Compositions comprising progesterone and uses thereof

Abstract

The disclosure relates to compositions comprising progesterone microparticles, methods of making such compositions, and therapeutic uses thereof. In particular, the disclosure relates to progesterone-containing compositions in which hyaluronic acid, or a salt form thereof, is used as the diluent.

Description

[0001] Compositions comprising progesterone and uses thereof

[0002] FIELD

[0003] The disclosure relates to compositions comprising progesterone microparticles, methods of making such compositions, and therapeutic uses thereof.

[0004] BACKGROUND

[0005] Progesterone is an endogenous steroid belonging to the progestogen family of hormones. Progesterone plays a major role in regulating the menstrual cycle, pregnancy and embryogenesis and is an important metabolic intermediate in the synthesis of other endogeneous steroids including the sex hormones and the corticosteroids. As such, progesterone finds utility in a wide range of treatments and therapies.

[0006] During an assisted reproductive technology (ART) treatment, such as IVF, patients typically have compromised progesterone secretion capabilities (in part due to the medications used to stimulate egg production during these treatments). However, relatively high levels of progesterone level are important to facilitate a successful implantation and early development of the embryo. Therefore, patients undergoing fertility treatment typically need progesterone supplementation. This need for progesterone supplementation can last for around 8-12 weeks before the patient begins to self-secrete enough progesterone again.

[0007] Current progesterone supplementation treatments include oral tablets, which suffer the drawback of low bioavailability. Other treatments include vaginally administered gels and capsules. The vaginal administration of these treatments can, however, cause site discomfort and irritation. Injectable formulations can offer a solution to low bioavailability and local site irritation in the vagina and oil-based formulations are also known for the delivery of progesterone. However, such oil-based formulations can cause pain at the site of administration. In addition, many of these treatments generally require administration at least once daily which can cause issues with patient compliance, in particular when the treatment causes discomfort, irritation or pain.

[0008] Exemplary progesterone-containing compositions are described in the literature. CN 107198677 describes an injectable formation of progesterone comprising a suspension of progesterone particles. CN 1845723 describes a non-oil based suspension comprising a micronized progesterone. CN112969466 describes a method of preparing progesterone particles, and formulations thereof, for injection.

[0009] However, there still remains a need for further progesterone compositions that can address one or more of the problems noted above. In particular, compositions that show good safety and good compatibility with the progesterone, and that can allow for a reduced frequency of dosing and / or that are suitable for administration by injection (e.g. compositions showing good levels of stability and injectability).

[0010] SUMMARY

[0011] The present disclosure is based upon the identification of new progesterone compositions that provide good pharmacokinetic properties. In particular, the present inventors have unexpectedly found that the choice of diluent can have a significant impact on the pharmacokinetic properties of a composition comprising progesterone microparticles.

[0012] Accordingly, disclosed herein are compositions comprising progesterone microparticles and a diluent selected from hyaluronic acid or a salt thereof. In particular, disclosed herein is a composition comprising:

[0013] (i) progesterone microparticles; and

[0014] (ii) a diluent selected from hyaluronic acid or a salt thereof; wherein the progesterone microparticles are dispersed or suspended in the diluent. The diluent may comprises a viscosity, when measured at a shear rate of 1 s-1and a temperature of 25 °C, of between about 0.01 and about 1 PaS, The composition may comprise the diluent in an amount between about 0.01 % (w / v) and about 5% (w / v) based on the total volume of the composition. The diluent may comprise an average molecular weight between about 0.01 MDa and about 5 MDa The diluent may be a hyaluronic acid salt, such as a metal hyaluronate.

[0015] The composition may be a liquid formulation. The composition may be formulated and / or administered as an injectable formulation. The composition may further comprise a wetting agent, a tonicity agent and / or a buffering agent.

[0016] There is further disclosed a method of preparing the composition, comprising the steps of:

[0017] (i) adding the progesterone microparticles to the diluent; and

[0018] (ii) mixing the progesterone microparticles with the diluent such that the progesterone microparticles are dispersed or suspended in the diluent.

[0019] The compositions of the present disclosure may find particular utility as pharmaceutical compositions.

[0020] Accordingly, there is disclosed the composition as described above or herein, or obtained or obtainable in accordance with the methods described above or herein, for use as a medicament or for use in therapy. In particular, the compositions described herein can facilitate the delivery of progesterone to a subject in need thereof. Consequently, the compositions of the disclosure may find use in any of the following:

[0021] (i) the treatment or prevention of any condition associated with reduced levels of progesterone or a progesterone deficiency;

[0022] (ii) supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF);

[0023] (iii) the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea; and

[0024] (iv) reducing the risk of miscarriage or pre-term labour.

[0025] The present disclosure also extends to methods of treating a subject in need thereof for any one of (i) to (iv) with the disclosed compositions. The present disclosure further extends to the use of the disclosed compositions in the manufacture of a medicament for use in any one of (i) to (iv).

[0026] In any of the compositions for use, the methods, and the uses described above, the composition may be administered to the subject in a therapeutically effective amount.

[0027] The compositions disclosed herein comprise a dispersion or suspension of progesterone microparticles in hyaluronic acid (or a salt thereof) and are particularly suitable for use as injectable formulations. It was unexpectedly found that this class of diluents facilitated a controlled and / or sustained release of progesterone in vivo. Indeed, compositions of this disclosure were able to provide not only therapeutically effective levels of progesterone in the plasma but also to maintain a steady plasma concentration of progesterone over a period of days, and, in some cases, weeks. Consequently, the compositions described herein offer the opportunity for new progesterone- supplementation treatment regimens which avoid the need for at least once-daily dosing.

[0028] DESCRIPTION

[0029] The current disclosure relates to a composition comprising:

[0030] (i) progesterone microparticles; and

[0031] (ii) a diluent selected from hyaluronic acid or a salt thereof; wherein the progesterone microparticles are dispersed or suspended in the diluent.

[0032] Indeed, as stated above, the present inventors have identified that using hyaluronic acid (or a salt thereof) as the diluent in a pharmaceutical composition for the release of progesterone can provide desirable pharmacokinetic properties. In addition, the compositions described herein may comprise a number of other properties that facilitate their use as an injectable formulation.

[0033] Diluent

[0034] As used herein, a diluent refers to an inactive pharmaceutical ingredient added to an active pharmaceutical ingredient to provide the composition (e.g. a pharmaceutical composition).

[0035] As described above, the progesterone microparticles may be dispersed or suspended in the diluent. As such, the composition may be considered as a dispersion or suspension of progesterone microparticles in the diluent. As used herein, a dispersion may refer to a system in which particles (in this case, progesterone microparticles) are dispersed (i.e. are spread out in) in a continuous phase of another material (in this case, the diluent). As used herein, a suspension may refer to a heterogeneous mixture of solid particles (in this case progesterone microparticles) spread throughout a liquid carrier (in this case the diluent), wherein the solid particles are not (or are not substantially) dissolved in the liquid carrier.

[0036] As stated above, in the compositions of the present disclosure, the diluent is selected from hyaluronic acid or a salt thereof.

[0037] As used herein, hyaluronic acid may refer to a polymer of disaccharides, which are composed of D-glucuronic acid and N-acetyl-D-glucosamine. These may be linked via alternating p-(1 — >4) and p-(1 — >3) glycosidic bonds.

[0038] As used herein, hyaluronic acid salts (also referred to as hyaluronates) may include metal salts of hyaluronic acid, such as sodium, potassium and the like. Accordingly, references to the diluent throughout this disclosure may embrace hyaluronic acid and also salt forms of hyaluronic acid such as sodium hyaluronate and potassium hyaluronate. Thus, the compositions of the disclosure include progesterone microparticles dispersed or suspended in a hyaluronic acid, or a hyaluronic acid salt such as sodium hyaluronate or potassium hyaluronate. In some embodiments, the diluent may be a metal hyaluronate. In some embodiments, the diluent may be sodium hyaluronate.

[0039] The diluent may comprise any suitable viscosity and / or be present in any suitable amount that: (i) provides a desired or target pharmacokinetic profile for the release of the progesterone; (ii) provides a stable dispersion or suspension of the progesterone microparticles in the diluent; and / or (iii) facilitates ease of withdrawal and / or injectability of the composition. In some embodiments, the diluent may comprise a viscosity of between about 0.01 and about 1 PaS, between about 0.025 and about 0.75 PaS, between about 0.05 and about 0.5 PaS, or between about 0.05 and about 0.46 PaS. In some embodiments, the diluent may comprise a viscosity of between about 0.1 PaS and about 0.30 PaS. In some embodiments, the diluent may comprise a viscosity of about 0.10 PaS, about 0.20 PaS, about 0.30 PaS, about 0.40 PaS or about 0.50 PaS. The viscosities described above, and as defined herein, refer to a viscosity measured at a shear rate of 1 s-1and a temperature of 25 °C. In particular the viscosities described herein may refer to a viscosity measured at a shear rate of 1 s-1and a temperature of 25 °C using a rheometer with rotating flat disc. By way of further example, the viscosities described herein may represent a dynamic viscosity.

[0040] In some embodiments, the composition may comprise the diluent in an amount between about 0.01 % (w / v) and about 5% (w / v), between about 0.05% and about 2.5% (w / v), or between about 0.1 % and about 1% (w / v) based on the total volume of the composition. In some embodiments, the composition may comprise the diluent in an amount between about 0.15% (w / v) and about 0.25% (w / v) based on the total volume of the composition. In some embodiments, the composition may comprise the diluent in an amount of about 0.15% (w / v), about 0.16% (w / v), about 0.17% (w / v), about 0.18% (w / v), about 0.19% (w / v), about 0.20% (w / v), about 0.21% (w / v), about 0.22% (w / v), about 0.23% (w / v), about 0.24% (w / v) or about 0.25% (w / v) based on the total volume of the composition.

[0041] Hyaluronic acid (and salt forms thereof) may be provided or obtained with a range of different molecular weights and diluents having a range of different molecular weights have been found to provide useful pharmaceutical compositions for the delivery of progesterone. In some embodiments, the diluent may comprise an average molecular weight between about 0.01 MDa and about 5 MDa, between about 0.1 MDa and about 4 MDa, or between about 0.3 MDa and about 3 MDa. In some embodiments, the diluent may comprise an average molecular weight between about 1 MDa and about 4 MDa, between about 2 MDa and 3 MDa. In some embodiments, the diluent may comprise an average molecular weight of about 1 .5 MDa, about 2.0 MDa, about 2.5 MDa, about 3.0 MDa, or about 3.5 MDa.

[0042] As used herein, the average molecular weight may refer to a weight average molecular weight.

[0043] In some embodiments, the composition may comprise the diluent in an amount between about 0.15% (w / v) and about 1.0% (w / v) based on the total volume of the composition, the diluent may comprise an average molecular weight between about 0.3 MDa and about 3 MDa, and / or the diluent may comprise a viscosity between about 0.05 PaS and about 0.5 PaS (when measured at a shear rate of 1 s-1and a temperature of 25 °C).

[0044] In some embodiments, the composition may comprise the diluent in an amount about 0.17% (w / v) based on the total volume of the composition, the diluent may comprise an average molecular weight of about 3 MDa and / or the diluent may comprise a viscosity of about 0.05 PaS (when measured at a shear rate of 1 s-1and a temperature of 25 °C).

[0045] In some embodiments, the composition may comprise the diluent in an amount about 1% (w / v) based on the total volume of the composition, the diluent may comprise an average molecular weight of about 0.30 MDa and / or the diluent may comprise a viscosity of about 0.05 PaS (when measured at a shear rate of 1 s-1and a temperature of 25 °C).

[0046] In some embodiments, the composition may comprise the diluent in an amount about 0.17% (w / v) based on the total volume of the composition, the diluent may comprise an average molecular weight of about 0.30 MDa and / or the diluent may comprise a viscosity of about 0.0025 PaS (when measured at a shear rate of 1 s-1and a temperature of 25 °C).

[0047] In some embodiments, the composition may comprise the diluent in an amount about 0.19% (w / v) based on the total volume of the composition, the diluent may comprise an average molecular weight of about 2.5 MDa and / or the diluent may comprise a viscosity of about 0.2 PaS (when measured at a shear rate of 1 s-1and a temperature of 25 °C).

[0048] In some embodiments, the diluent may be sterilised. By way of example, the hyaluronic acid (and salt forms thereof) may be sterilised. In some embodiments, the hyaluronic acid (or a salt form thereof) may be sterilised by a filtration process. An exemplary sterile filtration process for hyaluronic acid (or a salt form thereof) is described in W02009063291A1 , the contents of which are incorporated herein by reference. In some embodiments, the hyaluronic acid (or a salt form thereof) may be sterilised by a steam sterilisation process. An exemplary steam sterilisation process for hyaluronic acid (or a salt form thereof) is described in CN 106139178A, the contents of which are incorporated herein by reference.

[0049] Progesterone microparticles The compositions of the present disclosure comprise progesterone in the form of microparticles.

[0050] Progesterone (also known as pregn-4-ene-3, 20-dione and sometimes referred to as P4) is an endogeneous steroid and progestogen sex hormone involved in the menstrual cycle. The structure of progesterone is shown below:

[0051] Progesterone is present in the disclosed compositions in the form of microparticles.

[0052] As used herein, microparticles may refer to particles between about 0.1 pm and about 100 pm in size.

[0053] Thus, the progesterone microparticles that are dispersed or suspended in the compositions typically comprise a particle size between about 0.01 pm and about 100 pm, or between about 0.1 pm and about 50 pm. In some embodiments, the progesterone microparticles may comprise a particle size between about 1 pm and about 25 pm, or between about 1 pm and about 20 pm.

[0054] In some embodiments, the ranges described above may refer to a mean or average particle size diameter. In some embodiments, the ranges described above may refer to a particle size diameter where fifty percent of the distribution of the particles has a smaller diameter and fifty percent has a larger diameter (a D50 value). In some embodiments, the ranges described above may refer to a particle size diameter wherein ninety percent of the distribution of the particles has a smaller diameter and ten percent has a larger diameter (a D90 value).

[0055] In some embodiments, the progesterone microparticles may comprise a particle size distribution such that a D90 value lies between about 0.01 pm and about 100 pm, between about 0.1 pm and about 50 pm, or between about 1 pm and about 25 pm.

[0056] In some embodiments, the progesterone microparticles may comprise a relatively uniform size. The span of the size of the progesterone microparticles may provide an indication of the distribution of the particle sizes and / or uniformity of the particle size. The span of the microparticles may be determined in accordance with the following formula:

[0057] Span = (D90 - D10) / D50, wherein D90, D10 and D50 are as defined above and herein.

[0058] In some embodiments, the span of the progesterone microparticles may be less than or equal to about 20, less than or equal to about 10, less than or equal to about 5, or less than or equal to about 2.5, or less than or equal to about 1.75. In some embodiments, the span may be between about 1 and 2.

[0059] The progesterone microparticles may be present in the composition in any suitable amount to provide a desired therapeutic effect. In some cases, it will be appreciated that higher loadings of the microparticles can impact on other properties of the composition, such as the ease with which the dispersion or suspension can be prepared, the stability of the resultant dispersion or suspension, the ease of withdrawal of the composition into a syringe and / or the injectability of the composition. In some embodiments, the progesterone microparticles may be present in the composition in any suitable amount that provides both a desired therapeutic effect whilst also providing one or more other favourable properties, such as ease of suspension or dispersion of the progesterone microparticles in the diluent, good levels of stability, ease of withdrawal and / or good levels of injectability. In particular, the present inventors have identified that the use of hyaluronic acid (or a salt thereof) as the diluent can provide compositions with relatively high loadings of the progesterone microparticles, whilst also showing good levels of stability, good dispersibility during its preparation, ease of withdrawal and / or good injectability.

[0060] In some embodiments, the progesterone microparticles may be present in the composition at a concentration between about 1 mg / mL and about 500 mg / mL. By way of further example, in some embodiments, the progesterone microparticles may be present in the composition at a concentration between about 100 mg / mL and about 400 mg / mL, between about 150 mg / mL and about 300 mg / mL, or between about 250 mg / mL and about 300 mg / mL. In some embodiments, the progesterone microparticles may be present in the composition at a concentration of between about 275 mg / mL and about 300 mg / mL.

[0061] In some embodiments, the progesterone microparticles may comprise an average particle size between about 1 pm and about 20 pm, a span between about 1 and 2 and / or may be present in the composition at a concentration of between about 275 mg / mL and about 300 mg / mL.

[0062] Additional excipients In addition to the diluents described herein, the compositions of the present disclosure may further comprise one or more additional excipients. The one or more additional excipients may include, for example, a wetting agent, a tonicity agent and / or a buffering agent. In some embodiments, the compositions of the present disclosure may comprise a wetting agent and a buffering agent. In some embodiments, the compositions of the present disclosure may comprise a wetting agent, a tonicity agent and a buffering agent.

[0063] Thus, in some embodiments, the compositions may comprise a wetting agent. Suitable wetting agents may include polyoxyethylene sorbitan monolaurates. In some embodiments, the wetting agent may be polyoxyethylene (80) sorbitan monolaurate or polyoxyethylene (20) sorbitan monolaurate. In some embodiments, the wetting agent is polyoxyethylene (80) sorbitan monolaurate.

[0064] When present in the compositions of the disclosure, the wetting agent is present in any suitable amount. In some embodiments, the wetting agent may be present in the composition at a concentration between about 0.01 % w / v and about 10% w / v, between about 0.05% w / v and about 5% w / v, between about 0.075% w / v and about 1 % w / v, or between about 0.1 % w / v and about 0.25% w / v. In some embodiments, the wetting agent may be present in the composition at a concentration of about 0.15% w / v, about 0.16% w / v, about 0.17% w / v, about 0.18% w / v, about 0.19% w / v, or about 0.20% w / v.

[0065] As stated above, in some embodiments, the compositions may comprise a tonicity agent. Suitable tonicity agents may include sugars, sugar alcohols, and salts. In some embodiments, the tonicity agent may be a sugar alcohol, such as sorbitol or glycerin, or a salt, such as sodium chloride. In some embodiments, the tonicity agent may be sorbitol.

[0066] When present in the compositions of the disclosure, the tonicity agent is present in any suitable amount. In some embodiments, the tonicity agent may be present in the composition at a concentration between about 0.01 % w / v and about 10% w / v, between about 0.1% w / v and about 7.5% w / v, between about 2% w / v and about 5% w / v, or between about 3% w / v and about 4% w / v. In some embodiments, the tonicity agent may be present in the composition at a concentration of 3.5% w / v, or 3.6% w / v.

[0067] As stated above, in some embodiments, the compositions may comprise a buffering agent. The buffering agent may act to adjust or maintain a pH of the composition. In some embodiments, the buffering agent may act to adjust or maintain a pH of the composition at a physiological pH, or close to a physiological pH. Any suitable buffering agent may be employed in the compositions of this disclosure. Representative examples of suitable buffering agents include, but are not limited to, a phosphate buffer, citrate buffer, or tris buffer. In some embodiments, the buffering agent is phosphate- buffered saline (PBS) solution. In some embodiments, the buffering agent is a citrate buffer. For example, the buffering agent may comprise citric acid and trisodium citrate. By way of further example, the composition may comprise citric acid at a concentration ranging between about 0.001 % w / v and about 0.01 % w / v (e.g. about 0.005% w / v) and trisodium citrate at a concentration ranging between about 0.1 % w / v and about 1.5% w / v (e.g. about 0.85% w / v).

[0068] The compositions disclosed herein may comprise any suitable pH. In some embodiments, the compositions may comprise a pH that is around a physiological pH. In some embodiments, the composition may have a pH between about 6.5 and about 7.4, or between about 7.0 and about 7.4.

[0069] The compositions of the disclosure may comprise a liquid formulation. In some embodiments, the composition may be or comprise an aqueous formulation. In such embodiments, the diluent may form part of an aqueous carrier. In other words, the composition may comprise an aqueous carrier, the aqueous carrier comprising the diluent and, if present, any one or more additional excipients (e.g. a wetting agent and / or a buffering agent). In such embodiments, the progesterone microparticles may be dispersed or suspended throughout the aqueous carrier e.g. as a homogeneous or substantially homogeneous suspension or dispersion.

[0070] In some embodiments of the disclosure, the composition may comprise:

[0071] (i) progesterone microparticles at a concentration between about 150 mg / mL and about 400 mg / mL;

[0072] (ii) a diluent as defined herein having a viscosity between about 0.05 and about 0.5 PaS, when measured at a shear rate of 1 s-1and a temperature of 25 °C;

[0073] (iii) optionally a wetting agent at a concentration between about 0.1 % w / v and about 0.25% w / v; and

[0074] (iv) optionally a buffering agent.

[0075] In some embodiments of the disclosure, the composition may comprise:

[0076] (i) progesterone microparticles at a concentration between about 150 mg / mL and about 400 mg / mL;

[0077] (ii) a diluent as defined herein having a viscosity between about 0.05 and about 0.5 PaS, when measured at a shear rate of 1 s-1and a temperature of 25 °C; (iii) a wetting agent at a concentration between about 0.1% w / v and about 0.25% w / v; and

[0078] (iv) a buffering agent; and

[0079] (v) a tonicity agent.

[0080] Method of manufacture

[0081] As stated above, according to an aspect of the disclosure, there is provided a method of preparing a composition as described herein. In one example, the method may comprise the steps of:

[0082] (i) adding progesterone microparticles to a diluent, wherein the diluent is selected from hyaluronic acid or a salt thereof; and

[0083] (ii) mixing the progesterone microparticles with the diluent such that the progesterone microparticles are dispersed or suspended in the diluent.

[0084] The step of mixing the progesterone microparticles may be carried out using any suitable mixing method as known in the art. Suitable mixing methods may include, but are not limited to, dual-syringe plunger mixing, centrifugal mixing methods and / or agitator mixing methods. In some embodiments, the step of mixing is carried out to facilitate the formation of a homogeneous (or substantially homogeneous) and / or stable dispersion or suspension of the progesterone microparticles in the diluent.

[0085] As stated previously, the compositions of the present disclosure may comprise one or more additional excipients. Accordingly, in some embodiments, the method may comprise adding one or more additional excipients to the diluent, and optionally mixing the one or more additional excipients with the diluent, prior to the addition of the progesterone microparticles.

[0086] By way of further example, in some embodiments, the composition may further comprise a wetting agent, a tonicity agent and / or a buffering agent. In such embodiments, the method may comprise adding the wetting agent, the tonicity agent and / or the buffering agent to the diluent, and optionally mixing the wetting agent, the tonicity agent and / or the buffering agent with the diluent, prior to addition of the progesterone microparticles.

[0087] The one or more additional excipients (e.g. a wetting agent, the tonicity agent and / or buffering agent) may be any of those as described above and herein.

[0088] As stated above, in some embodiments, the compositions may be or comprise an aqueous formulation. In such examples, the method may comprise mixing the diluent with an aqueous solution, and optionally one or more additional excipients as noted above, to provide an aqueous carrier. The method may then comprise mixing the progesterone microparticles with the aqueous carrier such that the progesterone microparticles are dispersed or suspended in the aqueous carrier.

[0089] Medical Utility

[0090] The compositions of the present disclosure find particular utility as pharmaceutical compositions. In particular, the compositions described herein may find use as pharmaceutical compositions for the delivery of progesterone microparticles to a subject or patient.

[0091] Any suitable mode of administration may be used but the compositions find particular utility as injectable compositions. As noted above, the present inventors have unexpectedly identified that certain diluents can have a significant effect on the pharmacokinetic properties of a composition formulated for the delivery and / or release of progesterone. In particular, the present inventors have identified that, in contrast to other diluents, hyaluronic acid-based diluents can provide a controlled and / or sustained release of progesterone over a period of time following administration of the composition to a subject.

[0092] In particular, in some embodiments, compositions comprising a hyaluronic acidbased diluent can be used to maintain and / or provide a steady plasma concentration of progesterone in a subject. In some examples, compositions comprising a hyaluronic acid-based diluent can be used to provide a target plasma concentration of progesterone in a subject. By way of further example, in some embodiments, the compositions of the disclosure may be used to provide and / or maintain a steady plasma concentration and / or to provide a target plasma concentration of progesterone in a subject during a period of time following administration of the composition.

[0093] In some embodiments, the period of time following administration of the composition is between day 0 (i.e. the day of administration) or day 1 (i.e. the day following administration) and a later day after administration of the composition. By way of example, in some embodiments, the period of time is between day 1 and any one of day 4, day 5, day 6, day 7, day, 8, day 9, day 10, day 11 , day 12, day 13 or day 14 following administration of the composition.

[0094] As described herein, a target plasma concentration of progesterone may refer to a plasma concentration of progesterone that provides a desired therapeutic effect. Accordingly, and as would be understood by one of skill in the art, the precise target plasma concentration of progesterone may vary in accordance with the desired therapeutic effect. In some embodiments, and as described herein, a steady plasma concentration of progesterone may refer to a plasma concentration of progesterone that is maintained within a certain tolerance (e.g. within a certain percentage) of the target plasma concentration. The precise tolerance may depend upon the subject being treated and / or the desired therapeutic effect.

[0095] In some embodiments, and in use, the composition may provide an AUCo-y of progesterone in the plasma of at least 400 h*ng / mL, or at least about 500 h*ng / mL. As used herein, AUC0-7 may refer to an area under the curve in the initial 7 days following administration of the composition (i.e. between the day of administration, day 0, and day 7 following administration). This value may represent the definite integral of the concentration of progesterone in the plasma as function of time.

[0096] In some embodiments, and in use, the composition may maintain a plasma concentration at a level within about ± 1 ng / mL, about ± 2 ng / mL, about ± 3 ng / mL, about ± 4 ng / mL, about ± 5 ng / mL, about ± 10 ng / mL, or about ± 20 ng / mL of a target plasma concentration. In some embodiments, and in use, the composition may maintain a plasma concentration at a level within about ± 40%, about ± 30%, about ± 20%, about ± 10%, or about ± 5 % of a target plasma concentration.

[0097] In some embodiments, and in use, the composition may provide a target plasma concentration of progesterone of about 5 ng / mL to about 100 ng / mL, about 10 ng / mL to about 75 ng / mL, or about 15 ng / mL to about 50 ng / mL.

[0098] There is disclosed a composition as described herein, or obtainable in accordance with the methods described herein, for use as a medicament or for use in therapy.

[0099] In particular, the compositions described herein can facilitate the delivery of progesterone to a subject in need thereof. Consequently, the compositions of the disclosure may find use in any of the following:

[0100] (i) the treatment or prevention of any condition associated with reduced levels of progesterone or a progesterone deficiency;

[0101] (ii) supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF);

[0102] (iii) the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea; and

[0103] (iv) reducing the risk of miscarriage or pre-term labour. Methods of treating a subject in need thereof with a composition as described herein are also encompassed within the present disclosure. Accordingly, there is further provided:

[0104] (i) a method of treating or preventing a condition associated with reduced levels of progesterone or a progesterone deficiency in a subject in need thereof, comprising administering to the subject a composition as described herein;

[0105] (ii) a method of progesterone supplementation in a subject undergoing an assisted reproductive technology (ART) treatment, such as in vitro fertilization (IVF), comprising administering to the subject a composition as described herein;

[0106] (iii) a method of treating or preventing a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea in a subject in need thereof, comprising administering to the subject a composition as described herein; and

[0107] (iv) a method of reducing the risk of miscarriage or pre-term labour in a subject in need thereof, comprising administering to the subject a composition as described herein.

[0108] Uses of the compositions described herein, in the manufacture of a medicament, are further encompassed within the present disclosure. Accordingly, there is further provided:

[0109] (i) use of a composition as described herein, in the manufacture of a medicament for treating or preventing a condition associated with reduced levels of progesterone or a progesterone deficiency in a subject in need thereof;

[0110] (ii) use of a composition as described herein, in the manufacture of a medicament for progesterone supplementation in a subject undergoing an assisted reproductive technology (ART) treatment, such as in vitro fertilization (IVF);

[0111] (iii) use of a composition as described herein, in the manufacture of a medicament for treating or preventing a condition selected from infertility, miscarriage, preterm labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea in a subject in need thereof; and

[0112] (iv) use of a composition as described herein, in the manufacture of a medicament for reducing the risk of miscarriage or pre-term labour in a subject in need thereof. In any of the compositions for use, the methods, and the uses described above, the composition may be administered to the subject in a therapeutically effective amount. As used herein, a subject, a subject in need thereof, or a patient may refer to a mammalian subject, such as a human subject. In some examples, the mammalian subject may be a female mammalian subject.

[0113] Dosage regimen

[0114] The composition may be administered in any suitable dosage regimen to provide a desired therapeutic effect. The therapeutically effective amount and / or precise dosage regimen to be used may depend upon the therapeutic indication and / or the subject that is being treated.

[0115] It has been further observed by the present inventors that a repeated dosage regimen can provide an accumulation effect which might have therapeutic benefits in some indications. In such examples, a steady state will be reached after repeated administrations of the composition.

[0116] Thus, in some embodiments, the composition may be administered to a subject in need thereof, between 1 and 5 times per week, between 1 and 3 times per week, between 1 and 2 times per week, or once a week, or once every two weeks.

[0117] Additionally or alternatively, in some embodiments, the composition may be administered to a subject in need thereof, over a period of at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks. Additionally or alternatively, in some embodiments, the composition may be administered to a subject in need thereof, over a period between 4 and 16 weeks, such as a period between 8 and 12 weeks.

[0118] In some embodiments, the composition may be administered to a subject in need thereof once a week over a period of 4 weeks, or a period between 8 and 12 weeks.

[0119] In some embodiments, the composition may be administered to a subject in need thereof once a week, or once every two weeks, over a period between 8 and 12 weeks.

[0120] General Definitions

[0121] It should be noted that the terms “comprise”, “comprising” and / or “comprises” is / are used to denote that the various aspects, embodiments and examples of this disclosure “comprise” a particular feature or features. It should be understood that this / these terms may also encompass aspects, embodiments and / or examples which “consist essentially of” or “consist of” the relevant feature or features. Moreover, the entire contents of all references are to be regarded as incorporated herein by reference. As used herein, the term “about” when qualifying a number or value, may refer to values that lie within ± 5% of the value specified. For example, where the wetting agent is described as being present at a concentration of about 0.15% (w / v) a range of 0.1425% (w / v) to 0.1575% (w / v) is included.

[0122] In addition, as used herein, where any range is described as being between a lower limit and an upper limit, the defined range includes the defined endpoints (and so includes both the lower limit and upper limit values).

[0123] Additionally, in the present disclosure, the nomenclature used herein for defining compounds, in particular the compounds according to the disclosure, is in general based on the rules of the IIIPAC organisation for chemical compounds, specifically the “IIIPAC Compendium of Chemical Terminology (Gold Book)”, unless the context indicates otherwise.

[0124] DESCRIPTION OF FIGURES

[0125] The present disclosure will now be further described, by way of example only, with reference to the following Figures and examples.

[0126] Figure 1 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a CMC-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0127] Figure 2 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a Tris-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0128] Figure 3 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a dextran-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0129] Figure 4 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a PLGA-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0130] Figure 5 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a gelatin-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0131] Figure 6 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) formulations based on (i) a hyaluronic acid (HA)-based diluent; and (ii) a PVP-based diluent, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0132] Figure 7 shows the Area Under the Curve (AUC) for the plasma concentration of progesterone during the time period day 0 to day 7 following administration of exemplary progesterone formulations (in h*ng / mL).

[0133] Figure 8 shows the results of pharmacokinetic studies following administration of progesterone long-acting injectable (LAI) example formulations T11 , T13 and T14, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0134] Figure 9 shows the Area Under the Curve (AUC) for the plasma concentration of progesterone during the time period day 0 to day 7 following administration of the exemplary progesterone formulations T11 , T13 and T14 (in h*ng / mL).

[0135] Figure 10 shows the results of injectability studies on a number of exemplary formulations containing respectively (i) 200mg / mL syringe laid flat on bench for Omin; (ii) 200mg / mL syringe laid flat on bench for 10 min; (iii) 200 mg / mL syringe laid flat on bench for 30 min; (iv) 466 mg / mL; and (v) 425 mg / mL, with a plot showing the force (g) of injection against distance.

[0136] Figure 11 shows the results of pharmacokinetic studies following a weekly administration of an exemplary progesterone long-acting injectable (LAI) formulation, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0137] Figure 12 shows the results of pharmacokinetic studies following an administration of an exemplary progesterone long-acting injectable (LAI) formulation, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days).

[0138] Figure 13 shows the results of pharmacokinetic studies following an administration of an exemplary progesterone long-acting injectable (LAI) formulation T16, in particular the average concentration of progesterone in plasma (in ng / mL) is plotted against time (in days). EXAMPLES

[0139] Part A - Preparation of Progesterone Microparticles (Jet Milling)

[0140] Nozzle Micron Pilot machine was used to reduce progesterone particle size to the desired value using a jet milling process. The feeding pressure, milling pressure and feeding rate were selected to provide particles of the desired size and specification in accordance with known methods (see, for example, “Jet Milling And Particle Classification", article from Fluid Energy, Processing and Equipment Company, https: / / www.fluidenerqvpe.com / article / jet-millinq-and-particle-classfication / and Protonotariou et al, “Jet milling conditions impact on wheat flour particle size”, Journal of Food Engineering, Volume 292, April 2021, 110418, the contents of which are incorporated herein by reference). The desired size and specification of progesterone particles are shown in table 1 below.

[0141] Table 1 showing mean particle size and span range.

[0142] Particles were made in accordance to these specifications and were used in the examples described herein.

[0143] Particle size measurement

[0144] The particle size of the progesterone particles was measured in accordance with the following method.

[0145] 1. Mi II iQ water was ultrasounded.

[0146] 2. On a digital analytic scale, about 50mg progesterone particles was weighed and added to 2mL Eppendorf tubes.

[0147] 3. 1mL of dispersion medium (0.5% w / w Polysorbate 80) was added to the 2mL tube.

[0148] 4. The sample was vortexed until the suspensions looked homogeneous.

[0149] 5. The sample was ultrasounded for 10 min.

[0150] 6. The Mastersizer 3000 was used to measure particle size distribution using the following parameters:

[0151] Description Parameter Diluent 0.5% w / w polysorbate 80 solution

[0152] Circulation speed 1500-1800 rpm Particle Refractive Index (Rl) 1.59 Dispersant Refractive Index (Rl) 1.33 Target laser obscuration level 5% to 20%

[0153] 7. Each sample was vortexed before being added to the dispersion unit.

[0154] 8. The unit was washed with ultrasounded Millipore water once before the next sample was added.

[0155] 9. Measurement records (n=5, Dv10, Dv50 and Dv90 and Span) were exported in text file.

[0156] 10. The PSD curves (volume distribution) of the average measurements (n=5) were also reported.

[0157] Part B - Preparation of base medium

[0158] The preparation of various base media for the exemplary compositions disclosed herein is disclosed for the various different diluents tested.

[0159] B.1 - HA-based diluent

[0160] 1 . The required amount of sodium hyaluronate (HA) was weighed in a glass bottle. The required amount of buffer solution (e.g. phosphate buffered saline (PBS); or citrate buffer solution) was added to make HA solution with the desired concentration. This mixture was stirred, using a magnetic stirrer, until visually homogeneous.

[0161] 2. The required amount of polysorbate 80 (Tween 80) was added to the mixture, which was stirred until visually homogeneous.

[0162] 3. The dissolved solutions were stored at 2-8°C.

[0163] In the studies described in section D and shown in Figures 1 to 7, 3MDa sodium hyaluronate (HA) was used to provide a 0.17% HA solution and the concentration of polysorbate 80 was 0.17%w / v. In the study described in section G.3 and shown in Figure 13, 2.5MDa sodium hyaluronate (HA) was used to provide a 0.25% HA solution and the concentration of polysorbate 80 was 0.17%w / v.

[0164] B.2 - sodium Carboxymethyl cellulose (CMC) diluent

[0165] 1 . A 200ml aliquot of deionised (DI) water was obtained.

[0166] 2. 1g of sodium Carboxymethyl cellulose (CMC Na) was added. 3. After fully solubilized, 1 ml of polysorbate 80 was added.

[0167] 4. The solution was filtered under sterile conditions and filled into a 100ml bottle.

[0168] 5. The bottle was crimped with a stopper.

[0169] B.3 - Tris diluent

[0170] 1. A 50mM Tris buffer, pH 7.4 was prepared.

[0171] 2. The buffer was filtered under sterile conditions and filled into a glass vial.

[0172] 3. The vial was crimped with a stopper.

[0173] B.4 - Dextran 70 diluent

[0174] 1. A 100ml aliquot of deionised (DI) water was obtained.

[0175] 2. The water was mixed with 100ml phosphate buffered saline (PBS).

[0176] 3. Under stirring, 2g of dextran 70 was added.

[0177] 4. After fully solubilized, 1 ml of polysorbate 80 was added.

[0178] 5. The mixture was filled into a 100ml bottle.

[0179] 6. The bottle was crimped with a stopper.

[0180] B.5 - Poly(lactic-co-glycolic acid) copolymer (PLGA) diluent

[0181] 1. PLGA 502H was dissolved in triacetin at a concentration of 10% w / w.

[0182] 2. The mixture was sonicated and heated to fully dissolve.

[0183] 3. The mixture was filled into a 100ml bottle.

[0184] 4. The bottle was crimped with a stopper.

[0185] B.6 - Gelatin diluent

[0186] 1. A 200ml aliquot of deionised (DI) water was obtained.

[0187] 2. Under stirring, 32g of gelatin was added.

[0188] 3. After fully solubilized, 1 ml of polysorbate 80 was added.

[0189] 4. The solution was diluted with PBS (dilution: 3:1 with PBS).

[0190] 5. The mixture was filled into a 100ml bottle.

[0191] 6. The bottle was crimped with a stopper.

[0192] B.7 - Poly(1-vinyl-2- diluent

[0193] 1. A 50ml aliquot of deionised (DI) water was obtained.

[0194] 2. The water was mixed with 50ml PBS.

[0195] 3. Under stirring, 1001 ,04mg of PVP-K30 was added. 4. After fully solubilized, 502.44mg of polysorbate 80 was added.

[0196] 5. The mixture was filled into a 100ml bottle.

[0197] 6. The bottle was crimped with a stopper.

[0198] C - Preparation of exemplary progesterone formulations

[0199] Progesterone microparticles and the example diluent of choice (each separately prepared as outlined above in sections B.1 to B.7) were mixed in a centrifuge tube to obtain the desired concentration. Suspension was obtained by vortex in the centrifuge tube until visually homogeneous to provide the long-acting injectable (LAI) formulations used in the subsequent pharmacokinetic studies.

[0200] In the studies described in section D and shown in Figures 1 to 8, a concentration of 161 mg / mL of progesterone was used for each formulation.

[0201] D - Pharmacokinetic (PK) study

[0202] Beagle dogs (11-12m, ~10kg) underwent ovariectomy and hysterectomy and were rested for around 6 weeks to allow plasma progesterone concentration to drop below 20% of lower limit of quantitation (LLOQ) (LLOQ=1ng / mL). The exemplary progesterone formulations (as described in sections B and C above) were injected subcutaneously at the back of neck at day 0, and blood was withdrawn from forelimb cephalic vein or jugular vein at pre-determined time points (final time point being day 7 following administration). Plasma progesterone concentration was analyzed by LC-MS / MS. Animals were allowed to rest after each round of dosing until their plasma progesterone concentration dropped below 20% of LLOQ (1ng / mL) and were ready for the next round of dosing. Each formulation was injected and assessed for six animals (i.e. N=6 for each group).

[0203] The mean plasma progesterone concentration was calculated for each formulation and was plotted against time (in days). The results are illustrated in Figures 1 to 6.

[0204] The hyaluronic acid-based diluent was found to provide a sustained release of progesterone over 7 days. In particular, the hyaluronic acid-based diluent was found to maintain the progesterone plasma concentration for a longer time compared to the other diluents tested, CMC, Tris, dextran, PLGA, gelatin, and PVP. The area under the curve (AUC) over the period of time from day 0 to day 7 following administration of the exemplary progesterone formulations were calculated and the results are shown on Figure 7.

[0205] The use of a hyaluronic acid-based diluent in the progesterone formulation provided a higher AUC than was observed for the formulations based on the diluents dextran, PLGA, PVP and gelatin. Whilst the HA-based diluent provided a similar AUC to CMC and Tris, the use of the CMC and Tris diluents provided a poorer sustained release of the progesterone, with higher plasma concentrations of progesterone at earlier time points and a relatively rapid decline in plasma concentrations of progesterone, resulting in a lower plasma concentration of progesterone at later time points (see Figures 1 and 2).

[0206] E. Investigations into hyaluronic acid diluents

[0207] Further investigations were carried out into a series of hyaluronic acid-based diluents as outlined below.

[0208] E.1 Preparation of further exemplary formulations

[0209] Exemplary formulations T11 , T13, T14, T15 and T16 were made to study the effects of the molecular weight and viscosity of the HA-based diluent and to further study the pharmacokinetic properties of the exemplary formulations. The formulations were prepared in accordance with the method described in section B.1 and C above, using sodium hyaluronate having a molecular weight and in the concentrations outlined in table 2 below.

[0210] Table 2 shows the molecular weight (weight average molecular weight) of the sodium hyaluronate (HA), the concentration and viscosity used in exemplary formulations T11 , T13, T14, T15 and T16. * In formulations T11 , T13 and T14, the concentration of progesterone microparticles was 161 mg / mL, in formulation T15, the concentration of progesterone microparticles was 285 mg / mL. In formulations T11 , T13, T14 and T15 shown in Table 2, the concentration of Tween 80 was 0.17% w / v and 1X PBS was used as the buffer solution. In T16, the concentration of progesterone microparticles was 285mg / mL; the progesterone and the HA were sterilised; and the concentration of Tween 80 was 0.17% w / v. In T16, the formulation comprised a citrate buffer (citric acid (anhydrous) 0.005% w / v and trisodium citrate (0.85% w / v)), sorbitol (3.6% w / v) and water (q.s. to 100% w / v). The citrate buffer was observed to minimise the degradation of the sodium hyaluronate during the sterilisation process in comparison to a number of other buffers. The viscosity of these sodium hyaluronate diluents was also determined in accordance with the method described in section E.2.

[0211] The pharmacokinetic properties of exemplary formulations based on each of the sodium hyaluronate diluents were studied as outlined in section E.3.

[0212] E.2. Viscosity testing

[0213] Viscosities of the HA-based diluents as shown in table 2 were determined in accordance with the following method:

[0214] 1. The DHR equipment was activated and calibrated according to the instruction manual. The temperature was set at 25 °C.

[0215] 2. Samples were taken out from a 2-8 °C fridge and allowed to come to room temperature before using.

[0216] 3. 0.45 mL of each sample was added to the DHR heating platform by using a Piston pipette.

[0217] 4. Metal plate was lowered to be 1000um above the heating platform

[0218] 5. The excess sample, outside the metal plate, was wiped carefully with a ruler and a small cotton swab

[0219] 6. The viscosity of the sample was measured based on the above parameters shown below:

[0220] Diameter 40 mm

[0221] GAP 1000.0 urn

[0222] Material Aluminum

[0223] Environment system Peltier Plate

[0224] Minimum sample volume 1.26 ml Environmental Control Temperature 25 °C Soak time 0.0 s

[0225] Test parameters

[0226] Flow sweep

[0227] Shear rate 0.1 to 1000.0 1 / s

[0228] Points per decade 5

[0229] Equilibration time 5.0 s Averaging time 30.0 s

[0230] E.3 Pharmacokinetic Studies

[0231] The same cohort of beagle dogs as described in section D were used in these studies. The exemplary progesterone formulations T11 , T13 and T14 were injected subcutaneously at the back of neck at day 0, and blood was withdrawn from forelimb cephalic vein or jugular vein at pre-determined time points. Plasma progesterone concentration was analyzed by LC-MS / MS. Animals were allowed to rest after each round of dosing until their plasma progesterone concentration dropped below 20% of LLOQ (1 ng / mL) and were ready for the next round of dosing. Each formulation was injected and assessed for six animals (i.e. N=6 for each group).

[0232] The mean plasma progesterone concentration was calculated for each formulation and was plotted against time (in days). The results are illustrated in Figure 8.

[0233] The area under the curve (AUC) over the period of time from day 0 to day 7 following administration of the exemplary progesterone formulations T11 , T13 and T14 were calculated and the results are shown on Figure 9.

[0234] The inventors observed that formulation T14 yields a lower plasma concentration of progesterone and a lower AUC, but a longer release duration. It was further observed that example formulations T11 and T13 which have similar viscosities showed similar pharmacokinetic profiles, despite having a different molecular weight and being present at different concentrations.

[0235] F - Different Drug Loadings

[0236] Further studies were carried out to assess different drug loadings in the HA-based diluent formulations. F.1 - Injectability assessment

[0237] F.1a

[0238] The injectability of a number of example formulations was determined using the following method:

[0239] 1 . A syringe with the exemplary suspension was mounted on the TA (texture analyzer)

[0240] 2. Injectability was measured using the following parameters:

[0241] TEXTURE TA-XT

[0242] Equipment plus 100 Test mode Compression Pre-test speed 1.00 mm / sec Test speed 2.00 mm / sec Pst-test speed 0.00 mm / sec Target mode Distance Distance 20.00 mm Trigger type Auto Force Trigger force 5.0 g Break mode Off stop plot at After reset Tare mode Auto Advanced options On Control oven Disabled

[0243] Off (XT2

[0244] Frame deflection correction compatibility)

[0245] Injectability was determined to be “good” if force required to inject was < 1200g (Robinson, T. E., Hughes, E. A. B., Bose, A., Cornish, E. A., Teo, J. Y., Eisenstein, N. M., Grover, L. M., Cox, S. C., Filling the Gap: A Correlation between Objective and Subjective Measures of Injectability. Adv. Healthcare Mater. 2020, 9, 1901521).

[0246] F.1b In addition, a manual injection was also investigated for each example formulation and the ease of injectability was recorded. A smooth manual push was graded as having “good” injectability. F.2 - Ease of dispersion

[0247] The ease of dispersion of the progesterone (API = active pharmaceutical ingredient) in the diluent was also observed and recorded for each of the example formulations (easy, relatively easy or difficult).

[0248] F.3 - Ease of suspension withdrawal

[0249] The ease of withdrawal of the progesterone suspension into a syringe (25G needle) was also observed and recorded for each of the example formulations (easy, relatively easy or difficult).

[0250] F.4 - Results

[0251] The results of studies are illustrated in the table 3 below and also Figure 10.

[0252] Table 3 shows the results of the ease of dispersion, ease of suspension withdrawal and injectability studies for a number of different progesterone concentrations.

[0253] The results indicate that:

[0254] • API concentrations lower than or equal to 285mg / mL are easy to reconstitute;

[0255] • all example formulations shown in the table above required a force < 300g and so provided an easy injection (see, for example Figure 10).

[0256] G - Further Pharmacokinetic studies

[0257] G.1 - Drug accumulation The same cohort of beagle dogs as described in section D were used in these studies. The exemplary progesterone formulation T15 (as described in Table 2) was injected subcutaneously at the back of neck at day 0, and weekly thereafter. Blood was withdrawn from forelimb cephalic vein or jugular vein at pre-determined time points. Plasma progesterone concentration was analyzed by LC-MS / MS. Animals were allowed to rest after each round of dosing until their plasma progesterone concentration dropped below 20% of LLOQ (1 ng / mL) and were ready for the next round of dosing.

[0258] The results are shown in Figure 11. The inventors observed some drug accumulation and that drug accumulation plateaus at the fourth injection.

[0259] G.2 - 14-day release

[0260] Beagle dogs (11-12m, —10kg) underwent ovariectomy and hysterectomy and were rested for around 6 weeks to allow plasma progesterone concentration to drop below 20% of lower limit of quantitation (LLOQ) (LLOQ=1ng / mL). The exemplary progesterone formulation T15 (as described in Table 2) was injected subcutaneously at the back of neck at day 0. Blood was withdrawn from forelimb cephalic vein or jugular vein at predetermined time points. Plasma progesterone concentration was analyzed by LC- MS / MS. Animals were allowed to rest after each round of dosing until their plasma progesterone concentration dropped below 20% of LLOQ (1 ng / mL) and were ready for the next round of dosing. The formulation was injected and assessed for six animals (i.e. N=6 for each group).

[0261] The results are shown in Figure 12. The inventors observed that good levels of progesterone were maintained in the plasma for at least around 14 days following the initial administration.

[0262] G.3 - Sterilised formulation

[0263] Beagle dogs (11-12m, —10kg) underwent ovariectomy and hysterectomy and were rested for around 6 weeks to allow plasma progesterone concentration to drop below 20% of lower limit of quantitation (LLOQ) (LLOQ=1ng / mL). The exemplary progesterone formulation T16 (as described in Table 2) was injected subcutaneously at the back of neck at day 0. Blood was withdrawn from forelimb cephalic vein or jugular vein at predetermined time points. Plasma progesterone concentration was analyzed by LC- MS / MS. Animals were allowed to rest after each round of dosing until their plasma progesterone concentration dropped below 20% of LLOQ (1 ng / mL) and were ready for the next round of dosing. The formulation was injected and assessed for six animals (i.e. N=6 for each group). The results are shown in Figure 13.

[0264] While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the invention in its broader aspects.

Claims

CLAIMS1 . A composition comprising:(i) progesterone microparticles; and(ii) a diluent selected from hyaluronic acid or a salt thereof; wherein the progesterone microparticles are dispersed or suspended in the diluent.

2. A composition according to claim 1 , wherein the diluent comprises a viscosity, when measured at a shear rate of 1 s-1and a temperature of 25 °C, of between about 0.01 and about 1 PaS, between about 0.025 and about 0.75 PaS, or between about 0.05 and about 0.5 PaS.

3. A composition according to claim 1 or 2, wherein the composition comprises the diluent in an amount between about 0.01% (w / v) and about 5% (w / v), between about 0.05% and about 2.5% (w / v), or between about 0.1 % and about 1 % (w / v) based on the total volume of the composition.

4. A composition according to any one of the preceding claims, wherein the composition comprises the diluent in an amount between about 0.15% (w / v) and about 0.25% (w / v), such as about 0.17% (w / v), about 0.18% (w / v), about 0.19% (w / v), or about 0.20% (w / v) based on the total volume of the composition.

5. A composition according to any one of the preceding claims, wherein the diluent comprises an average molecular weight between about 0.01 MDa and about 5 MDa, between about 0.1 MDa and about 4 MDa, or between about 0.3 MDa and about 3 MDa.

6. A composition according to any one of the preceding claims, wherein the composition comprises the diluent in an amount between about 0.15% (w / v) and about 1.0% (w / v) based on the total volume of the composition and the diluent comprises an average molecular weight between about 0.3 MDa and about 3 MDa.

7. A composition according to any one of the preceding claims, wherein the composition comprises the diluent in an amount about 0.19% (w / v) based on the total volume of the composition and the diluent comprises an average molecular weight of about 2.5 MDa.

8. A composition according to any one of the preceding claims, wherein the diluent is a hyaluronic acid salt, such as a metal hyaluronate, optionally wherein the diluent is sodium hyaluronate.

9. A composition according to any one of the preceding claims, wherein the progesterone microparticles have a particle size between about 0.01 pm and about 100 pm, between about 0.1 pm and about 50 pm, between about 1 pm and about 25 pm, or between about 1 pm and about 20 pm.

10. A composition according to any one of the preceding claims, wherein the progesterone microparticles are present in the composition at a concentration between about 1 mg / mL and about 500 mg / mL, between about 100 mg / mL and about 400 mg / mL, between about 150 mg / mL and about 300 mg / mL, between about 250 mg / mL and about 300 mg / mL, or between about 275 mg / mL and about 300 mg / mL.

11. A composition according to any one of the preceding claims, wherein the composition has a pH between about 6.5 and about 7.4, or between about 7.0 and about 7.4.

12. A composition according to any one of the preceding claims, wherein the composition comprises one or more additional excipients.

13. A composition according to claim 12, further comprising a wetting agent.

14. A composition according to claim 13, wherein the wetting agent is a polyoxyethylene sorbitan monolaurate, optionally wherein the polyoxyethylene sorbitan monolaurate is polyoxyethylene (80) sorbitan monolaurate or polyoxyethylene (20) sorbitan monolaurate.

15. A composition according to claim 13 or 14, wherein the wetting agent is present in the composition at a concentration between about 0.01% w / v and about 10% w / v, between about 0.05% w / v and about 5% w / v, between about 0.075% w / v and about 1% w / v, or between about 0.1% w / v and about 0.25% w / v.

16. A composition according to any one of the preceding claims, wherein the composition is formulated as an injectable formulation.

17. A composition according to any one of the preceding claims, wherein the composition is a liquid formulation, optionally an aqueous formulation.

18. A composition according to any one of the preceding claims, wherein the composition further comprises a buffering agent.

19. A composition according to claim 18, wherein the buffering agent is a phosphate buffer, citrate buffer, or tris buffer.

20. A composition according to any one of the preceding claims, wherein the composition comprises a tonicity agent, optionally wherein the tonicity agent is a sugar alcohol.

21. A composition according to any one of the preceding claims, wherein the composition comprises:(i) progesterone microparticles at a concentration between about 150 mg / mL and about 400 mg / mL;(ii) a diluent having a viscosity between about 0.05 and about 0.5 PaS, when measured at a shear rate of 1 s-1and a temperature of 25 °C;(iii) a wetting agent at a concentration between about 0.1% w / v and about 0.25% w / v;(iv) a buffering agent; and(v) optionally a tonicity agent.

22. A composition according to any one of the preceding claims, wherein the composition provides a controlled and / or sustained release of progesterone over a period of time following administration of the composition.

23. A composition according to any one of the preceding claims, wherein the composition maintains a steady plasma concentration of progesterone and / or provides a target plasma concentration of progesterone during a period of time following administration of the composition.

24. A composition according to any one of claims 23 or 24, wherein the period following administration of the composition is between day 0 or day 1 and a later day after administration of the composition, optionally during the period of time between day 0 or day 1 and day 4, day 5, day 6, day 7, day, 8, day 9, day 10, day 11 , day 12, day 13 or day 14 following administration of the composition.

25. A method of preparing a composition according to any one of claims 1 to 24, comprising the steps of:(i) adding the progesterone microparticles to the diluent; and(ii) mixing the progesterone microparticles with the diluent such that the progesterone microparticles are dispersed or suspended in the diluent.

26. The method of claim 25, optionally wherein the method comprises adding a wetting agent, a tonicity agent and / or a buffering agent to the diluent prior to addition of the progesterone microparticles.

27. A composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, for use in therapy.

28. A composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, for use in the treatment or prevention of a condition associated with reduced levels of progesterone or a progesterone deficiency.

29. A composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, for use in supplementing progesterone levels in a subject undergoing an assisted reproductive technology (ART) procedure, such as in vitro fertilization (IVF).

30. A composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, for use in the treatment or prevention of a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea.

31. A composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, for use in reducing the risk of miscarriage or pre-term labour.

32. A composition for use of any one of claims 27 to 31, wherein the composition is administered to a subject in need thereof, between 1 and 5 times per week, between 1 and 3 times per week, between 1 and 2 times per week, or once a week or once every two weeks.

33. A composition for use of claim 32, wherein the composition is administered to a subject in need thereof, over a period of at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks.

34. A composition for use of claim 32 or 33, wherein the composition is administered to a subject in need thereof once a week over a period of 4 weeks, or a period between 8 and 12 weeks.

35. A method of treating or preventing a condition associated with reduced levels of progesterone or a progesterone deficiency in a subject in need thereof, comprising administering to the subject a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26.

36. A method of progesterone supplementation in a subject undergoing an assisted reproductive technology (ART) treatment, such as in vitro fertilization (I VF), comprising administering to the subject a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26.

37. A method of treating or preventing a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea in a subject in need thereof, comprising administering to the subject a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26.

38. A method of reducing the risk of miscarriage or pre-term labour in a subject in need thereof, comprising administering to the subject a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26.

39. The method according to any one of claims 35 to 38, wherein the composition is administered to the subject in need thereof, between 1 and 5 times per week, between 1 and 3 times per week, between 1 and 2 times per week, or once a week, or once every two weeks.

40. The method of claim 39, wherein the composition is administered to a subject in need thereof, over a period of at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks.

41. The method of claim 39 or 40, wherein the composition is administered to a subject in need thereof once a week over a period of 4 weeks, or a period between 8 and 12 weeks.

42. Use of a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, in the manufacture of a medicament for treating or preventing a condition associated with reduced levels of progesterone or a progesterone deficiency in a subject in need thereof.

43. Use of a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, in the manufacture of a medicament for progesterone supplementation in a subject undergoing an assisted reproductive technology (ART) treatment, such as in vitro fertilization (I VF) .

44. Use of a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, in the manufacture of a medicament for treating or preventing a condition selected from infertility, miscarriage, pre-term labour, endometriosis, adenomyosis, irregular menstruation, dysfunctional uterine bleeding, endometrial hyperplasia and amenorrhea in a subject in need thereof.

45. Use of a composition according to any one of claims 1 to 24, or obtainable in accordance with the method of claim 25 or 26, in the manufacture of a medicament for reducing the risk of miscarriage or pre-term labour in a subject in need thereof.

46. The use according to any one of claims 42 to 45, wherein the composition is administered to the subject in need thereof, between 1 and 5 times per week, between 1 and 3 times per week, between 1 and 2 times per week, or once a week, or once every two weeks.

47. The use of claim 46, wherein the composition is administered to a subject in need thereof, over a period of at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks or at least 12 weeks.

48. The use of claim 46 or 47, wherein the composition is administered to a subject in need thereof once a week over a period of 4 weeks, or a period between 8 and 12 weeks.

Images