula is C43H67N11O12S2, and its molecular weight is 994.19 g / mol.

[0033] The active ingredient of the compositions described herein may be atosiban (i.e., the free base form of atosiban) or a pharmaceutically acceptable salt thereof (collectively referred to herein as “atosiban”). Non-limiting examples of pharmaceutically acceptable salts include acetate, pamoate, hydrochloride, hydrobromide, sulphate, phosphate, phytate, mesylate, docusate, maleate, fumarate, lactate, tartrate, citrate and gluconate salts. As noted above, TRACTOCILE® is an aqueous formulation of atosiban acetate. Thus, in some embodiments, the active ingredient of a composition as described herein is or comprises atosiban acetate. In other embodiments, the active ingredient of a composition as described herein is or comprises atosiban pamoate, which has been recently described in CN114249800A (filed September 22, 2020) and PCT / EP2024 / 058944 (filed April 2, 2024).

[0034] Atosiban pamoate is an acid addition salt of atosiban and pamoic acid. Pamoic acid has the chemical name 4,4’-methylene-bis(3-hydroxy-2-naphthoic acid), and the following chemical structure:

[0035] Methods of preparing atosiban pamoate are described in CN114249800A and PCT / EP2024 / 058944. As described in CN114249800 A, atosiban pamoate may be prepared by an ion-exchange chromatographic method using a reversed-phase polymer filler as a stationary phase. The column is equilibrated prior to loading of an atosiban peptide solution and, subsequently, a pamoic acid inorganic salt aqueous solution and an organic solvent are loaded onto the column in certain proportions for the ion exchange reaction. As described in PCT / EP2024 / 058944 (the entire84904-2534-7671.1Atty. Docket No. 052209-0673 P3125 contents of which are incorporated herein by reference), atosiban pamoate may be prepared by a precipitation method, comprising contacting and / or reacting together a first atosiban salt (other than atosiban pamoate, e.g., atosiban acetate) and an inorganic pamoate salt in an aqueous solvent (e.g., water), wherein atosiban pamoate is formed as a jelly-like precipitate and harvested by a redissolving and lyophilization process.

[0036] In some embodiments, the atosiban pamoate is a hemi salt, e.g., having a molar ratio of atosiban to pamoate of about 2:1. Without being bound by theory, hemi salt forms of atosiban pamoate may permit higher drug loading than a mono salt form, thereby permitting formulations having a reduced volume, which in turn can benefit patient comfort and compliance.

[0037] In some embodiments, the atosiban is in a particulate form (e.g., a particle form). For example, the atosiban may be prepared by spray-drying and formulated as spray-dried particles. Thus, in some embodiments, the compositions described herein comprise spray-dried particles of atosiban. For example, spray-dried atosiban particles suitable for use in a composition as described herein may have a substantially spherical or near- spherical shape, and a longest diameter from about 0.1 pm to about 50 pm (microns), such as from about 0.5 pm to about 25 pm, or from about 1 pm to about 10 pm, including from about 1 pm and about 8 pm, such as 1 pm to 10 pm, or 1 pm to 8 pm. The atosiban content (e.g., purity) of the atosiban particles may be least about 90%, such as at least 90%, at least 95%, at least 97%, or at least 99%, or greater, based on the total weight of the particles. In specific embodiments, the atosiban particles are prepared without carrier ingredients and have an atosiban content (e.g., purity) of at least 99%, based on the total weight of the particles.

[0038] In specific embodiments, the compositions described herein comprise spray-dried particles of atosiban pamoate (e.g., atosiban pamoate hemi salt). For example, spray-dried atosiban pamoate particles suitable for use in a composition as described herein may have a substantially spherical or near-spherical shape, and a longest diameter from about 0.1 pm to about 50 pm (microns), such as from about 0.5 pm to about 25 pm, or from about 1 pm to about 10 pm, including from about 1 pm and about 8 pm, such as 1 pm to 10 pm, or 1 pm to 8 pm. The atosiban pamoate content (e.g.,94904-2534-7671.1Atty. Docket No. 052209-0673 P3125 purity) of the atosiban pamoate particles may be least about 90%, such as at least 90%, at least 95%, at least 97%, or at least 99%, or greater, based on the total weight of the particles. In specific embodiments, the atosiban pamoate particles are prepared without carrier ingredients and have an atosiban pamoate content (e.g., purity) of at least 99%, based on the total weight of the particles.

[0039] Spray-dried particles of atosiban (e.g., spray-dried atosiban pamoate particles, or spray- dried particles of atosiban free base or other pharmaceutically acceptable salts of atosiban) may be prepared by any suitable method, such as by using spray-drying techniques known in the art. For example, as described in PCT7EP2024 / 058944 (the entire contents of which are incorporated herein by reference), spray-dried atosiban pamoate particles may be prepared from a loading solution of atosiban pamoate in an aqueous solvent system such as a 5: 1 (v / v) alcohol: water mixture (wherein the alcohol may be a C1-C4 alcohol such as methanol) or a 3: 1 (v / v) acetonitrile: water mixture. Any suitable spray-drying equipment may be used, such as a Mini Spray Dryer B-290 (Buchi, Switzerland). Any suitable spray-drying parameters may be used, such as an inlet temperature between about 95 °C and about 105 °C, a feed rate of the loading solution between about 3 mL / min and about 6 mL / min, an atomizing gas flow rate between about 439 L / h and about 1052 L / h, and a drying gas flow rate between about 20 m3 / h and about 50 m3 / h.Oil-Based Atosiban Pharmaceutical Compositions

[0040] As noted above, the pharmaceutical compositions described herein comprise atosiban particles (e.g., spray-dried atosiban particles, including spray-dried atosiban pamoate particles, such as spray-dried particles of atosiban pamoate hemi salt) formulated in a pharmaceutically acceptable oil carrier. Without being bound by theory, it is believed that compositions described herein comprising spray-dried particles of a hydrophobic salt of atosiban (such as atosiban pamoate or atosiban docusate) in an oil carrier achieve prolonged drug release in vivo after intramuscular administration, which is advantageous for its use for inhibiting uterine contractions.

[0041] In some embodiments, the pharmaceutically acceptable oil comprises one or more selected from a pharmaceutically acceptable medium chain triglyceride oil (“MCT oil”) and a pharmaceutically acceptable vegetable oil.104904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0042] In some embodiments the oil is or comprises MCT oil. As described in the United States Pharmacopeia (“USP”) and European Pharmacopeia (“Ph. Eur.”), “MCT” refers to a mixture of triglycerides of saturated fatty acids, mainly of caprylic acid (CsHieCh) and capric acid (C10H20O2), typically derived from coconut oil or palm oil. USP-grade / Ph. Eur.-grade MCT oils contain not less than 95% of saturated fatty acids with 8 and 10 carbon atoms, have 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, MCT oil used in a pharmaceutical composition as described herein contains not less than 95% of saturated fatty acids with 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).

[0043] In some embodiments the oil is or comprises vegetable oil. In some embodiments, the vegetable oil comprises a long chain fatty acid (e.g., having 13-21 carbon atoms), such as sesame oil, soybean oil, peanut oil, olive oil, or castor oil. In some embodiments, the vegetable oil comprises one or more selected from sesame oil, soybean oil, peanut oil, olive oil, and castor oil. In some embodiments, the vegetable oil comprises one or more selected from sesame oil, soybean oil, peanut oil, and olive oil. In some embodiments the oil is or comprises sesame oil. In some embodiments the oil is or comprises soybean oil. In some embodiments the oil is or comprises peanut oil. In some embodiments the oil is or comprises olive oil. In some embodiments the oil is or comprises castor oil. In some embodiments, the oil does not comprise castor oil.

[0044] In any embodiments, the oil or oil carrier may have a low viscosity, such as a viscosity of about 50 cP or less at room temperature (e.g., at 20 °C), such as a viscosity of 50 cP or less at room temperature, including a viscosity of about 25-35 cP at room temperature. In some embodiments, the oil is or comprises MCT oil having a viscosity of about 25-35 cP at room temperature (e.g., at 20 °C). In some embodiments, the oil is or comprises vegetable oil having a viscosity of 50 cP or less at room temperature (e.g., at 20 °C). In some embodiments, the oil carrier comprises MCT oil and vegetable oil, and optionally has a viscosity of about 50 cP or less at room temperature (e.g., at 20 °C), including a viscosity of about 25-35 cP at room temperature.114904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0045] In any embodiments, a pharmaceutical composition as described optionally may comprise one or more additional pharmaceutically acceptable carrier ingredients such as one or more antioxidants, antimicrobial agents, emulsifiers, solvents, and the like. Non-limiting examples of suitable antioxidants include benzyl alcohol, and tocopherols such as alpha tocopherol, butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), DL-methionine, arginine, cysteine, ascorbic palmitate, sodium metabisulfite, sodium thiosulfate, propyl gallate, gamma linoleic acid, ascorbic acid, and ethylenediaminetetraacetic acid (EDTA). Non-limiting examples of suitable antimicrobial agents include benzyl alcohol, butylated hydroxy toluene (BHT), and butylated hydroxy anisole (BHA) (which also act as antioxidants), as well as benzoic acid, ascorbic acid, and benzoates such as sodium benzoate. Non-limiting examples of suitable emulsifiers include polysorbate 20, polysorbate 60, polysorbate 80, lecithin, and sorbitan monooleate. Non-limiting examples of suitable solvents include ethanol, propylene glycol, polyethylene glycol (PEG), glycerin, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide (DMA), and triacetin. When present, the anti oxi dant(s) and / or antimicrobial agent(s) may be present in any suitable amount. For example, a composition as described herein may comprise one or more antioxidants in a total amount of from about 0.001% w / w to about 1% w / w, or any value therebetween, may additionally or alternatively comprise one or more antimicrobial agents in a total amount of from about 0.001% w / w to about 1% w / w, or any value therebetween, may additionally or alternatively comprise one or more emulsifiers in a total amount of from about 0.01% w / w to about 10% w / w, or any value therebetween, and may additionally or alternatively comprise one or more solvents in a total amount of from about 0.1% to 10% w / w, or any value therebetween.

[0046] In some embodiments, a pharmaceutical composition as described herein is formulated only with the atosiban particles and oil carrier. That is, in some embodiments, a pharmaceutical composition as described herein does not comprise additional carrier ingredients.

[0047] In accordance with any embodiments, a pharmaceutical composition as described herein may be prepared as a sterile composition.124904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0048] The atosiban pharmaceutical compositions described herein may be in the form of a suspension, e.g., wherein atosiban particles are dispersed in the oil carrier. In specific embodiments, pharmaceutical compositions described herein comprise spray-dried atosiban pamoate particles (e.g., spray-dried particles of atosiban pamoate hemi salt) dispersed in an oil carrier, such as an MCT oil carrier.

[0049] In some embodiments, a pharmaceutical composition as described herein comprises from about 1% w / w to about 50% w / w atosiban particles, including from about 1% w / w to about 50% w / w, including from about 5% w / w to about 20% w / w, such as from 5% w / w to 20% w / w. Thus, in some embodiments, a pharmaceutical composition as described herein comprises 1% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, or more, atosiban particles, or any value therebetween. Conversely, a pharmaceutical composition as described herein may comprise from about 50% w / w to about 99% w / w of the oil carrier (e.g., the oil and any other carrier ingredients, such as those discussed below), including from 50% w / w to 99%, from about 80% w / w to about 95% w / w, such as from 80% w / w to 95% w / w, or any value therebetween.

[0050] In specific embodiments, a pharmaceutical composition as described herein comprises from about 1% w / w to about 50% w / w atosiban pamoate particles (e.g., spray-dried particles of atosiban pamoate hemi salt), including from about 1% w / w to about 50% w / w, including from about 5% w / w to about 20% w / w, such as from 5% w / w to 20% w / w. Thus, in some embodiments, a pharmaceutical composition as described herein comprises 1% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w, 50% w / w, or more, atosiban pamoate particles, or any value therebetween. Conversely, a pharmaceutical composition as described herein may comprise from about 50% w / w to about 99% w / w of the oil carrier (e.g., the oil and any other carrier ingredients, such as those discussed below), including from 50% w / w to 99%, from about 80% w / w to about 95% w / w, such as from 80% w / w to 95% w / w, or any value therebetween.134904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0051] In some embodiments, the composition is formulated to provide a therapeutically effective dose of atosiban in a volume suitable for bolus injection, such as in a volume of about 1-5 mL. In some embodiments, the composition is formulated to provide a therapeutically effective dose of atosiban in a volume of about 1 mL, about 2 mL, about 3 mL, about 4 mL, or about 5 mL, or any volume therebetween. In specific embodiments, the composition is formulated to provide a therapeutically effective dose of atosiban in a volume of about 2 mL.

[0052] An ideal injectable drug product has relatively high drug loading to provide an effective dose in a small injection volume while maintaining good injectability. However, drug loading and injectability may be competing properties. Thus, it may be necessary to balance drug loading and injectability when developing an injectable pharmaceutical product.

[0053] As discussed below, a therapeutically effective dose of atosiban may be from about 1 mg to about 1000 mg, including from about 100 mg to about 500 mg, including about 350 mg, such as 330.75 mg (all based on atosiban free base). Thus, in some embodiments, a composition as described herein comprises from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL, such as from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of about 2 mL. In some embodiments, a composition as described herein comprises about 330.75 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL, such as about 330.75 mg atosiban (on a free base basis) in a volume of about 2 mL.

[0054] In some embodiments, a pharmaceutical composition as described herein comprises an atosiban content of 10 mg / mL to about 300 mg / mL (based on atosiban free base), including from about 50 mg / mL to about 250 mg / mL, such as from about 80 mg / mL to about 180 mg / mL. Thus, in some embodiments, a pharmaceutical composition as described herein may have an atosiban content of 10 mg / mL, 50 mg / mL, 80 mg / mL, 100 mg / mL, 120 mg / mL, 140 mg / mL, 160 mg / mL, 180 mg / mL, 200 mg / mL, 225 mg / mL, 250 mg / mL, 300 mg / mL, or any value therebetween, based on atosiban free base. In specific embodiments, a pharmaceutical composition as described herein has an atosiban content of 83 mg / mL, 126 mg / mL, or 171 mg / mL, based on atosiban free base.144904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0055] As noted above, the atosiban may be formulated as atosiban free base or a pharmaceutically acceptable salt thereof, such as atosiban pamoate (e.g., atosiban pamoate hemi salt), atosiban docusate, or atosiban acetate. As also noted above, in specific embodiments the atosiban is formulated as atosiban pamoate (e.g., atosiban pamoate hemi salt).

[0056] As illustrated in the examples below, the compositions described herein exhibit good dispersity, injectability and syringeability. Advantageously, the compositions described herein exhibit injectability and syringeability properties that make them suitable for administration by injection, such as by intramuscular injection. For example, a low injection force may be associated with lower pain perception, and thus improve patient comfort and compliance. In some embodiments, atosiban pharmaceutical compositions described herein exhibit an injection force from a 25-guage needle of less than 1200g (considered to be “easy”), including an injection force from a 25-guage needle of 1000g or less, 750g or less, or 500g or less. In some embodiments, atosiban pharmaceutical compositions described herein exhibit an injection force from a 25-guage needle of from about 300g to about 500g, such as an injection force from a 25-guage needle of from 300g to 500g.Ready-To-Use Compositions And Kits

[0057] In some embodiments, a pharmaceutical composition as described herein is provided in a ready-to-use format. A ready-to-use format may comprise a pharmaceutical composition as described herein formulated for administration by bolus injection. In some embodiments, the pharmaceutical composition is suitable for administration by intramuscular injection. In some embodiments, the pharmaceutical composition is provided ready-to-use in a pre-filled syringe, such as pre-filled syringe suitable for intramuscular injection. In other embodiments, the pharmaceutical composition is provided ready-to-use in a vial.

[0058] In other embodiments, a kit for preparation of a pharmaceutical composition as described herein is provided. A kit may comprise a first container containing dry atosiban (e.g., spray-dried atosiban particles in powder form and, optionally, additional dry pharmaceutically acceptable carrier ingredients) and a second container containing an oil carrier for the atosiban (e.g.,154904-2534-7671.1Atty. Docket No. 052209-0673 P3125 comprising MCT oil and / or vegetable oil and, optionally, additional pharmaceutically acceptable carrier ingredients). As noted above, in some embodiments a pharmaceutical composition as described herein is formulated only with the atosiban particles and oil carrier. Thus, in some embodiments, a kit comprises a first container containing dry atosiban (e.g., spray-dried atosiban particles in powder form) and a second container containing an oil carrier for the atosiban (e.g., MCT oil and / or vegetable oil). Optionally, a kit may include instructions for combining the dry atosiban and oil carrier to obtain a pharmaceutical composition suitable for administration by bolus injection, such as by intramuscular injection.

[0059] In other kit embodiments, a kit may comprise a first container containing atosiban particles (e.g., spray-dried particles of atosiban pamoate) formulated in first amount of a first oil carrier and a second container containing a second amount of a second oil carrier. In such embodiments, the first and second oil carrier may comprise the same components or different components. For example, the first and second oil carrier may comprise the same oil and the same or different optional additional pharmaceutically acceptable carrier ingredients. As noted above, in some embodiments a pharmaceutical composition as described herein is formulated only with the atosiban particles and oil carrier. Thus, in some embodiments, a kit comprises a first container containing atosiban particles (e.g., spray-dried particles of atosiban pamoate) formulated in first amount of oil carrier and a second container containing a second amount of oil carrier. Optionally, a kit may include instructions for combining contents of the first and second containers to obtain a pharmaceutical composition suitable for administration by bolus injection, such as by intramuscular injection.

[0060] In any embodiments a kit optionally may further comprise a syringe, such as a syringe suitable for intramuscular injection.Example Compositions

[0061] The following are disclosed as specific illustrative embodiments of compositions as described herein.164904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0062] The compositions described in the table below are formulated with spray-dried particles of atosiban pamoate (hemi salt) in MCT oil. The particles have an atosiban pamoate content (e.g., purity) of 99% or greater, based on the total weight of the particles, and a substantially spherical or near-spherical shape with a longest diameter from about 0.1 pm to about 50 pm. In the table below, target injection volume refers to a volume of the composition expected to provide a therapeutically effective dose of atosiban for inhibiting uterine contractions, e.g., in the treatment of subjects underdoing IVF-ET.

[0063] Formulation A may be prepared by formulating 100 mg spray-dried atosiban pamoate particles in 0.400 mL MCT oil; Formulation B may be prepared by formulating 75 mg spray-dried atosiban pamoate particles in 0.425 mL MCT oil; Formulation C may be prepared by formulating 50 mg spray-dried atosiban pamoate particles in 0.450 mL MCT oil. These amounts of these formulations may be prepared in 2 ml vials and vortexed for 1 minute to fully disperse the particles in the oil carrier.Therapeutic Methods Uses

[0064] The present disclosure also provides uses of the compositions described herein in treatment methods comprising administering an atosiban pharmaceutical composition as described herein to a subject in need thereof.

[0065] Assisted reproduction technology (ART) methods often involve ovarian stimulation, egg retrieval, and in vitro fertilization followed by embryo transfer (ET) into a subject’s uterus for174904-2534-7671.1Atty. Docket No. 052209-0673 P3125 implantation and development. Success of embryo implantation depends on several factors, and is considered to be undermined by uterine contractions, which may be increased following ovarian stimulation. It has been observed that frequent uterine contractions are correlated with lower pregnancy rates. Uterine contractions are stimulated by oxytocin; therefore, inhibition of oxytocin receptors may improve success of ET and hence IVF success by decreasing uterine contractions. Atosiban, a combined receptor antagonist for oxytocin and vasopressin Via, acts on the uterus to suppress uterine contractions and has been approved for use to prevent premature delivery. Several observational clinical studies have suggested that the use of atosiban around the time of ET may result in higher pregnancy rates, especially in women with repeated implantation failure.

[0066] Thus, in some embodiments, uses and treatments described herein comprise administering an atosiban pharmaceutical composition as described herein to a female human subject in need of inhibition of uterine contractions, such as for IVF-ET. In some aspects, the method is for inhibiting uterine contractions for IVF-ET in a subject who has experienced repeated embryo implantation failure (RIF). In specific embodiments, the subject being treated has previously experienced one or two embryo implantation failures, e.g., the subject is undergoing a third (or subsequent) embryo transfer.

[0067] The composition may be administered by injection, such as by extravascular injection, such as by intramuscular injection.

[0068] The composition may be administered at any therapeutically effective dose by any suitable dosing regimen.

[0069] As noted above, without being bound by theory, it is believed that embodiments of the atosiban pharmaceutical compositions described herein comprising spray-dried particles of a hydrophobic salt of atosiban (such as atosiban pamoate or atosiban docusate) in an oil carrier achieve prolonged drug release in vivo after intramuscular administration. Indeed, in some embodiments, the atosiban pharmaceutical compositions described herein comprising spray-dried particles of atosiban pamoate exhibit a rate of absorption that is slower than the rate of elimination, referred to as a “flip-flop pharmacokinetics” phenomenon. This is in contrast to aqueous atosiban184904-2534-7671.1Atty. Docket No. 052209-0673 P3125 acetate formulations (e.g., TRACTOCILE®) which is essentially an immediate release formulation with an atosiban half-life of less than 20 minutes, with atosiban quickly eliminated from circulating blood. Thus, also in contrast to the complicated dosing regimens used for TRACTOCILE® (e.g., an initial intravenous bolus injection followed by continuous intravenous infusion), due to its sustained release properties, an atosiban pharmaceutical composition as described herein (particularly embodiments comprising spray-dried particles of a hydrophobic salt of atosiban such as atosiban pamoate or atosiban docusate) can be administered by a single extravascular (e.g., intramuscular) injection. Thus, in some embodiments (e.g., embodiments comprising spray-dried particles of a hydrophobic salt of atosiban such as atosiban pamoate or atosiban docusate), when administered in a composition as described herein, the atosiban exhibits good residence time after IM injection and achieves a prolonged duration of drug release.

[0070] On the other hand, bioavailability after intramuscular injection of an atosiban pharmaceutical composition as described herein is lower than that observed after intravenous injection of an aqueous solution (considered to have a bioavailability of 100%). This lower bioavailability coupled with fast clearance of atosiban from blood circulation indicates that a higher dose of atosiban is needed to achieve and sustain a therapeutic concentration of atosiban in blood for a few hours, as compared to TRACTOCILE® intravenous infusion dosing.

[0071] Thus, in some embodiments, the dose of an atosiban pharmaceutical composition as described herein administered to a subject in need thereof provides from about 10 mg to about 1000 mg atosiban (based on atosiban free base), including from about 100 mg atosiban to about 500 mg atosiban (based on atosiban free base), including about 350 mg atosiban, such as 330.75 mg atosiban (based on atosiban free base). Accordingly, in some embodiments, the dose administered provides an amount of atosiban of from about 10 mg to about 1000 mg, including about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg atosiban, all based on atosiban free base. In specific embodiments, the dose administered provides 330.75 mg atosiban based on atosiban free base. In some embodiments, the dose is provided in a volume of composition of from about 2 mL to about 5 mL, such as a volume of composition of about 2 mL. In some embodiments, the dose194904-2534-7671.1Atty. Docket No. 052209-0673 P3125 administered provides about 330.75 mg atosiban (on a free base basis), optionally in a volume of from about 2 mL to about 5 mb, such as about 330.75 mg atosiban (on a free base basis) in a volume of about 2 mL. As noted above, the atosiban may be formulated as atosiban free base or a pharmaceutically acceptable salt thereof, such as atosiban pamoate (e.g., atosiban pamoate hemi salt) or atosiban acetate. As also noted above, in specific embodiments the atosiban is formulated as atosiban pamoate (e.g., atosiban pamoate hemi salt).

[0072] In some embodiments, the dose is administered in a single bolus injection, e.g., a single bolus intramuscular 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.EXAMPLES

[0073] 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 disclosure. Other aspects of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.Example 1

[0074] Spray-dried particles of atosiban pamoate salt do not disperse well in aqueous media and tend to form a gel, even if formulated with surfactants such as poloxamer 188 and polyvinyl alcohol. Instead, it was determined that atosiban pamoate can be formulated in oil-based compositions as described herein, which are suitable for administration by injection, such as intramuscular injection.

[0075] To assess properties of atosiban pamoate particles formulated in different oil carriers, 50 mg of spray-dried atosiban pamoate particles (spray-dried particles of atosiban pamoate hemi salt) were weighed into 2 mL vials, 0.45 mL of a test oil (castor oil, soybean oil, sesame oil, or medium-chain triglyceride oil (MCT oil)) was added, and the vials were vortexed for 1 minute. Visual inspection and microscopy observation were performed to evaluate the appearance and dispersity of the oil suspension formulations. The syringeability and injectability of the oil204904-2534-7671.1Atty. Docket No. 052209-0673 P3125 suspensions were investigated to evaluate whether the formulations would be suitable for administration by injection. Solubility and stability of the atosiban pamoate in various oils were studied.

[0076] The spray-dried atosiban pamoate particles could be well-dispersed in soybean oil, sesame oil and MCT oil, and presented as white to light yellow suspension in the vials. However, the atosiban pamoate particles were hard to disperse in castor oil, and visible large agglomerates were still observed after vortexing. These results were attributed to the relatively higher viscosity of castor oil as compared to the other test oils. Microscope observations were consistent with visual inspection, with good dispersity of the spray-dried atosiban pamoate particles being observed in soybean oil, sesame oil and MCT oil, and large agglomerates being observed in the castor oil formulation.

[0077] The syringeability and injectability of the three oil formulations with good dispersity (soybean oil, sesame oil and MCT oil) were investigated. All three formulations exhibited good syringeability through a 25-guage needle (0.5mmxl6mm). Furthermore, a texture analyzer (TA.XTPlus, Stable Micro Systems Products) was utilized to evaluate injectability using a ImL BD syringe (Becton-Dickinson) with a 25-guage needle (0.5mmxl6mm). Results are shown in FIG. 1. All three oil formulations exhibited an injection force less than 500g, indicating good injectability (an injection force < 1200g is considered to be “easy”). The MCT oil formulation exhibited the lowest injection force (indicating the easiest).

[0078] The equilibrium solubility of the spray-dried atosiban pamoate particles in the different oils was assessed and determined to be very low (especially for MCT), which may be beneficial to the chemical stability of the oil suspensions. In particular, oil formulations were prepared as described above and stored at room temperature protected from light. At predetermined time points (4 hours, 24 hours, and 48 hours), the formulations were centrifuged at 10,000 rpm for 10 minutes, and 200 pL of supernatant were transferred into a 10 ml volumetric flask, and analyzed by reversephase UPLC to determine the equilibrium solubility of atosiban pamoate salt in the various oils.214904-2534-7671.1Atty. Docket No. 052209-0673 P3125Equilibrium Solubility Of Atosiban Pamoate In Various Oils

[0079] Short-term stability of these oil formulations was assessed over 5 days and determined to be stable. There was no increase in impurity content or total impurities for all three oil formulations, indicating the good short-term chemical stability of the atosiban pamoate particles in all three oils.Short-Term Stability Of Atosiban Pamoate Oil Formulations

[0080] The low injection force of the formulations tested above indicated that drug loading (e.g., concentration) could be increased while still obtaining a composition suitable for injection. (Generally, injection force increases with drug loading.) To investigate, three formulations were prepared with different drug loading: Formulation A was prepared with 100 mg spray-dried atosiban pamoate particles in 0.400 mL MCT oil; Formulation B was prepared with 75 mg spray-224904-2534-7671.1Atty. Docket No. 052209-0673 P3125 dried atosiban pamoate particles in 0.425 mL MCT oil; Formulation C was prepared with 50 mg spray-dried atosiban pamoate particles in 0.450mL MCT oil. All compositions were vortexed for 1 min to fully disperse the particles in the oil. All three formulations exhibited good syringeability through a 25-gauge needle (0.5mmxl6mm). Injectability data acquired by texture analyzer demonstrated that the injection force increased from ~250g to ~370g with increasing drug loading, but the formulation with the highest solid concentration (Formulation A) still exhibited acceptable injectability. Formulation A could provide a target clinical dose of atosiban of 330.75 mg (based on the free base) in a volume of about 2 mL, while Formulation C could provide a target clinical dose of atosiban of 330.75 mg (based on the free base) in a volume of about 4 mL.Example 2: Pharmacokinetic Study In Canines

[0081] The in vivo pharmacokinetics (PK) of atosiban pharmaceutical compositions as described herein were evaluated in female beagle dogs. The study included three groups (n=3 for each), with two groups administered different aqueous atosiban acetate formulations by different dosing regimens, and one group administered a representative atosiban pharmaceutical composition of the present invention by a single IM injection.

[0082] As the “Reference drug,” the aqueous atosiban acetate formulation of TRACTOCILE® was administered by bolus intravenous injection (0.180 mg / kg) followed by intravenous infusion (first intravenous infusion at 0.481 mg / kg / h for Ih; second intravenous infusion at 0.160 mg / kg / h for 2h, for a total dose of 0.981 mg / kg).

[0083] As an IM comparator, an aqueous atosiban acetate formulation having a higher concentration of atosiban acetate than TRACTOCILE® was administered by a single IM injection. The free base atosiban concentration of this formulation was 114 mg / mL. The dose administered was 8.823 mg / kg.

[0084] As a representative atosiban pharmaceutical composition of the present invention, a formulation of spray-dried atosiban pamoate was prepared in low viscosity MCT oil (e.g., having234904-2534-7671.1Atty. Docket No. 052209-0673 P3125 a viscosity of 25-35 mP at 20 °C). The free base atosiban concentration was 83 mg / mL. The dose administered was 8.823 mg / kg.

[0085] Results are shown in FIG. 2 and summarized in the table below (data is shown as mean ± SD (n=3)).Testing formulation AUC o-«> C max T max1Reference drug 4431 + 481 1960 + 250 1.00 + 0.001Atosiban acetate single IM injection6 J13823 + 1686 6600 + 2462 0.31 +0.17(solution)■Atosiban pamoate single IM injectionP 6 J16929 + 5421 1403 + 197 1.17 + 0.76(suspension)

[0086] The results show that at the same dose on a free base basis, the atosiban pharmaceutical composition of the present invention (atosiban pamoate suspension administered by single IM injection) exhibited an extended drug release profile as compared to the atosiban acetate solution administered by single IM injection, with a higher AUCo-® and longer duration of atosiban plasma concentration above 600 ng / mL (the atosiban free base blood concentration), although the Cmax of the composition of the present disclosure was only a fraction of that of the atosiban acetate solution administered by single IM injection. Without being bound by theory, the very high Cmax of the atosiban acetate solution administered by single IM injection may be ascribed to the rapid diffusion of the aqueous atosiban acetate solution into muscular tissue and adsorption by the blood capillary system into blood circulation. In contrast, the Cmax of the composition of the present invention was slightly lower than that for the Reference drug. Thus, the composition of the present disclosure exhibited a long duration of atosiban plasma concentration above 600ng / mL without the safety concerns associated with a very high Cmax.244904-2534-7671.1Atty. Docket No. 052209-0673 P3125

[0087] A further PK study was conducted with a composition of the present invention having higher drug loading, in particular, an atosiban free base concentration of 171 mg / mL. The injection dose was kept at 8.823 mg / kg for each animal (n=3) as in the study summarized above. Results are shown in FIG. 3 in comparison to the composition of the present invention having an atosiban free base concentration of 83 mg / mL (n=3). As seen in the figure, there was no significant difference in the pK profiles between the two formulations. These results support formulating compositions of the present invention with high drug loading to reduce injection volume.Example 3: Pharmacodynamic Study In Canines

[0088] To study in vivo pharmacodynamics (PD) of atosiban pharmaceutical compositions as described herein, a canine model was developed. Specifically, a non-pregnant oxytocin-induced uterine contraction canine PD model was developed using female beagle dogs aged 3-4 years having had multiple deliveries. The dogs were surgically implanted with balloon catheters to measure uterine contractions during the study. For model verification, the ability to measure uterine contractions induced by administration of oxytocin (intravenously infused at 300-600 mU / kg / h) was confirmed. For the study, the inhibitory effect of atosiban on oxytocin-induced uterine contractions was assessed.

[0089] Six animals with stable oxytocin-induced uterine contraction frequency who passed the model verification were selected for the study. The animals were first treated with the Reference drug as described above (n=6) and then, after a wash-out period of at least one week, were treated with a single IM injection of the higher-drug loading composition of the present invention described above (having an atosiban free base concentration of 171 mg / mL) (n=5).

[0090] After monitoring stable oxytocin-induced uterine contractions for 1 hour (at least two contractions within 20 minutes), the test drug was administered and oxytocin infusion was continued for five hours. Uterine contraction signals were monitored through 1 hour after stopping oxytocin infusion. Based on the PK study data summarized above, it was expected that administration of the Reference drug would result in a rapid drop in plasma drug concentration after 3 hours (e.g., after the end of the Reference drug infusion). Thus, it was predicted that the254904-2534-7671.1Atty. Docket No. 052209-0673 P3125Reference drug would inhibit uterine contractions for about 3 hours (e.g., during the Reference drug infusion). Hence, uterine contraction frequency within 3 hours post-dosing was recorded (as the mean number of uterine contractions per 20 minutes). To better understand uterine contraction frequency before and after drug intervention (as well as trends over time), uterine contraction frequency before drug intervention was defined as “100%” and uterine contraction frequency in the following 0-3 hours and 3-5 hours were presented as “percentage change” relative to uterine contraction frequency before drug intervention. Results are shown in FIG. 4.

[0091] As seen in the figure, comparable uterine contraction inhibitory effects were observed for both treatments. Moreover, the data suggest that the composition of the present invention (atosiban pamoate suspension administered by single IM injection) exhibited a longer duration of efficacy than the Reference drug, which is consistent with the relative PK profiles reported above.

[0092] Collectively, these experiments show that spray-dried atosiban pamoate particles as described herein can be formulated in a pharmaceutically acceptable oil carrier (e.g., low viscosity MCT oil) to provide a suspension formulation with satisfactory dispersity, syringeability and injectability. The spray-dried atosiban pamoate particles exhibited a low solubility in MCT oil and good chemical stability over 5 days, indicating the good compatibility of the atosiban pamoate particles with the MCT oil carrier. The canine PK study in female beagle dogs showed that compositions of the present disclosure exhibited a longer duration of elevated drug plasma levels when administered by single IM injection as compared to the Reference drug administered by 3 hour intravenous infusion, which makes the compositions of the present invention administered by a single IM injection a drug candidate for indications such as IVF-ET, including IVF-ET in patients having repeated implantation failure (RIF).Example 4: Prophetic Clinical Example

[0093] An atosiban pharmaceutical composition as described herein (e.g., comprising spray-dried particles of atosiban pamoate hemi salt dispersed in MCT oil) is administered to a subject undergoing IVF-ET by a single intramuscular (IM) injection. The subject may have experienced repeated embryo implantation failure (RIF). The subject may have previously experienced one or264904-2534-7671.1Atty. Docket No. 052209-0673 P3125 two embryo implantation failures, e.g., the subject may be undergoing a third (or subsequent) embryo transfer. The atosiban exhibits good residence time after IM injection and achieves a prolonged drug release duration. The treatment reduces uterine contractions and facilitates embryo implantation.274904-2534-7671.1

Claims

Atty. Docket No. 052209-0673 P3125WHAT IS CLAIMED IS:

1. A pharmaceutical composition of atosiban, comprising atosiban particles in a pharmaceutically acceptable oil carrier.

2. The composition of claim 1, wherein the atosiban is a hydrophobic salt of atosiban.

3. The composition of claim 1, wherein the atosiban is in the form of spray-dried particles of a hydrophobic salt of atosiban.

4. The composition of claim 1, wherein the atosiban is atosiban pamoate.

5. The composition of claim 4, wherein the atosiban pamoate is a hemi salt having a molar ratio of atosiban to pamoate of about 2: 1.

6. The composition of claim 4 or claim 5, wherein the atosiban pamoate is in the form of spray-dried particles of atosiban pamoate.

7. The composition of claim 6, wherein the spray-dried atosiban pamoate particles are dispersed in the oil carrier.

8. The composition of claim 6 or claim 7, wherein the spray-dried atosiban pamoate particles have a substantially spherical or near-spherical shape, and a longest diameter of from about 0.1 pm to about 50 pm (microns).

9. The composition of any one of claims 6-8, wherein the spray-dried particles of atosiban pamoate have an atosiban pamoate content selected from at least 90% w / w, at least 95% w / w, and at least 99% w / w.

10. The composition of any one of the preceding claims, wherein the pharmaceutically acceptable oil comprises one or more selected from a pharmaceutically acceptable medium chain triglyceride oil (MCT oil) and a pharmaceutically acceptable vegetable oil.284904-2534-7671.1Atty. Docket No. 052209-0673 P312511. The composition of claim 10, wherein the pharmaceutically acceptable oil comprises MCT oil having a viscosity of about 25-35 cP at 20°C.

12. The composition of claim 10 or claim 11, wherein the pharmaceutically acceptable oil comprises a pharmaceutically acceptable vegetable oil selected from soybean oil, sesame oil, olive oil, and peanut oil.

13. The composition of claim 12, wherein the pharmaceutically acceptable oil has a viscosity lower than 50 cP at 20°C.

14. The composition of any one of the preceding claims, further comprising one or more additional pharmaceutically acceptable carrier ingredients, optionally where the one or more additional pharmaceutically acceptable carrier ingredients are selected from antioxidants, antimicrobial agents, emulsifiers, and solvents.

15. The composition of any one of the preceding claims, prepared as a sterile composition.

16. The composition of any one of the preceding claims, wherein the composition comprises from about 1 % w / w to about 50% w / w of the atosiban particles, optionally wherein the composition comprises from about 5% w / w to about 20% w / w the atosiban particles.

17. The composition of any one of the preceding claims, wherein the composition comprises from about 50% w / w to about 99% w / w of the oil carrier.

18. The composition of any one of the preceding claims, wherein the composition comprises a therapeutically effective dose of atosiban in a volume of from about 1 mL to about 5 mL.

19. The composition of any one of the preceding claims, wherein the composition comprises from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL.

20. The composition of any one of the preceding claims, wherein the composition comprises from about 100 mg to about 500 mg atosiban (on a free base basis) in a volume of about 2 mL.294904-2534-7671.1Atty. Docket No. 052209-0673 P312521. The composition of any one of the preceding claims, wherein the composition comprises about 330.75 mg atosiban (on a free base basis) in a volume of from about 2 mL to about 5 mL.

22. The composition of any one of the preceding claims, wherein the composition comprises about 330.75 mg atosiban (on a free base basis) in a volume of about 2 mL.

23. The composition of any one of the preceding claims, wherein the composition exhibits an injection force from a 25-guage needle selected of less than 1200g.

24. The composition of any one of the preceding claims, wherein the composition exhibits an injection force from a 25-guage needle selected from 1000g or less, 750g or less, and 500g or less.

25. The composition of any one of the preceding claims, wherein the composition exhibits an injection force from a 25-guage needle of from about 300g to about 500g.

26. A kit for preparation of a composition of any one of the preceding claims comprising (i) a first container containing the atosiban particles and (ii) a second container containing the pharmaceutically acceptable oil.

27. The kit of claim 26, wherein the first container contains dry atosiban particles in powder form.

28. The kit of claim 26, wherein (i) the first container contains atosiban particles in a first oil carrier comprising the pharmaceutically acceptable oil, and (ii) the second container contains a second oil carrier comprising the pharmaceutically acceptable oil.

29. A method of administering atosiban to a subject in need thereof, comprising administering a composition according to any one of claims 1-25 to a subject in need thereof.

30. A method of inhibiting uterine contractions in a subject in need thereof, comprising administering a composition according to any one of claims 1-25 to a subject in need thereof.304904-2534-7671.1Atty. Docket No. 052209-0673 P312531. An atosiban pharmaceutical composition according to any one of claims 1-25 for use in inhibiting uterine contractions in a subject in need thereof.

32. Use of atosiban in the preparation of a medicament for inhibiting uterine contractions in a subject in need thereof, wherein the medicament comprises an atosiban pharmaceutical composition according to any one of claims 1-25.

33. The method, composition for use, or use of any one of claims 29-32, wherein the composition is administered by injection.

34. The method, composition for use, or use of any one of claims 29-32, wherein the composition is administered by intramuscular injection.

35. The method, composition for use, or use of any one of claims 29-34, wherein the subject is undergoing in vitro fertilization embryo transfer (IVF-ET).

36. The method, composition for use, or use of any one of claims 29-35, wherein the subject has experienced repeated implantation failure (RIF).

37. The method, composition for use, or use of claim 35 or claim 36, wherein the subject has previously experienced two embryo implantation failures.

38. The method, composition for use, or use of any one of claims 35-37, wherein the subject is undergoing a third or subsequent embryo transfer.

39. The method, composition for use, or use of any one of claims 29-38, wherein the method comprises administering a single bolus injection of the composition by intramuscular injection.

40. The method, composition for use, or use of claim 39, wherein the single bolus injection provides a therapeutically effective dose of atosiban.

41. The method, composition for use, or use of claim 39 of claim 40, wherein the single bolus injection provides a dose of atosiban of from 100 mg to 500 mg (on a free base basis).314904-2534-7671.1Atty. Docket No. 052209-0673 P312542. The method, composition for use, or use of any one of claims 39-41, wherein the single bolus injection provides a dose of atosiban of about 330.75 mg (on a free base basis).324904-2534-7671.1

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