Progesterone preparations

Abstract

The present invention relates to a pharmaceutical composition in the form of a suspension comprising progesterone particles, with wet media milling, in a liquid carrier comprising one or more vegetable oils, the progesterone particles having a Dv50 of less than 8 μm, preferably less than 6 μm, more preferably less than 5 μm, as measured by laser light diffraction. The present invention also relates to a process for preparing such a pharmaceutical composition, comprising at least the step of subjecting a combination of progesterone and a liquid carrier to a wet media milling operation to produce a suspension of progesterone particles having a Dv50 of less than 8 μm, as measured by laser light diffraction.

Description

[Technical Field]

[0001] The present invention relates to progesterone compositions and formulations. More particularly, the present invention provides novel compositions comprising progesterone particles suspended in an oily carrier, which can be suitably filled into capsules to provide formulations suitable for administration (among other things) via the oral route. The present invention also provides methods for producing such compositions and formulations, and the use of the compositions and formulations in therapeutic and / or prophylactic treatment methods. [Background technology]

[0002] Progesterone (P) is a natural / endogenous steroid hormone that binds to its specific receptor and induces specific progestational effects. In addition, progesterone can interfere with the binding sites of other steroids. Therefore, the natural hormone exhibits antiestrogenic and antiandrogenic activity, as well as antimineralocorticoid effects. Based on this activity profile, progesterone has been approved and used as a drug, particularly as adjunctive therapy in postmenopausal women with an intact uterus undergoing estrogen replacement therapy, as a supplement for the luteal phase during in vitro fertilization (IVF) cycles, and as a means of supporting pregnancy, i.e., preventing premature birth and miscarriage. Drugs currently approved for these indications typically come in the form of pre-filled capsules and tablets containing micronized progesterone for oral administration. It is also available in the form of vaginal or rectal suppositories or pessaries, topical creams and gels, oil solutions for intramuscular injection, and aqueous solutions for subcutaneous injection.

[0003] The oral bioavailability of progesterone is very low. This is due to the fact that progesterone is poorly absorbed from the gastrointestinal tract and undergoes extensive metabolism in the liver, resulting in almost complete inactivation during first-pass liver administration. It has also been demonstrated that the intestine plays an important role in progesterone metabolism, due in part to metabolism by cytochrome P450 enzymes found in the mucosa of the small intestine and / or due to the action of gut microflora, which are thought to similarly metabolize progesterone.

[0004] Due to its low oral bioavailability, when the oral route of administration is chosen, relatively high doses of progesterone are typically used to achieve significant circulating progesterone levels, which means that the levels of its metabolites are also relatively high.

[0005] Since the 1980s, suitable oral progesterone preparations have been provided for the first time.It has been found that micronized progesterone preparations can partially solve the problem of low oral bioavailability and can provide sufficient plasma and tissue levels of progesterone.Micronization is a method of reducing the average diameter of particles of solid materials.By micronizing progesterone, its particles become smaller and its surface area increases, thereby enhancing intestinal absorption.

[0006] The first oral formulation containing micronized progesterone was marketed under the trade name Utrogestan® and was developed by LABORATOIRES BESINS-ISCOVESCO and described in French Patent Application Publication No. 2408345. The formulation was provided in the form of soft capsules containing micronized progesterone in an oily suspension. The oil serving as the base of the oily suspension was peanut oil.

[0007] The suspension and partial solubilization of progesterone in oil containing medium- to long-chain fatty acids has been shown to subsequently improve the bioavailability of oral progesterone. Due to the lipophilicity of progesterone, it is theorized that once released in the gastrointestinal environment, the progesterone molecules and oil form chyle particles that bypass the liver's first-pass effect by entering the lymphatic circulation. Compared to progesterone obtained by simple milling, peak progesterone levels after a single 200 mg oral dose were estimated to be 1.4-fold higher as a result of micronization, 1.2-fold higher as a result of oil suspension, and 3.2-fold higher as a result of the combination of micronization and oil suspension.

[0008] Although the initially developed Utrogestan® represented a significant advance in progesterone therapy modalities, the use of peanut oil as a carrier oil proved somewhat disadvantageous due to the increasing prevalence of peanut allergies in the 1980s and 1990s. U.S. Patent Application Publication No. 2005 / 0004076 describes modifications to the original Utrogestan® formulation, in which peanut oil was replaced with one of a select number of alternative vegetable oils, eliminating the risk of allergic reactions while simultaneously preserving all of the physicochemical and pharmacokinetic characteristics of the original Utrogestan® formulation, which was a key factor in its success. U.S. Patent Application Publication No. 2005 / 0004076 explains that the process for producing the original Utrogestan® formulation on a commercial scale involves several highly delicate additional steps, and it was crucial that the modifications to the formulation not increase and / or create new manufacturing challenges.

[0009] Based on the present invention described in U.S. Patent Application Publication No. 2005 / 0004076, sunflower oil was ultimately selected as a replacement for peanut oil in the next generation Utrogestan® formulation. Pharmacokinetic studies conducted in healthy volunteers demonstrated that after oral administration of two 100 mg capsules (200 mg) of the new formulation, plasma progesterone levels increased to a C of 13.8 ng / ml + / - 2.9 ng / ml within 2.2 + / - 1.4 hours. max The observed elimination half-life is 16.8 + / - 2.3 hours. For comparison, normal progesterone levels during the luteal phase of the menstrual cycle are 6.7 to 22.2 ng / mL. Peak progesterone levels after oral progesterone administration occur approximately 1 to 3 hours later. The formulation adequately reproduces the antiestrogenic effect of the natural hormone on the endometrium at a daily dose of 200 mg. It also reproduces the antimineralocorticoid effect and has no androgenic activity. No side effects have been reported as far as lipid profile, coagulation factors, and blood pressure are concerned.

[0010] Around 2004, an oral micronized progesterone formulation called Yimaxin was approved in China. According to Wang et al. (Clinical Re-evaluation on Bioequivalence and Relative Bioavailability of Micronized Progesterone Hard Capsule (Yimaxin) and Micronized Progesterone Soft Capsule (Utrogestan) under Vaginal and Oral Administration Routes. Pak J Med Sci. Nov-Dec 2021;37(7):1740-1746), this formulation was developed as an alternative to Utrogestan® without the "oil-based excipients." Yimaxin is provided in the form of an ultra-micronized solid dispersion of progesterone in glyceryl monostearate. The manufacturing process involves the first step of mixing molten glyceryl monostearate and progesterone, followed by spray drying to produce a solid dispersion, and the second step of jet milling the solid dispersion. According to Wang et al., Yimaxin results in lower exposure than Utrogestan® after oral administration, but higher exposure after vaginal administration. The study results described by Wang et al. further suggest that Utrogestan® has a more favorable safety profile after oral administration. Summary of the Invention [Problem to be solved by the invention]

[0011] Despite the fact that several oral progesterone formulations are currently available, there is still room for improvement. For one thing, oral bioavailability for all formulations remains relatively low, and achieving further increases is particularly desirable. Furthermore, reduced food effect, interindividual variability, etc. compared to currently available formulations would also be meaningful improvements. It would be particularly desirable to achieve any such improvements without having to resort to highly complex manufacturing processes and without introducing new formulation stability challenges, etc.

[0012] It is an object of the present invention to provide a progesterone formulation that is suitable for oral administration and that achieves any and all such improved pharmacokinetic, pharmacodynamic and / or safety profiles and that can be manufactured at the required quality / stability using processing steps that are relatively inexpensive and easy to perform. [Means for solving the problem]

[0013] In a first aspect, the present invention provides a liquid composition comprising wet-medium-milled progesterone particles in a liquid vegetable oil containing carrier, which can be filled into a capsule to produce a unit dosage form suitable for oral administration and achieve improved pharmacokinetic, pharmacodynamic, and / or safety profiles. According to the present invention, the wet-medium-milling of progesterone is typically carried out in the (final) liquid carrier. The inventors have established that this technique allows for the production of micronized progesterone particles of significantly smaller size than can be produced by conventional dry milling or grinding techniques. The resulting suspension can be readily filled into suitable capsules, such as soft gelatin capsules.

[0014] The inventors have further established that certain vegetable oils and certain vegetable oil mixtures can provide particularly good results. Without wishing to be bound by any theory, it is hypothesized that the best-performing vegetable oil (mixture) has a relatively low viscosity, but has other properties, such as fatty acid composition, which may also affect the relevant properties of the liquid composition. As illustrated in additional experimental results, compositions according to the present invention exhibit particularly favorable dissolution rates in suitable in vitro dissolution tests (and in comparison with Utrogestan®), which are generally considered to be a suitable proxy for improved oral bioavailability. The oils used according to the present invention are not known to be associated with a wide range of allergen responses.

[0015] It has further been established that the incorporation of small amounts of soybean phospholipid (soybean lecithin) favorably affects the properties of the composition, including storage stability.

[0016] Finally, this method for the preparation of pharmaceutical compositions is easy to operate in high throughput in recirculation mode without the need to apply an intermediate degassing step.

[0017] Therefore, in a first aspect, the present invention provides a pharmaceutical composition in the form of a suspension comprising wet-medium-milled, preferably wet-medium-nanomilled, progesterone particles in a liquid carrier comprising one or more vegetable oils.

[0018] In a second aspect, there is provided a method for preparing a pharmaceutical composition in the form of a suspension comprising progesterone particles with wet medium milling in a liquid carrier, the method comprising: a) providing a liquid carrier comprising one or more vegetable oils; b) providing progesterone in the form of a dry powder; c) combining progesterone and a liquid carrier; d) subjecting the combination of progesterone and liquid carrier to a wet medium milling operation, preferably a wet medium nanomilling operation; A method is provided that includes:

[0019] In a third aspect of the invention, there is provided a pharmaceutical composition obtainable by the method of the invention.

[0020] In a further aspect of the present invention, there are provided unit dosage forms comprising the pharmaceutical compositions of the present invention and their therapeutic and prophylactic uses.

[0021] These and other aspects of the present invention and its preferred embodiments will become apparent to those skilled in the art based on the following detailed description and examples. DETAILED DESCRIPTION OF THE INVENTION

[0022] As will be apparent from the foregoing, a first aspect of the present invention relates to a pharmaceutical composition in the form of a suspension comprising progesterone particles with wet medium milling, preferably progesterone particles with wet medium nanomilling, in a liquid carrier comprising one or more vegetable oils.

[0023] In the context of the present invention, the term "progesterone" is used to mean the endogenous human progestogenic hormone having the following molecular structure: [ka] Progesterone is also known as pregnenedione, D4-pregnene-3,20-dione; Δ-4-pregnene-3,20-dione; or pregn-4-ene-3,20-dione. As will be clear to those skilled in the art, based on the present teachings, the fraction of progesterone contained in the suspension will be present in dissolved form. In this document, when progesterone is generally referred to, for example, in connection with quantitative characterization, this refers to the total progesterone content, i.e., the progesterone suspended together with dissolved progesterone. When "progesterone particles" are essentially referred to and / or particle (size) characteristics are described, it will be clear to those skilled in the art that this only relates to the suspended progesterone fraction.

[0024] The term "pharmaceutical composition," as used herein, refers to a composition comprising one or more active pharmaceutical compounds ("APIs"), in this case progesterone, optionally in combination with another API, e.g., estrogen, and one or more non-pharmacologically active substances, which may be collectively referred to as "excipients," wherein all APIs and excipients are of a quality and / or grade considered suitable and safe for administration to humans in the amounts required for the desired therapeutic effect. Typically, all APIs and excipients are of pharmaceutical grade. The term "pharmaceutical composition" encompasses, but is not limited to, pharmaceutical formulations, as that term is used herein, to mean a pharmaceutical composition in its final form for administration to humans (or animals), e.g., a unit dose form. In particular, the term "pharmaceutical composition" also encompasses bulk products comprising one or more APIs in combination with one or more excipients.

[0025] The term "involving wet medium milling," as used herein, refers to a product resulting from milling or grinding, a process of reducing the particle size of an API, in this case progesterone, in a liquid medium using a milling medium. As will be apparent to one skilled in the art, based on the present teachings, the liquid medium in the present invention is typically an oily liquid, i.e., a liquid that contains one or more oils as a primary component.

[0026] Thus, the term "involving nanomilling," as used herein, refers to a product resulting from nanomilling, a process of reducing the particle size of an API, in this case progesterone, in a liquid medium using a milling medium, typically to a particle size of about 1 μm or less (mean, average, or median). Within the context of the present invention, the term "nanomilling" is considered to be synonymous with and interchangeable with the terms "wet medium nanomilling," "liquid medium nanomilling," and "(wet) nanogrinding," among others.

[0027] In this document, all particle sizes characterized for progesterone particles with wet media milling are based on volume-weighted particle size distributions measured using laser light diffraction unless otherwise specifically indicated. Such volume-weighted particle size distributions are preferably measured according to the present invention using a Malvern Mastersize instrument, such as a Malvern® Mastersizer 2000 equipped with a Hydro 2000S module (Malvern 5 Instruments), or equivalent instrument, typically according to the method described herein below (see Examples, "Methodology (General)"). As will be understood by those skilled in the art, the term "Dv50" as used herein refers to the point in the size distribution that is equal to or less than 50% of the total volume of material in the "contained" sample. Similarly, the term "Dv90" refers to the point in the size distribution that is equal to or less than 90% of the total volume of material in the contained sample. The term "Dv10" refers to the point in the size distribution that is equal to or less than 10% of the total volume of material in the contained sample. The term D[4,3], as used herein, refers to the average diameter of particle sizes based on the volume weighted average result, also referred to as the De Broucker mean.

[0028] In a preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the progesterone particles have a Dv50 of less than 8 μm, preferably less than 6 μm, less than 5 μm, less than 4 μm, less than 3.5 μm or less than 3 μm, as measured by laser light diffraction. Furthermore, the Dv50 is typically greater than 1 μm, greater than 2 μm or greater than 2.5 μm.

[0029] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the progesterone particles have a Dv90 of less than 10 μm, preferably less than 9 μm, more preferably less than 8 μm. Furthermore, the Dv90 is typically greater than 3 μm, greater than 4 μm or greater than 5 μm.

[0030] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the progesterone particles have a Dv10 of less than 2 μm, preferably less than 1.5 μm, more preferably less than 1 μm. Furthermore, Dv10 is typically greater than 0.25 μm, greater than 0.5 μm or greater than 0.75 μm.

[0031] In a preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the progesterone particles have a D[4,3] of less than 10 μm, preferably less than 9.5 μm, more preferably less than 9 μm. Furthermore, D[4,3] is typically greater than 1 μm, greater than 1.5 μm or greater than 2 μm.

[0032] As described hereinabove, progesterone particles are suspended in a liquid carrier comprising one or more vegetable oils.As will be understood by those skilled in the art, the term "liquid" refers to the property that the composition can flow under the influence of force.According to the present invention, the carrier is typically liquid at ambient temperature, for example, about 20°C.

[0033] As used herein, the term "vegetable oil" refers to any fatty substance, including triglycerides, diglycerides, monoglycerides, and combinations thereof, extracted from oily plant parts, such as lipid-containing plant seeds, nuts, or fruits. As will be understood by those skilled in the art, products that undergo conventional (physical) refining and / or refining processes after their extraction, such as degumming, neutralization, bleaching, winterization, deodorization, etc., are encompassed by the term vegetable oil. Products of chemical reactions involving vegetable oils, such as transesterification products, are usually referred to as "synthetic oils" and are typically not encompassed by the term "vegetable oil." Vegetable oils typically comprise any one or more of triglycerides, diglycerides, monoglycerides, and / or combinations thereof of fatty acids, as known by those skilled in the art. The term "oil," as used herein, is readily interchangeable with "lipids" and "fats," and refers to lipophilic, high-boiling organic compounds that are liquid at body temperature, i.e., about 37°C. In a preferred embodiment of the present invention, the oil contained in the liquid medium is liquid at body temperature, i.e., about 37° C. More preferably, an oil is used that is liquid at ambient temperature, i.e., about 20° C.

[0034] According to the present invention, vegetable oils may contain saturated, monounsaturated, and / or polyunsaturated fatty acids. The most abundant saturated fatty acids in vegetable oils typically include palmitic acid, stearic acid, arachidic acid, and lauric acid. The most abundant monounsaturated fatty acids in many vegetable oils include oleic acid and eicosenoic acid. The most abundant polyunsaturated fatty acids in vegetable oils include linoleic acid and alpha-linolenic acid.

[0035] In certain embodiments of the present invention, the liquid carrier preferably comprises one or more vegetable oils having a linoleic acid content of at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 60% w / w, and / or a linoleic acid content of less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w. In further preferred embodiments of the present invention, the total linoleic acid content of the liquid carrier is at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 60% w / w, and / or the total linoleic acid content of the liquid carrier is less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w.

[0036] In certain embodiments of the present invention, the liquid carrier preferably comprises one or more vegetable oils having an alpha-linolenic acid content of at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 57.5% w / w, and / or an alpha-linolenic acid content of less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w. In further preferred embodiments of the present invention, the total alpha-linolenic acid content of the liquid carrier is at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 57.5% w / w, and / or the total alpha-linolenic acid content of the liquid carrier is less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w.

[0037] According to the present invention, the liquid carrier preferably comprises one or more vegetable oils having a polyunsaturated fatty acid content of at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 60% w / w, and / or a polyunsaturated fatty acid content of less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w. In a further preferred embodiment of the present invention, the total polyunsaturated fatty acid content of the liquid carrier is at least 10% w / w, e.g., at least 25% w / w, at least 40% w / w, at least 50% w / w, at least 55% w / w, or at least 60% w / w, and / or the total polyunsaturated fatty acid content of the liquid carrier is less than 80% w / w, e.g., less than 75% w / w, less than 70% w / w, or less than 65% w / w.

[0038] Gadoleic acid (20:1 n-11), or cis-9-eicosenoic acid, is a fatty acid found in relatively low amounts in some vegetable oils. While the inventors do not wish to be bound by any theory, it is believed that vegetable oils containing gadoleic acid are particularly preferred for incorporation into the present compositions. Therefore, according to certain embodiments of the present invention, the liquid carrier preferably comprises one or more vegetable oils having a gadoleic acid content of at least 0.1% w / w, e.g., at least 0.5% w / w, at least 1% w / w, or at least 1.5% w / w, and / or a gadoleic acid content of less than 10% w / w, e.g., less than 7.5% w / w, less than 5% w / w, less than 4% w / w, or less than 3% w / w. In further preferred embodiments of the present invention, the total gadoleic acid content of the liquid carrier is at least 0.1% w / w, such as at least 0.5% w / w, at least 1% w / w or at least 1.5% w / w, and / or the total gadoleic acid content of the liquid carrier is less than 10% w / w, such as less than 7.5% w / w, less than 5% w / w, less than 4% w / w or less than 3% w / w.

[0039] In another preferred embodiment of the present invention, the pharmaceutical composition as defined herein is characterized in that the one or more vegetable oils are -gadolei acid at levels of 0.01-30% w / w; Linoleic acid at a level of 0.5 to 70% w / w; or - alpha-linolenic acid at levels of 0.5 to 70% w / w A pharmaceutical composition is provided comprising:

[0040] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the one or more vegetable oils are selected from the group consisting of rapeseed oil, hemp oil, camelina oil, sesame oil, olive oil, linseed oil, palm oil, chia oil, sunflower oil and corn germ oil, preferably selected from the group consisting of sunflower oil, olive oil, linseed oil, chia oil, palm oil, corn germ oil and camelina oil.

[0041] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the carrier comprises a combination of two or more vegetable oils.

[0042] In one such embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the carrier comprises a combination of olive oil and linseed oil. In a preferred embodiment, there is provided a pharmaceutical composition as defined herein, wherein the olive oil and linseed oil are combined in a ratio of 2.5 / 1 to 8 / 1, preferably 3 / 1 to 6 / 1, more preferably 3.5 / 1 to 5 / 1, for example, a ratio of about 4 / 1. In another preferred embodiment, there is provided a pharmaceutical composition as defined herein, wherein the olive oil and linseed oil are combined in a ratio of 1 / 1 to 3 / 1, preferably 1.25 / 1 to 2 / 1, more preferably 1.4 / 1 to 1.75 / 1, and most preferably, a ratio of about 1.5 / 1.

[0043] In another preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the carrier comprises a combination of corn germ oil and linseed oil. In a preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the corn germ oil and linseed oil are present in a ratio within the range of 2.5 / 1 to 8 / 1, preferably 3 / 1 to 6 / 1, more preferably 3.5 / 1 to 5 / 1, and most preferably a ratio of about 4 / 1.

[0044] In a preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the liquid carrier comprises at least 80 wt.%, preferably at least 90 wt.%, more preferably at least 95 wt.%, at least 96 wt.%, at least 97 wt.%, at least 98 wt.%, at least 99 wt.% or at least 99.5 wt.%, based on the total weight of the carrier, of one or more oil combinations as defined herein. In another preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein, wherein the liquid carrier consists (essentially) of one or more vegetable oil combinations as defined herein.

[0045] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the carrier further comprises soy lecithin, in preferred embodiments the soy lecithin is present in an amount greater than 0.01%, greater than 0.1%, or greater than 0.3% w / w based on the total weight of the suspension and / or less than 15%, less than 10%, or less than 5% w / w based on the total weight of the suspension.

[0046] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein, wherein the carrier does not comprise soy lecithin.

[0047] In a preferred embodiment of the present invention there is provided a pharmaceutical composition as defined herein comprising progesterone in an amount of more than 0.05 mg / ml of liquid carrier, more than 0.1 mg / ml of liquid carrier, more than 0.15 mg / ml of liquid carrier, more than 0.2 mg / ml, more than 0.25 mg / ml of liquid carrier, more than 0.3 mg / ml of liquid carrier, more than 0.35 mg / ml of liquid carrier and / or less than 0.5 mg / ml of liquid carrier or less than 0.45 mg / ml of liquid carrier, for example about 0.2 or about 0.4 mg / ml of liquid carrier. In further preferred embodiments, progesterone is present in an amount of more than 0.05 mg / ml vegetable oil, more than 0.1 mg / ml vegetable oil, more than 0.15 mg / ml vegetable oil, more than 0.2 mg / ml, more than 0.25 mg / ml vegetable oil, more than 0.3 mg / ml vegetable oil, more than 0.35 mg / ml vegetable oil, and / or less than 0.5 mg / ml vegetable oil or less than 0.45 mg / ml vegetable oil, for example, about 0.2 or about 0.4 mg / ml vegetable oil. In further preferred embodiments, progesterone is present in an amount of more than 10% w / w, more than 15% w / w, more than 20% w / w, more than 25% w / w, more than 30% w / w, or more than 35% w / w by total weight of the suspension, and / or less than 50% w / w or less than 45% w / w by total weight of the suspension, for example, about 20% w / w or about 40% w / w.

[0048] The pharmaceutical compositions of the present invention have been found to exhibit highly desirable rheological profiles, such as relatively high static viscosities combined with shear-thinning behavior. High static viscosities are believed to contribute to the stability of the suspension, while shear-thinning behavior is advantageous, particularly in terms of processing and manufacturing. Viscosity can be measured using a suitable viscometer with settings compatible with viscous (oily) materials. For example, viscosity can be measured using viscometers from Brookfield (Brookfield Viscometer), Lamy Rheoloy (Rheomat RM100), Anton Paar (Rheoplus Viscometer), etc., with appropriate settings. Whenever viscosity values ​​are defined / quantified in this document, they refer to viscosity measured using a Lamy Rheology® Rheomat RM100 viscometer, typically using the settings and methodology described herein below (see Examples, 'Methodology (General')).

[0049] In a preferred embodiment of the present invention, the pharmaceutical composition as defined herein is characterized in that the liquid carrier is 1.5 seconds -1 and typically less than 200 Pa.s, preferably less than 175 Pa.s, less than 150 Pa.s or less than 140 Pa.s at a shear rate of 1000 Pa.s.

[0050] In a further preferred embodiment of the present invention, the pharmaceutical composition as defined herein is characterized in that the liquid carrier is soluble in water for 5 seconds or more. -1 and typically less than 100 Pa.s, preferably less than 80 Pa.s, 70 Pa.s or less than 60 Pa.s (at ambient temperature).

[0051] In a further preferred embodiment of the present invention, the pharmaceutical composition as defined herein is characterized in that the liquid carrier is -1 In one embodiment, the pharmaceutical composition has a viscosity (at ambient temperature) in the range of 2 to 20 Pa sec, for example, in the range of 4 to 17.5 Pa sec, in the range of 6 to 15 Pa sec, or in the range of 8 to 14 Pa sec, at a shear rate of 1000 rpm.

[0052] In a preferred embodiment of the present invention, the pharmaceutical composition defined herein is in unit dosage form, wherein each unit comprises progesterone in an amount of 20 mg or more, e.g., 50 mg or more, 75 mg or more, 100 mg or more, and / or in an amount of 600 mg or less, e.g., 500 mg or less, 400 mg or less, or 300 mg or less. In a preferred embodiment of the present invention, the pharmaceutical composition defined herein is in unit dosage form, wherein each unit comprises progesterone in an amount of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg.

[0053] The term "unit dosage form," as used herein, refers to a single, discrete entity for pharmaceutical administration containing a consistent, predetermined amount of API (or APIs) together with any suitable pharmaceutical carriers and / or excipients. Typically, a unit dosage form contains the amount of API (or APIs) required per administration interval to produce the desired therapeutic effect, although situations can be envisioned in which such an amount is divided across two or even more units and administered together and / or simultaneously. Generally, the unit dosage form can be a discrete solid entity, such as a capsule (e.g., a hard or soft capsule, preferably a soft gelatin capsule, with a solid or liquid fill). Solid formulations, such as tablets, caplets, powders, (encapsulated) pellets, and the like, are also envisioned. For the production of solid formulations, the suspension of the present invention can, for example, be used to impregnate an absorbent support present in powder form. This absorbent support may be of the maltodextrin and / or derivatives, silica and / or derivatives, cyclodextrin and / or derivatives, or cellulose powder and / or derivatives type, or a combination thereof, or any other pharmaceutical raw material with equivalent properties. The powder thus obtained can then be processed into hard capsules or tablets using further excipients, such as binders, disintegrants, diluents, lubricants, etc. The unit dosage form of the present invention can also be an individually packaged amount of suspension (in ampoules or sachets).

[0054] According to the present invention, the compositions are preferably provided in unit dosage forms suitable for oral, vaginal and / or rectal administration, more preferably oral and / or vaginal administration.

[0055] In a preferred embodiment of the present invention, the pharmaceutical composition defined herein is provided in the form of a capsule filled with a combination of progesterone particles with wet medium milling in a liquid carrier. Preferably, according to the present invention, the capsule is of the soft gelatin type. Preferably, the unit dosage form according to the present invention comprises a round (spherical) capsule having a diameter in the range of 5 to 35 mm, preferably in the range of 10 to 30 mm, more preferably in the range of 12 to 23 mm, and most preferably in the range of 15 to 25 mm. Suitable capsules include those referred to in the art as 1-round, 2-round, 3-round, 4-round, 5-round, 6-round, 7-round, 9-round, or 15-round. In another embodiment, the capsule is rectangular in shape with a length in the range of 16 to 20 mm, preferably in the range of 14 to 18 mm, more preferably in the range of 8 to 12 mm, and most preferably in the range of 15 to 25 mm, and / or a diameter in the range of 4.0 to 10.0 mm, preferably in the range of 4.5 to 9.5 mm, more preferably in the range of 5.0 to 9.0 mm, and most preferably in the range of 5.5 to 8.5 mm. Suitable capsules include those referred to in the art as Rectangular 3, Rectangular 4, Rectangular 5, Rectangular 6, Rectangular 7, Rectangular 8, Rectangular 9.5, Rectangular 11, and Rectangular 14. In further embodiments of the invention, the capsules may be oval, for example, Oval 2, Oval 3, Oval 4, Oval 5, Oval 6, Oval 7, Oval 8.5, Oval 10, Oval 12, and Oval 16.

[0056] In a preferred embodiment of the present invention, a pharmaceutical composition as defined herein is provided, further comprising an estrogen component. The term "estrogenic component" as used herein refers to and includes substances capable of eliciting an estrogen response in vivo, and precursors capable of liberating such estrogen components in vivo when used in accordance with the present invention. For estrogen components to elicit such responses, they must usually bind to estrogen receptors, which are found in various tissues in mammals. Exemplary non-limiting estrogens include estradiol, estriol, estrone, estetrol, ethinylestradiol, and / or derivatives thereof, including, but not limited to, conjugated and esterified estrogens. In a particularly preferred embodiment of the present invention, the estrogen component is estradiol.

[0057] According to preferred embodiments, estradiol may be present in an amount of greater than 2 μg / ml of liquid carrier, greater than 0.002 mg / ml of liquid carrier, or greater than 0.004 mg / ml of liquid carrier, and / or less than 0.2 mg / ml of liquid carrier, less than 0.1 mg / ml of liquid carrier, or less than 0.05 mg / ml of liquid carrier. In further preferred embodiments, estradiol is present in an amount of greater than 2 μg / ml of vegetable oil, greater than 0.002 mg / ml of vegetable oil, or greater than 0.004 mg / ml of vegetable oil, and / or less than 0.2 mg / ml of vegetable oil, less than 0.1 mg / ml of vegetable oil, or less than 0.05 mg / ml of vegetable oil. In further preferred embodiments, estradiol is present in an amount greater than 0.002%, greater than 0.02%, or greater than 0.04% w / w based on the total weight of the suspension, and / or in an amount less than 20%, less than 10%, or less than 5% w / w based on the total weight of the suspension. A preferred embodiment of the present invention provides a pharmaceutical composition as defined herein, in unit dosage form, wherein each dosage unit comprises estradiol in an amount of 0.01 mg or more, e.g., 0.1 mg or more, 1 mg or more, 2 mg or more, and / or 20 mg or less, e.g., 15 mg or less, 10 mg or less, or 5 mg or less. A preferred embodiment of the present invention provides a pharmaceutical composition as defined herein, in unit dosage form, wherein each dosage unit comprises estradiol in an amount of about 0.01 mg, about 0.1 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 2 mg, about 4 mg, or about 8 mg.

[0058] In preferred embodiments of the present invention, the suspension comprises or consists (essentially) of more than 95% w / w, more than 97.5% w / w, more than 99% w / w, more than 99.5% w / w, more than 99.9% w / w of a combination of progesterone and a liquid carrier as defined herein. In preferred embodiments of the present invention, the suspension comprises or consists (essentially) of more than 95% w / w, more than 97.5% w / w, more than 99% w / w, more than 99.5% w / w, more than 99.9% w / w of a combination of progesterone and one or more vegetable oils. In preferred embodiments of the present invention, the suspension comprises or consists (essentially) of more than 95% w / w, more than 97.5% w / w, more than 99% w / w, more than 99.5% w / w, more than 99.9% w / w of a combination of progesterone, one or more vegetable oils, and soy lecithin. In preferred embodiments of the present invention, the suspension comprises or consists (essentially) of more than 95% w / w, more than 97.5% w / w, more than 99% w / w, more than 99.5% w / w, more than 99.9% w / w of a combination of progesterone, one or more vegetable oils, soy lecithin and optionally one or more further ingredients selected from the group consisting of estrogenic compounds, antioxidants and stabilizers.

[0059] A second aspect of the present invention relates to a method for preparing a pharmaceutical composition, typically a composition as defined herein above, in the form of a suspension comprising progesterone particles with wet medium milling, preferably progesterone particles with wet medium nanomilling, in a liquid carrier comprising one or more vegetable oils, the method comprising: a) providing a liquid medium comprising one or more vegetable oils; b) preparing progesterone in powder form; c) combining progesterone and a liquid medium; d) subjecting the combination of progesterone and liquid medium to a wet medium milling operation to produce a suspension of progesterone particles with wet medium milling in a liquid carrier comprising one or more vegetable oils; The present invention relates to a method comprising:

[0060] In certain embodiments of the present invention, the liquid medium provided in step a) of the method is the final liquid carrier of the pharmaceutical composition as previously defined herein. In such embodiments, as will be understood by those skilled in the art, based on the present teachings, the wet medium milling step directly results in a final pharmaceutical composition that can be filled directly into a capsule, for example, to produce a unit dosage form as previously defined herein. However, embodiments are also envisioned in which the liquid medium provided in step a) does not contain all of the components / materials of the final liquid carrier of the pharmaceutical composition as previously defined herein. In such embodiments, the liquid medium provided in step a) contains at least one or more vegetable oils as previously defined herein, while certain other components, such as additional amounts of one or more vegetable oils (which may be the same or different from the vegetable oils contained in the liquid medium), soy lecithin, and / or any further optional components, may be admixed with the liquid medium during or after step c) and / or with the composition accompanying wet medium milling during or after step d).

[0061] The progesterone provided in step b) typically takes the form of a powder, although the exact size and / or shape of the powder particles is not particularly critical. As explained elsewhere herein, the inventors have established that a wet medium milling operation in a liquid (oily) medium allows for a particle size reduction that cannot be achieved using conventional (dry) milling and / or grinding of progesterone powder. Furthermore, the particle size of progesterone obtained by wet medium milling according to the present invention is typically less than that of standard micronized progesterone products. Therefore, as will be understood by those skilled in the art, based on the present teachings, embodiments are contemplated in which the progesterone provided in step b) is a (conventional) micronized progesterone product that can be obtained through various methods within common general knowledge and / or supplied by commercial suppliers. Also contemplated are embodiments in which the progesterone provided in step b) takes the form of a dry, free-flowing powder with coarse particles, the particle size of which is (significantly) greater than that of standard micronized progesterone products.

[0062] Step c) of the method can be carried out in any conceivable manner. An embodiment is envisioned in which the liquid medium and progesterone are combined and mixed by some conventional form of stirring or (low shear) mixing to produce a uniform suspension that can be fed into a milling device. As will be understood by those skilled in the art, based on the present teachings, the order in which the various components of the liquid medium and progesterone are added to the mixture is not particularly critical. In one embodiment, a mixture containing all of the vegetable oil, preferably any additional excipients that should be present in the final suspension, is first produced, after which the progesterone is added to the liquid medium, and the resulting mixture is mixed. An embodiment is also envisioned in which the progesterone and the liquid medium are fed separately to the milling device, in which case step c) is carried out within the milling device, i.e., simultaneously with (part of) step d). An embodiment is also envisioned in which, after the wet medium milling step, one or more vegetable oil fractions that form the liquid carrier are added. As explained elsewhere herein, the inventors have established that the ratio of progesterone to liquid medium during the milling operation influences the degree of particle size reduction under a given set of operating conditions. The higher the (relative) amount of progesterone during the milling operation, the smaller the particles (or the more quickly a particular range of particle size reduction is achieved). Therefore, in a particularly preferred embodiment of the present invention, step c) comprises combining progesterone and liquid medium in amounts resulting in a (relative) amount of progesterone greater than 30% w / w, greater than 35% w / w, or greater than 40% w / w, and the method comprises a subsequent step e) of adding an additional amount of one or more vegetable oils (forming a carrier) to reduce the relative amount of progesterone in the final formulation, as needed, for example, to one of the relative amounts previously defined herein (relative to the final product). Optionally, excipients other than vegetable oils that may be present according to the present invention can also be added to the suspension obtained after milling. However, this is less preferred from the standpoint of process efficiency.

[0063] As defined elsewhere herein, wet media milling (or wet media nanomilling) refers to a process for reducing the particle size of an API in a liquid medium via grinding using a milling medium. In this process, the milling medium is loaded into a chamber containing an agitator. Examples of suitable mills include disc grinder systems and pin milling systems. According to the present invention, pin milling systems are preferred because they typically do not require the application of an intermediate degassing step, can be operated at high throughput in a recirculation mode, and have been found to provide particularly favorable particle size characteristics, especially a particularly narrow particle size distribution. An example of a preferred pin milling system is a Netzsch High Speed ​​Mill System Zeta® Type LMZ apparatus equipped with a DeltaVita® stainless steel pin agitator.

[0064] In a wet media milling operation, a suspension containing the API is directed through a milling chamber, where an agitator rotates rapidly, creating turbulence in the media. As the suspension enters and passes through the milling chamber, shear forces and impaction by the milling media disrupt the crystalline structure, resulting in smaller particles. The API suspension exits the milling chamber through a screen, which separates the suspension containing the API (nano)particles from the milling media. The milling process generates significant heat. A coolant can be pumped around the milling chamber to control the temperature. Therefore, according to a preferred embodiment of the present invention, there is provided a method as defined herein, wherein step d) comprises directing a combination of step c) through a milling chamber equipped with an agitator and loaded with milling media, while the agitator is operated to create shear forces and impaction between the milling media and the progesterone particles contained in the suspension.

[0065] Various types of milling media are known in the art. In accordance with the present invention, the milling media are typically polymeric or ceramic beads. Several factors contribute to the selection of the milling media type. Ceramic media are denser, meaning they impart more energy to the system and can reduce the particle size of APIs with a strong crystal lattice structure. However, ceramic media can cause increased metal contamination in the suspension as they grind. Polymeric media, such as polystyrene media, are less dense, allowing them to run at higher speeds and for longer periods of time without significant metal contamination. The diameter of milling media beads in pharmaceutical processes typically ranges from 0.2 μm to 1 mm. The selection of media size ultimately depends on the desired final particle size of the suspension. Smaller media can achieve smaller particle sizes, reducing potential contamination compared to larger media. Tests have also shown that smaller media can reduce the time required to reach a given particle size. In a preferred embodiment of the present invention, there is provided a method as defined herein, wherein the milling medium applied in step d) is yttrium-stabilized zirconium oxide milling beads having a diameter in the range of 0.2 mm to 1.0 mm. A suitable example of such a milling medium is VitaBeads® Nano. The agitator speed ultimately controls how much energy is introduced into the suspension during milling. Higher agitator speeds, for example, in the thousands of RPM, result in a more rapid reduction in particle size due to an increased number of interparticle collisions. However, issues such as temperature sensitivity and the level of milling impurities affect the feasibility of increasing the agitator speed. The inventors have determined that for optimal results, the agitator speed and bead size are related to the ratio "R," defined as follows: R = [bead diameter (mm)] / [stirrer speed (rpm)] × 1000; It has been established that it is advantageous to select R to be 0.6 or less, for example, 0.55 or less, 0.50 or less, 0.45 or less, or 0.4 or less. In a preferred embodiment, the agitator speed and bead size are selected so that R is in the range of 0.1 to 0.5, more preferably in the range of 0.1 to 0.45, and most preferably 0.15 to 0.4.

[0066] The processing time required for suspension depends on the desired particle size and suspension composition. In simpler cases where only slight particle size reduction is required or the API is quickly milled, processing time is relatively short. However, if challenges arise, such as a slower milling speed being required or the API having a high crystal lattice energy, processing can take much longer, even multiple days. Increasing the amount of medium in the milling chamber can reduce milling time by resulting in a greater number of collisions within the chamber. However, medium loading must be adjusted for each API based on the desired particle size reduction and API properties.

[0067] In a preferred embodiment of the present invention, the volume of beads to be loaded into the milling chamber is at least 75% of the total volume of the chamber, and the particle size is reduced as greatly as possible. In a particularly preferred embodiment of the present invention, the volume of beads to be loaded into the milling chamber is at least 77.5%, at least 80%, at least 82.5%, or at least 85% of the total volume of the chamber, typically 85-95% of the total volume of the chamber.

[0068] As will be appreciated by those skilled in the art, based on the present teachings, step d) is performed in a manner, and for a period of time, to produce a composition involving milling having progesterone particles within particle size specifications, typically Dv10, Dv50, Dv90, and / or D[4,3] values ​​as provided herein. Given the present teachings, it is within the ordinary skill of one of ordinary skill in the art to determine whether a given setting will result in a product that conforms to the specifications, and therefore to set up the wet media milling process in a manner to achieve this.

[0069] In a preferred embodiment of the present invention there is provided a method as defined herein, further comprising a step f) of filling the suspension obtained in step d) or e) as described herein above into capsules, such as capsules already defined herein, and optionally producing a pharmaceutical kit by packaging a plurality of such capsules in any suitable manner, for example in a blister strip that can be inserted into a cardboard box, together with instructions for use.

[0070] A further aspect of the present invention relates to pharmaceutical compositions, unit dosage forms and / or kits obtainable by any of the methods previously defined herein, wherein the compositions obtained by said methods have the product characteristics previously defined herein, although it is understood by the inventors that the present invention is not limited by any (such) theory.

[0071] Yet a further aspect of the present invention relates to a pharmaceutical unit dosage form in the form of a capsule, preferably a soft gelatin capsule, comprising a pharmaceutical composition, preferably a composition as defined herein, comprising progesterone with a wet medium milling suspended in a liquid carrier comprising a vegetable oil, wherein the pharmaceutical unit dosage form has a USP 3 in vitro dissolution profile characterized in that more than 70% of the progesterone is dissolved after 45 minutes and / or more than 20% of the progesterone is dissolved after 10 minutes. The in vitro release characteristics defined herein, unless otherwise specifically stated, typically refer to values ​​determined using USP Dissolution System 3 with 250 mL of 0.01 N HCl and 2% SDS as dissolution medium at a temperature of 37°C, using the settings and methodology (further) described herein below (see Examples, 'Methodology (General')). In a preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein in the form of a filled soft gelatin capsule, characterized in that after 10 minutes, at least 20%, at least 30%, at least 40%, at least 50%, or at least 60% is dissolved in the USP 3 in vitro dissolution test. In a further preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein in the form of a filled soft gelatin capsule, characterized in that after 20 minutes, at least 40%, at least 45%, at least 50%, at least 55%, or at least 60% is dissolved in the USP 3 in vitro dissolution test. In a further preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein in the form of a filled soft gelatin capsule, characterized in that after 30 minutes, at least 50%, at least 55%, at least 60%, at least 65%, or at least 70% is dissolved in the USP 3 in vitro dissolution test.In a further preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein in the form of a filled soft gelatin capsule, characterized in that after 40 minutes at least 65%, at least 70%, at least 75%, at least 80% or at least 85% is dissolved in the USP 3 in vitro dissolution test. In a further preferred embodiment of the present invention, there is provided a pharmaceutical composition as defined herein in the form of a filled soft gelatin capsule, characterized in that after 60 minutes at least 80%, at least 85%, at least 90%, at least 92.5% or at least 95% is dissolved in the USP 3 in vitro dissolution test.

[0072] Furthermore, a further aspect of the invention as outlined relates to the use of the pharmaceutical composition of the invention in the prophylactic and / or therapeutic treatment of a subject in need thereof. - a method for the therapeutic and / or prophylactic treatment of a subject in need thereof, which method comprises administering to said subject a pharmaceutical composition of the invention; - a pharmaceutical composition of the invention for use in a method for therapeutic and / or prophylactic treatment of a subject in need thereof; and - Use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the therapeutic and / or prophylactic treatment of a subject in need thereof. to provide.

[0073] In a preferred embodiment of the invention, the therapeutic and / or prophylactic treatment is a method for treating and / or preventing a disease or condition selected from the list below, or the treatment, prevention and / or alleviation of symptoms associated with such a disease or condition: - Luteal phase insufficiency, - Menstrual irregularities, -premenstrual syndrome, - breast pain, - benign mastopathy, - Premenopausal, - Infertility due to luteal phase deficiency, -Disorders resulting from menopause, - local contraception, -Recurrent miscarriage in cases of luteal phase deficiency, - premature birth, -acne, -Alopecia, -osteoporosis, - Endometrial cancer; and -Epilepsy

[0074] In a preferred embodiment, the present invention relates to the use of the present pharmaceutical composition, unit dosage form, and / or capsule with estrogen in postmenopausal women with an intact uterus as hormone replacement therapy (HRT). In another preferred embodiment, the present invention relates to the use of the present pharmaceutical composition, unit dosage form, and / or capsule for luteal phase supplementation during assisted reproductive technology (ART) cycles. In another preferred embodiment, the present invention relates to the use of the present pharmaceutical composition, unit dosage form, and / or capsule for preventing preterm birth in women with singleton pregnancies who have a short cervix (cervix ≦25 mm by mid-trimester ultrasound) and / or a history of spontaneous preterm birth. In another preferred embodiment, the present invention relates to the use of the present pharmaceutical composition, unit dosage form, and / or capsule for preventing endometrial hyperplasia in non-hysterectomized postmenopausal women receiving conjugated estrogen tablets. In another preferred embodiment, the present invention relates to the use of the present pharmaceutical composition, unit dosage form, and / or capsule for secondary amenorrhea.

[0075] In a preferred embodiment of the present invention, treatment involves oral or vaginal administration of a pharmaceutical composition.

[0076] In a further preferred embodiment of the invention, treatment comprises once-daily administration of one, two or three, preferably one or two, unit dosage forms or capsules as defined herein. In another embodiment of the invention, treatment comprises twice-daily administration of one or two, preferably one, unit dosage form or capsule as defined herein.

[0077] Unless otherwise defined, all terms used in disclosing the present invention, including technical and scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0078] As used herein, "A," "an," and "the" refer to both the singular and the plural unless the context clearly dictates otherwise. By way of example, "a compartment" refers to one or more compartments.

[0079] "About," as used herein to refer to a measurable value such as a parameter, amount, time period, etc., is meant to encompass a variation of the particular value and of no more than + / - 10%, more preferably no more than + / - 5%, and even more preferably no more than + / - 1% from the particular value, to the extent that such variation is appropriate for practice in the invention of this disclosure. However, it should be understood that the value to which the modifier "about" refers is itself specifically disclosed.

[0080] "Comprise," "comprising," "comprises," and "comprised of," as used herein, are synonymous with "include," "including," "includes," or "contain," "containing," "contains," and are inclusive or open-ended terms that specify the presence of what follows, e.g., a component, and do not exclude or preclude the presence of additional, unrecited components, features, elements, members, steps that are known in the art or disclosed herein.

[0081] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints. One of ordinary skill in the art will recognize that the present invention may encompass any number of the specific features described above.

[0082] Throughout this text, the use of a term in parentheses generally means that the term in parentheses identifies possible alternatives or possible meanings and therefore should not be considered limiting.

[0083] The advantages of the present invention will become apparent from the following examples, which are given below by way of illustration only and are not limiting. [Brief explanation of the drawings]

[0084] [Figure 1] Schematic of the assembly used for USP3 experiments. Dimensions are given in millimeters (mm). [Figure 2] Graph showing the dissolution profile (in percent dissolution units) of progesterone batch 8301189F6 (upper curve) versus Utrogestan® (lower curve) as a function of time. [Figure 3] Graph showing dynamic viscosity values ​​(mPa.sec) as a function of shear rate (sec −1 ) for progesterone batch 8301189F6 (upper curve) versus Utrogestan® (lower curve). [Example]

[0085] Methodology (general) Particle size measurement Particle size distribution ("PSD") characteristics are determined using a Malvern® Mastersizer 2000 instrument equipped with a Hydro 2000SM wet sample dispersion unit, operated with the settings summarized in Table 1.

[0086] [Table 1]

[0087] Viscosity measurement The rheological profile (dynamic viscosity) is determined using a LAMY RHEOLOGY® Rheomat RM100 instrument, operated with the settings summarized in Table 2.

[0088] [Table 2]

[0089] USP3 dissolution In vitro release characteristics are determined using a USP dissolution system 3, shown diagrammatically in Figure 1. The assembly consists of a set of cylindrical, flat-bottomed glass tubes; a set of glass reciprocating cylinders; inert fittings (stainless steel type 316 or other suitable material); and screens made of suitable nonsorbing and nonreactive material designed to fit over the top and bottom of the reciprocating cylinders; a vertically reciprocating cylinder inside the vessel; and, if necessary, a motor and drive assembly for horizontally directing the reciprocating cylinders to different rows of the vessel. During testing, the vessel is partially immersed in a suitable water bath of any convenient size that allows the temperature to be maintained at 37 ± 0.5°C. Furthermore, none of the components of the assembly, including the environment in which the assembly is placed, contribute to significant movement, agitation, or vibration due to the smooth vertical reciprocating cylinders. An apparatus is used that allows the reciprocating speed to be selected and maintained at the specific immersion speed indicated in the individual monographs within ±5%. An apparatus that allows observation of the specimen and reciprocating cylinders is preferred. The vessel is provided with an evaporation cap that remains in place throughout the test period. Components conform to the dimensions shown below unless otherwise specified in the individual monographs.

[0090] The measurement is carried out at a temperature set at 37° C., using 250 mL of 0.01 N HCl and 2% SDS as dissolution medium.

[0091] Example 1: Pharmaceutical composition in the form of a suspension with wet medium milling according to the invention A suspension is prepared (on a pilot scale) using wet medium milling according to the present invention, consisting of a liquid carrier containing olive oil and linseed oil in an 80 / 20 ratio (w / w) and progesterone in a relative amount of 40 wt.% based on the total weight of the suspension. For this purpose, supplemented USP olive oil (Henry Lamotte Oils GmbH, Bremen, Germany) and virgin linseed oil (Biocoop, France) are mixed to form 1.4 kg of a uniform 80 / 20 mixture. Micronized progesterone is added to the oil mixture in an amount that results in a suspension containing 40 wt.% progesterone. In the resulting suspension, before the nanomilling step, the micronized progesterone particles have the following PSD: Dv10=7.58 μm, Dv50=15.88 μm, Dv90=26.45 μm, and D[4.3]=16.35 μm. For milling, a Netzsch Zeta® Labstar LMZ machine equipped with a DeltaVita® pin agitator is used. VitaBeads® Nano (0.8 mm) are used as milling medium in an amount of 1,656 kg. The volume of beads introduced into the milling chamber represented 85% of the total volume of the milling chamber. The milling machine is operated at 2,000 rpm. The product temperature is maintained below 45°C. The wet medium milling operation is continued for 90 minutes. The suspension with wet medium milling thus obtained is called batch 8301189F6. The main characteristics of this batch are summarized in Table 3 below.

[0092] [Table 3]

[0093] Example 2: Characterization of Suspension with Wet Media Milling (vs. Utrogestan®) A portion of the product batch (8301189F6) produced in Example 1 is used for characterization of physicochemical characteristics, including particle size distribution and viscosity measurements.

[0094] The results of the PSD measurements are summarized in Table 4. The results of the kinematic viscosity measurements are summarized in Table 5 and plotted in Figure 2.

[0095] [Table 4]

[0096] [Table 5]

[0097] Example 3: In vitro dissolution study of suspension with wet media milling versus Utrogestan® An in vitro dissolution test was performed on the final product produced in Example 1 (i.e., batch 8301189F6 suspension, after filling into gelatin capsules) using 200 mg Utrogestan® capsules as a control.

[0098] The in vitro dissolution profile was determined using the USP3 apparatus as described above. Seven tanks were placed in a water bath at a constant temperature, and then 1000 ml of dissolution medium was transferred to each of the seven tanks. One capsule was placed in each of the six tanks (three capsules filled with the product from the batch in Example 1 and three Utrogestan® capsules were tested), and the basket was then immersed in the dissolution medium with a distance of 25 mm ± 2 mm between the basket and the bottom of the tank. The basket was stirred, and then a control solution was prepared. Samples were collected at each scheduled interval (5 min, 10 min, 15 min, 30 min, 60 min, 90 min) and then analyzed by UV spectrophotometry (λ: 248 nm).

[0099] The results of the dissolution experiments are summarized in Table 6 and plotted in Figure 3.

[0100] [Table 6]

[0101] The results shown in Table 6 and Figure 3 indicate that capsules filled with compositions according to the invention have dissolution profiles characterized by a higher release rate and / or a larger area under the curve compared to Utrogestan®. These in vitro release characteristics mean that the formulations of the invention will also have a higher bioavailability of progesterone in vivo, meaning that it may be feasible to reduce the (daily) dose of administered progesterone compared to Utrogestan® for comparable efficacy.

[0102] Example 4: Pharmaceutical composition in the form of a suspension with wet medium milling according to the invention A suspension is prepared (on a pilot scale) using wet medium milling according to the present invention, consisting of a liquid carrier containing olive oil (Societe Industrielle des Oleagineux, Saint-Laurent-Blangy, France) and progesterone in a relative amount of 40 wt.% based on the total weight of the suspension. Micronized progesterone is added to the oil in an amount that results in a suspension containing 40 wt.% progesterone. In the resulting suspension, the micronized progesterone particles have the following PSDs: Dv10 = 11.057 μm, Dv50 = 23.065 μm, Dv90 = 40.337 μm, and D[4,3] = 24.287 μm. A Netzsch Zeta® Labstar LMZ apparatus equipped with a DeltaVita® pin stirrer is used for milling. VitaBeads® Nano (0.3 mm) are used as milling medium in an amount of 1,656 kg. The volume of beads introduced into the milling chamber represented 85% of the total volume of the milling chamber. The milling device is operated at 2,000 rpm. The product temperature is maintained below 45°C. The wet medium milling operation is continued for 15 minutes. The suspension with wet medium milling thus obtained is called batch 8301235B. The main characteristics of this batch are summarized in Table 7 below.

[0103] [Table 7]

[0104] Example 5: Characterization of Suspensions with Wet Media Milling (vs. Utrogestan®) A portion of the product batch (8301235B) produced in Example 4 is used for characterization of physicochemical characteristics, including particle size distribution and viscosity measurements.

[0105] The results of the PSD measurements are summarized in Table 8. The results of the kinematic viscosity measurements are summarized in Table 9.

[0106] [Table 8]

[0107] [Table 9]

Claims

1. 1. A pharmaceutical composition in the form of a suspension comprising progesterone particles with wet media milling in a liquid carrier comprising one or more vegetable oils, wherein the progesterone particles have a Dv50 of less than 8 μm, preferably less than 6 μm, more preferably less than 5 μm, as measured by laser light diffraction.

2. 2. The pharmaceutical composition of claim 1, wherein the progesterone particles have a Dv90 of less than 12 μm, preferably less than 10 μm, more preferably less than 8 μm.

3. 3. The pharmaceutical composition according to claim 1 or 2, wherein the progesterone particles have a Dv10 of less than 2 μm, preferably less than 1.5 μm, more preferably less than 1 μm.

4. The liquid carrier has a viscosity of 1.5 seconds or less as measured using a Rheomat RM100 (LAMY RHEOLOGY®) viscometer at a temperature in the range of 21.5 to 24.5°C. －１ 4. The pharmaceutical composition of claim 1, having a viscosity of at least 80 Pa.sec at a shear rate of 100 psi.

5. the one or more vegetable oils - gadoleic acid at a level of 0.01 to 30% w / w; Linoleic acid at a level of 0.5 to 70% w / w; or Alpha linolenic acid at a level of 0.5 to 70% w / w The pharmaceutical composition according to any one of claims 1 to 4, comprising:

6. 6. The pharmaceutical composition of any one of claims 1 to 5, wherein the one or more vegetable oils are selected from the group consisting of sunflower oil, olive oil, linseed oil, chia oil, palm oil, corn germ oil, and camelina oil.

7. 7. The pharmaceutical composition of claim 1, wherein the carrier comprises a combination of two or more vegetable oils.

8. 8. The pharmaceutical composition of claim 7, wherein the carrier comprises a combination of olive oil and linseed oil.

9. 9. The pharmaceutical composition of claim 8, wherein the olive oil and linseed oil are combined in a ratio ranging from 8 / 1 to 2.5 / 1, preferably from 6 / 1 to 3 / 1, more preferably from 5 / 1 to 3.5 / 1, and most preferably in a ratio of about 4 / 1.

10. 8. The pharmaceutical composition of claim 7, wherein the carrier comprises a combination of corn germ oil and linseed oil.

11. 11. The pharmaceutical composition of claim 10, wherein the corn germ oil and linseed oil are present in a ratio ranging from 8 / 1 to 2.5 / 1, preferably from 6 / 1 to 3 / 1, more preferably from 5 / 1 to 3.5 / 1, and most preferably in a ratio of about 4 / 1.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the carrier further comprises soy lecithin.

13. 13. The pharmaceutical composition of any one of claims 1 to 12, wherein the carrier does not include soy lecithin.

14. 14. The pharmaceutical composition of any one of claims 1 to 13, wherein the liquid carrier comprises at least 80 wt.%, preferably at least 90 wt.%, more preferably at least 95 wt.%, of the combination of one or more oils, based on the total weight of the carrier.

15. 15. The pharmaceutical composition of any one of claims 1 to 14, comprising 0.1 to 0.8 mg of progesterone per ml of liquid carrier.

16. 16. The pharmaceutical composition according to any one of claims 1 to 15, in unit dosage form, wherein each dosage unit contains 20 mg to 600 mg of progesterone, preferably about 100 mg of progesterone, about 200 mg of progesterone or about 300 mg of progesterone.

17. 17. The pharmaceutical composition according to claim 16, wherein the unit dosage form is a capsule, in particular a soft gelatin capsule, filled with the suspension.

18. 18. A pharmaceutical composition according to any preceding claim, wherein the progesterone is present at a level in the range of 20-60% w / w, based on the total weight of the suspension.

19. 19. The pharmaceutical composition according to any one of claims 1 to 18, for use in the prophylactic and / or therapeutic treatment of a subject in need thereof, the treatment comprising oral or vaginal administration of said composition.

20. 1. A method for preparing a pharmaceutical composition in the form of a suspension comprising progesterone particles in a liquid carrier with wet medium milling, comprising: a) providing a liquid carrier comprising one or more vegetable oils; b) providing progesterone in powder form; c) combining the progesterone and the liquid carrier; d) subjecting the combination of progesterone and liquid carrier to a wet medium milling operation to produce a suspension of progesterone particles having a Dv50 of less than 8 μm as measured by laser diffraction; A method comprising:

21. 21. The method of claim 20, further comprising the step e) of filling the suspension obtained in step d) into capsules.

22. 22. A pharmaceutical composition obtainable by the method according to claim 20 or 21.

23. 23. The pharmaceutical composition of any one of claims 1 to 19 and claim 22, having a USP 3 in vitro dissolution profile characterized by an amount dissolved after 20 minutes of at least 40% as measured in a USP 3 in vitro dissolution test performed in 250 mL of 0.01 N HCl and 2% SDS as the dissolution medium and at a temperature set at 37°C, and at least 40% after 20 minutes.

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