Modified release composition

Abstract

A modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

Description

[0001] MODIFIED RELEASE COMPOSITION

[0002] TECHNICAL FIELD

[0003] The present invention relates to a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers. The present invention also relates to a method of manufacturing a modified release composition and a method of treating infertility and / or preventing miscarriages using a modified release composition.

[0004] BACKGROUND

[0005] Dydrogesterone, also known as isopregnenone, dehydroprogesterone, didrogesteron, 6- dehydro-9p,10a-progesterone, or 9p,10a-pregna-4,6-diene-3, 20-dione, is a progestin or a synthetic progestogen, which has the following formula:

[0006] It has been used to treat a variety of indications, including gynaecological disorders, infertility, prevention of miscarriages and as a component of menopausal hormone therapy.

[0007] Conventional dydrogesterone formulations on the market are in the form of immediate release tablets. Therefore, in cases where a patient is required to take tablets of dydrogesterone more than once a day, this can lead to a decrease in patient compliance. Accordingly, the present invention seeks to overcome this problem by providing a modified release composition comprising dydrogesterone which is administered in a single dose to improve patient compliance. Moreover, a further aim of the present invention is to provide a modified release composition which would allow the active ingredient to have the desired release profile e.g. release of dydrogesterone over an extended period of time but with a fast onset. SUMMARY OF THE INVENTION

[0008] According to an aspect of the present invention, there is provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 20% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0009] The composition may provide a mean dydrogesterone plasma AUC<o-24h) value relative to that of an immediate release formulation comprising dydrogesterone, of at least about 1.0, or at least about 1.05, or at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1 .5, or at least about 2.0, or at least about 2.5, or at least about 3.0, where the AUC(o-24h) values may be determined under similar conditions.

[0010] The composition may comprise dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of 10% to 40%; one or more release controlling polymers in an amount of 20 to 60%; and one or more pharmaceutically acceptable excipients.

[0011] The composition may comprise dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of 10% to 40%; one or more release controlling polymers in an amount of 20 to 60%; one or more fillers in an amount of 20% to 65%; and one or more lubricants and / or glidants in an amount of 0.1 % to 10%.

[0012] The weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between 1 :6 and 2:1.

[0013] The weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between 1 :6 and 2:1.

[0014] The weight ratio between the filler and the one or more release controlling polymers may be between 1 :3 and 5:2.

[0015] The dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of 10% to 40%, preferably 15% to 35%, by weight based on the total weight of the composition. The composition may comprise 15 to 50 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0016] The one or more release controlling polymers may be present in an amount of 20 to 60%, preferably 30 to 40% by weight based on the total weight of the composition.

[0017] The one or more release controlling polymers may be hydroxypropyl methylcellulose.

[0018] The filler may be present in an amount of 20% to 65%, preferably 30% to 60%, by weight based on the total weight of the composition.

[0019] The filler may be lactose, and more preferably lactose monohydrate.

[0020] The composition may provide a mean dydrogesterone plasma AUC(o-24h) equivalent to 2 immediate release formulations each comprising 10 mg of dydrogesterone.

[0021] The composition may provide a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 25 ng*hr / mL.

[0022] The composition may provide a mean dydrogesterone plasma AUC(o-24h) equivalent to 3 immediate release formulations each comprising 10 mg of dydrogesterone.

[0023] The composition may provide a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 70 ng*hr / mL.

[0024] The composition may be free from floating agents and / or gas-generating agents.

[0025] According to a further aspect of the present invention, there is provided a method of manufacturing a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers, and one or more pharmaceutically acceptable excipients, the method comprising the steps of:

[0026] 1) providing a dry mixture of dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers and one or more pharmaceutically acceptable excipients;

[0027] 2) adding water to said dry mixture; 3) performing a granulation step to provide a granulated mixture; and

[0028] 4) drying said mixture to remove the water.

[0029] In a further embodiment according to the present invention, there is provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0030] There is also provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0031] In another embodiment, there is provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0032] According to yet a further aspect of the present invention, there is provided a method of treating infertility and / or preventing miscarriages using a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers and one or more pharmaceutically acceptable excipients.

[0033] According to another aspect of the present invention, the composition may be used in the treatment of gynaecological disorders, menstrual disorders, infertility, prevention of miscarriages, as part of in vitro fertilisation (IVF) treatment or as a component of menopausal hormone therapy.

[0034] The composition may be used in the treatment of endometriosis or as part of in vitro fertilisation (IVF) treatment.

[0035] The composition may be administered once daily. DETAILED DESCRIPTION OF THE INVENTION

[0036] According to an aspect of the present invention, there is provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, and one or more release controlling polymers, and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 20% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0037] The term “modified release” as used herein refers to the release of a drug over an extended period of time for example, from about 2 hours to about 24 hours, from about 2 hours to about 16 hours, from about 2 hours to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 7 hours, from about 2 hours to about 6 hours, from about 2 hours to about 5 hours, and from about 2 hours to about 4.5 hours. The term “modified release” includes but is not limited to extended release, sustained release, controlled release, delayed release and combinations thereof. In an embodiment according to the present invention, 20-30% of the drug is released over a period of about 0.5 to about 2 hours, 50-90% of the drug is released over about 1 to about 3 hours and 80-100% of the drug is released over about 2 to about 4.5 hours. In a further embodiment according to the present invention, 15-70% of the drug is released over a period of about 0.5 to about 2 hours, 35-90% of the drug is released over about 1 to about 3 hours and 80- 100% of the drug is released over about 2.5 to about 4 hours. The release of dydrogesterone may be identified based on dissolution apparatus 1 of USP (basket), using 600 ml of dissolution medium 0.3% Sodium Laurylsulfate in water with a stir rate of 150 rpm.

[0038] The term “immediate release” as used herein refers to the release of a drug over a period of time less than 2 hours, for example less than 1 hour, or less than 45 minutes. The term “immediate release” may also be referred to as instant release.

[0039] The dydrogesterone may be provided in the composition in a free form or as a pharmaceutically acceptable salt. The term “salt” as used herein refers to a salt of dydrogesterone that is derived from suitable inorganic and organic acids and bases. Examples of salts of a basic group include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as trifluoroacetic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-C4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate.

[0040] In some aspects, dydrogesterone may exist in an unsolvated form as well as the solvated form, including the hydrated form. “Hydrate” refers to a complex formed by combination of water molecules with molecules or ions of the solute. “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent may be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrate. Some examples of solvents include, but are not limited to, methanol, acetonitrile, N,N- dimethylformamide, tetra hydrofuran, dimethylsulfoxide, and water. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.

[0041] The dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 10% to about 40%, preferably about 15% to about 40%, preferably about 15% to about 35%, preferably about 16% to about 35%, preferably about 17% to about 34%, preferably about 18% to about 33%, and preferably about 18% to about 32%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition. The modified release composition according to the present invention may comprise about 10 mg or more, preferably greater than 10 mg, preferably about 15 to about 40 mg, preferably about 20 to about 40 mg, preferably about 20 to about 30 mg and preferably about 20 mg or about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. In an embodiment, the composition may comprise about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg, of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0042] As used herein, and in the absence of a specific reference to a particular pharmaceutically acceptable salt and / or solvate of dydrogesterone, any dosages, whether expressed in e.g. milligrams or as a % by weight, should be taken as referring to the amount of dydrogesterone in free base form. For example, a reference to “20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof” means an amount of dydrogesterone or a pharmaceutically acceptable salt thereof which provides the same amount of dydrogesterone as 20 mg of dydrogesterone free base.

[0043] The modified release composition further comprises one or more release controlling polymers. As used herein, the term “release controlling polymer” refers to any polymer material suitable for pharmaceutical dosage forms that retard the release of drug substances from such dosage forms. Examples of suitable release controlling polymers can be found in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990. Suitable release controlling polymers include hydrophilic or hydrophobic polymers comprising one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose (hypromellose) having a viscosity greater than 10 mPa s (10 cps) in 2% water at 20°C (e.g., type 2208, type 2910, methocel K15M, methocel E15LV), carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C - NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers such as methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS), Carbomer (e.g., Carbomer 971 P) and combinations thereof. The release controlling polymer is preferably hydroxypropyl methyl cellulose (hypromellose).

[0044] In an aspect of the present invention, the modified release composition may contain more than one type of release controlling polymer. For instance, the modified release composition may contain two different types of release controlling polymers. As used herein, the term “different type” refers to polymers that can be distinguished by any chemical or physical property. The two or more polymers may differ by their molecular weight, chemical structure, release profile or grade. In a preferred aspect of the present invention, the modified release composition may contain two different types of release controlling polymers that differ by their release profile or grade. In a further preferred aspect of the present invention, the modified release composition may contain two different types of hydroxypropyl methyl cellulose (hypromellose) polymers, for example, a combination of methocel K15M and methocel E15LV.

[0045] The one or more release controlling polymers may be present in an amount of about 20% to about 60%, preferably about 25% to about 60%, preferably about 25% to about 55%, preferably about 28% to about 50%, preferably about 30% to about 40%, preferably about 30% to about 35%, or preferably about 25% to about 35%, by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about

[0046] 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about

[0047] 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about

[0048] 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about

[0049] 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% by weight based on the total weight of the composition. In the case where the modified release composition comprises two or more release controlling polymers, the weight percentages specified herein refers to the total amount of release controlling polymers present in the modified release composition. The modified release composition according to the present invention further contains one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0050] Suitable fillers / diluents include, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, lactose monohydrate, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, and combinations thereof. The filler is preferably lactose, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 20% to about 65%, preferably about 20% to about 60%, preferably about 25% to about 60%, preferably about 30% to about 60%, preferably about 30% to about 55%, and preferably about 30% to about 50%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59% or about 60%, by weight based on the total weight of the composition.

[0051] Suitable binders include, microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP 90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropyl cellulose, copovidone, and combinations thereof. The binder may be present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1% to about 10%, by weight based on the total weight of the composition.

[0052] Suitable lubricants / glidants include, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silicon dioxide (e.g., Aerosil 200), colloidal anhydrous silica, aluminum or calcium silicate, stearic acid, cutina, magnesium trisilicate, powdered cellulose, talc and combinations thereof. The lubricant / glidant is preferably colloidal anhydrous silica and / or magnesium stearate, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1% to about 10%, preferably about 0.5% to about 5%, and preferably about 1% to about 3%, by weight based on the total weight of the composition. Suitable disintegrants include, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (pirimojel and explotab) and / or combinations thereof. The disintegrant may be present in an amount of about 0.01 % to about 15%, preferably about 0.05% to about 12%, and preferably about 0.1% to about 10%, by weight based on the total weight of the composition.

[0053] Suitable plasticizers include, propylene glycol, phthalates, polyethylene glycols, sebacates, or citrates such as dibutyl phthalate, diethyl phthalate, dibutyl sebecate, triethyl citrate, acetyl tributyl citrate and polyethylene glycol. The plasticizer may be present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0054] The modified release composition according to the present invention may provide a mean dydrogesterone plasma AUC(o-24h) value relative to that of an immediate release formulation comprising dydrogesterone, of at least about 1.0, or at least about 1.05, or at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 2.0, or at least about 2.5, or at least about 3.0, where the AUC(o-24h) values may be determined under similar conditions.

[0055] The composition may provide a mean dydrogesterone plasma AUC(o-24h) value relative to that of commercially available Duphaston® tablets of at least about 1.0, or at least about 1 .05, or at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1.4, or at least about 1.5, or at least about 2.0, or at least about 2.5, or at least about 3.0, where the AUC(o-24h) values may be determined under similar conditions.

[0056] The modified release composition according to the present invention may provide a mean dydrogesterone plasma AUC(o-24h) equivalent to at least two immediate release formulations each comprising 10 mg of dydrogesterone.

[0057] “AUG” as used herein means area under the plasma concentration-time curve, as calculated by the trapezoidal rule over a time interval (e.g. complete 24-hour interval); and signifies the extent of the absorption of a drug. “Cmax” as used herein means the highest plasma concentration of the drug attained within the dosing interval (e.g., 24 hours).

[0058] In some embodiments, modified release composition may provide a mean dydrogesterone plasma AUC(o-24h) equivalent to 2 to 4 immediate release formulations each comprising 10 mg of dydrogesterone. For example, the modified release composition may provide a mean dydrogesterone plasma AUC(o-24h) equivalent to 2, 3 or 4 immediate release formulations each comprising 10 mg of dydrogesterone. In a preferred embodiment according to the present invention, the modified release composition may provide a mean dydrogesterone plasma AUC<o- 24h) equivalent to 2 or 3 immediate release formulations each comprising 10 mg of dydrogesterone.

[0059] In some embodiments, each immediate release formulation comprising 10 mg of dydrogesterone may provide a mean dydrogesterone plasma AUC(o-24h) of about 4 to about 25 ng*hr / mL, preferably about 6 to about 20 ng*hr / mL, preferably about 7 to about 18 ng*hr / mL and preferably about 8 to about 15 ng*hr / mL.

[0060] The Cmax and AUC(o-24h) are calculated using a non-compartmental analysis model using Phoenix® WinNonlin® - Software, Version 8.3.5 (Certara USA, Inc.) for analysis of Dydrogesterone and Dihydrodydrogesterone.

[0061] The immediate release formulation comprising 10 mg of dydrogesterone may be any commercially available immediate release product containing 10 mg of dydrogesterone, such as Duphaston®.

[0062] In an embodiment according to the present invention, the modified release composition according to the present invention may provide a mean dydrogesterone plasma AUC<o-24h) equivalent to two immediate release formulations each comprising 10 mg of dydrogesterone, such as Duphaston®.

[0063] In a further embodiment according to the present invention, the modified release composition according to the present invention may provide a mean dydrogesterone plasma AUC<o-24h) equivalent to three immediate release formulations each comprising 10 mg of dydrogesterone, such as Duphaston®. In a further aspect of the present invention, the modified release composition may be free from floating agents. Such floating agents may include sodium carbonate, sodium bicarbonate, calcium carbonate, adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, sodium citrate and citric acid.

[0064] In another aspect of the present invention, the modified release composition may be free from gas-generating agents. Such gas-generating agents may include carbonate and bicarbonate salts, that generate CO2 in the presence of acidic gastric fluid such as citric acid.

[0065] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 1 :6 and about 2:1 , preferably between about 1 :4 and about 3:2, preferably between about 1 :2 and about 4:3 and preferably between about 1 :2 and about 1 :1.

[0066] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 1 :6 and about 2:1 , preferably between about 1 :4 and about 3:2, preferably between about 1 :3 and about 2:1 , and preferably between about 1 :3 and about 1 :1.

[0067] In an aspect of the present invention, the weight ratio between the filler and the one or more release controlling polymers may be between about 1 :3 and about 5:2, preferably between about 1 :2 and about 7:3, preferably between about 3:4 and about 2:1 , and preferably between about 4:5 and about 5:3.

[0068] In an embodiment, the modified release composition according to the present invention may be formulated as a single dosage form, preferably as a single tablet, and more preferably as a single oral tablet.

[0069] The modified release composition according to the present invention may be manufactured by a granulation process.

[0070] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the one or more release controlling polymers may be present in an amount of about 25% to about 60% by weight based on the total weight of the composition.

[0071] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the one or more release controlling polymers may be present in an amount of about 25% to about 35% by weight based on the total weight of the composition.

[0072] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 1 :6 and about 2: 1.

[0073] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the one or more fillers may be present in an amount of about 20% to about 60% by weight based on the total weight of the composition.

[0074] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 1 :6 and about 2:1.

[0075] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between the filler and the one or more release controlling polymers may be between about 1 :3 and about 5:2.

[0076] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and lactose, wherein lactose may be present in an amount of about 20% to about 60% by weight based on the total weight of the composition. In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 10% to about 30% by weight based on the total weight of the composition; the one or more release controlling polymers may be present in an amount of about 30% to about 35% by weight based on the total weight of the composition; and the one or more fillers may be present in an amount of about 30% to about 60% by weight based on the total weight of the composition.

[0077] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and lactose, wherein dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 10% to about 30% by weight based on the total weight of the composition; the one or more release controlling polymers may be present in an amount of about 30% to about 35% by weight based on the total weight of the composition; and lactose may be present in an amount of about 30% to about 60% by weight based on the total weight of the composition.

[0078] In an aspect of the present invention, there may be provided a modified release composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 30% by weight based on the total weight of the composition; one or more release controlling polymers in an amount of about 30% to about 35% by weight based on the total weight of the composition; one or more fillers in an amount of about 30% to about 60% by weight based on the total weight of the composition; and one or more lubricants or glidants in an amount of about 0.5% to about 5% by weight based on the total weight of the composition.

[0079] In an aspect of the present invention, there may be provided a modified release composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 10% to about 30% by weight based on the total weight of the composition; one or more release controlling polymers in an amount of about 30% to about 35% by weight based on the total weight of the composition; lactose in an amount of about 30% to about 60% by weight based on the total weight of the composition; silicon dioxide in an amount of about 0.5% to about 2% by weight based on the total weight of the composition; and magnesium stearate in an amount of about 0.5% to about 2% by weight based on the total weight of the composition.

[0080] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein 20-30% of dydrogesterone may be released over a period of about 0.5 to about 2 hours, 50-90% of dydrogesterone may be released over about 1 to about 3 hours and 80-100% of dydrogesterone may be released over about 2 to about 4.5 hours.

[0081] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein 15-70% of dydrogesterone may be released over a period of about 0.5 to about 2 hours, 35-90% of dydrogesterone may be released over about 1 to about 3 hours and 80-100% of dydrogesterone may be released over about 2.5 to about 4 hours.

[0082] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 20% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0083] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 25% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0084] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 25% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0085] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 30% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0086] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 30% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0087] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 35% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0088] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 35% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0089] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 40% of dydrogesterone in 1 hour and not less than 70% of dydrogesterone within 4 hours. In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 50% of dydrogesterone in 1 hour and not less than 70% of dydrogesterone within 4 hours.

[0090] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 40% of dydrogesterone in 1 hour and not less than 75% of dydrogesterone within 4 hours.

[0091] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 50% of dydrogesterone in 1 hour and not less than 75% of dydrogesterone within 4 hours.

[0092] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 40% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 4 hours.

[0093] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 50% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 4 hours.

[0094] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 40% of dydrogesterone in 1 hour and not less than 85% of dydrogesterone within 4 hours. In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 50% of dydrogesterone in 1 hour and not less than 85% of dydrogesterone within 4 hours.

[0095] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 40% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 4 hours.

[0096] In an aspect of the present invention, there may be provided a modified release composition comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases not more than 50% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 4 hours.

[0097] In an aspect of the present invention, there may be provided a modified release composition for use in the treatment of endometriosis, comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0098] In an aspect of the present invention, there may be provided a modified release composition for use as part of in vitro fertilisation (IVF) treatment, comprising, dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0099] Low Dose Embodiment

[0100] According to an aspect of the present invention, there is provided a modified release composition comprising 15 to 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of 10 to 25 ng*hr / mL. The dydrogesterone may be provided in the composition in a free form or as a pharmaceutically acceptable salt as described herein.

[0101] The dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 15% to about 25%, preferably about 16% to about 24%, preferably about 17% to about 23%, preferably about 18% to about 22%, preferably about 19% to about 21 %, and preferably about 20%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24% or about 25%, by weight based on the total weight of the composition.

[0102] The modified release composition according to the present invention may comprise about 15 to about 25 mg, preferably about 16 to about 24 mg, preferably about 17 to about 23 mg, preferably about 18 to about 22 mg, preferably about 19 to about 21 mg and preferably about 20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. In an embodiment, the composition may comprise about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg or about 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the composition comprises 20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0103] The modified release composition further comprises one or more release controlling polymers as described herein. In a preferred embodiment, the release controlling polymer is hydroxypropyl methyl cellulose (hypromellose).

[0104] The one or more release controlling polymers may be present in an amount of about 30% to about 40%, preferably about 31% to about 39%, preferably about 32% to about 38%, preferably about 33% to about 37%, and preferably about 34 to about 36% by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition. In the case where the modified release composition comprises two or more release controlling polymers, the weight percentages specified herein refers to the total amount of release controlling polymers present in the modified release composition. The modified release composition may provide a mean dydrogesterone plasma AUC(o-24h) of about

[0105] 10 to about 25 ng*hr / mL, preferably about 10 to about 20 ng*hr / mL, preferably about 15 to about

[0106] 20 ng*hr / mL and preferably about 15 to about 19 ng*hr / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dydrogesterone plasma AUC(o-24h) of about 10 ng*hr / mL, preferably about 11 ng*hr / mL, preferably about 12 ng*hr / mL, preferably about 13 ng*hr / mL, preferably about 14 ng*hr / mL, preferably about 15 ng*hr / mL, preferably about 16 ng*hr / mL, preferably about 17 ng*hr / mL, preferably about 18 ng*hr / mL, preferably about 19 ng*hr / mL, preferably about 20 ng*hr / mL, preferably about 21 ng*hr / mL, preferably about 22 ng*hr / mL, preferably about 23 ng*hr / mL, preferably about 24 ng*hr / mL or preferably 25 ng*hr / mL. As used herein, AUC(o-24h) refers to the area under the plasma concentration curve from zero to twenty four hours, as measured using a 20 mg dose of dydrogesterone.

[0107] The modified release composition may provide a mean dydrogesterone plasma Cmax of about 2 to about 5 ng / mL, preferably about 2 to about 4 ng / mL, preferably about 2 to about 3 ng / mL, and preferably about 2.5 to about 3 ng / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dydrogesterone plasma Cmax of about 2 ng / mL, preferably about 2.1 ng / mL, preferably about 2.2 ng / mL, preferably about 2.3 ng / mL, preferably about 2.4 ng / mL, preferably about 2.5 ng / mL, preferably about 2.6 ng / mL, preferably about 2.7 ng / mL, preferably about 2.8 ng / mL, preferably about 2.9 ng / mL, preferably about 3.0 ng / mL, preferably about 3.1 ng / mL, preferably about 3.2 ng / mL, preferably about 3.3 ng / mL, preferably about 3.4 ng / mL, preferably about 3.5 ng / mL, preferably about 3.6 ng / mL, preferably about 3.7 ng / mL, preferably about 3.8 ng / mL, preferably about 3.9 ng / mL, preferably about 4.0 ng / mL, preferably about 4.1 ng / mL, preferably about 4.2 ng / mL, preferably about 4.3 ng / mL, preferably about 4.4 ng / mL, preferably about 4.5 ng / mL, preferably about 4.6 ng / mL, preferably about 4.7 ng / mL, preferably about 4.8 ng / mL, preferably about 4.9 ng / mL, or preferably about 5.0 ng / mL. As used herein, Cmax refers to the maximum observed plasma concentration of dydrogesterone.

[0108] The modified release composition may provide a mean dihydrodydrogesterone plasma AUC(o-24h) of about 350 to about 750 ng*hr / mL, preferably about 400 to about 700 ng*hr / mL, preferably about 450 to about 650 ng*hr / mL, preferably about 500 to about 600 ng*hr / mL, and preferably about 500 to about 550 ng*hr / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dihydrodydrogesterone plasma AUC(o-24h) of about 350 ng*hr / mL, preferably about 360 ng*hr / mL, preferably about 370 ng*hr / mL, preferably about 380 ng*hr / mL, preferably about 390 ng*hr / mL, preferably about 400 ng*hr / mL, preferably about 410 ng*hi7mL, preferably about 420 ng*hr / mL, preferably about 430 ng*hr / mL, preferably about 440 ng*hr / mL, preferably about 450 ng*hr / mL, preferably about 460 ng*hr / mL, preferably about 470 ng*hr / mL, preferably about 480 ng*hr / mL, preferably about 490 ng*hr / mL, preferably about 500 ng*hr / mL, preferably about 510 ng*hr / mL, preferably about 520 ng*hr / mL, preferably about 530 ng*hr / mL, preferably about 540 ng*hr / mL, preferably about 550 ng*hr / mL, preferably about 560 ng*hr / mL, preferably about 570 ng*hr / mL, preferably about 580 ng*hr / mL, preferably about 590 ng*hr / mL, preferably 600 ng*hr / mL, preferably about 610 ng*hr / mL, preferably about 620 ng*hr / mL, preferably about 630 ng*hr / mL, preferably about 640 ng*hr / mL, preferably about 650 ng*hr / mL, preferably about 660 ng*hr / mL, preferably about 670 ng*hr / mL, preferably about 680 ng*hr / mL, preferably about 690 ng*hr / mL, preferably 700 ng*hr / mL, preferably about 710 ng*hr / mL, preferably about 720 ng*hr / mL, preferably about 730 ng*hr / mL, preferably about 740 ng*hr / mL, or preferably about 750 ng*hr / mL.

[0109] The modified release composition may provide a mean dihydrodydrogesterone plasma Cmax of about 50 to about 110 ng / mL, preferably about 55 to about 105 ng / mL, preferably about 60 to about 100 ng / mL, preferably about 65 to about 95 ng / mL, preferably about 70 to about 90 ng / mL, and preferably about 75 to about 85 ng / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dihydrodydrogesterone plasma Cmax of about 50 ng / mL, preferably about 51 ng / mL, preferably about 52 ng / mL, preferably about 53 ng / mL, preferably about 54 ng / mL, preferably about 55 ng / mL, preferably about 56 ng / mL, preferably about 57 ng / mL, preferably about 58 ng / mL, preferably about 59 ng / mL, preferably about 60 ng / mL, preferably about 61 ng / mL, preferably about 62 ng / mL, preferably about 63 ng / mL, preferably about 64 ng / mL, preferably about 65 ng / mL, preferably about 66 ng / mL, preferably about 67 ng / mL, preferably about 68 ng / mL, preferably about 69 ng / mL, preferably about 70 ng / mL, preferably about 71 ng / mL, preferably about 72 ng / mL, preferably about 73 ng / mL, preferably about 74 ng / mL, preferably about 75 ng / mL, preferably about 76 ng / mL, preferably about 77 ng / mL, preferably about 78 ng / mL, preferably about 79 ng / mL, preferably about 80 ng / mL, preferably about 81 ng / mL, preferably about 82 ng / mL, preferably about 83 ng / mL, preferably about 84 ng / mL, preferably about 85 ng / mL, preferably about 86 ng / mL, preferably about 87 ng / mL, preferably about 88 ng / mL, preferably about 89 ng / mL, preferably about 90 ng / mL, preferably about 91 ng / mL, preferably about 92 ng / mL, preferably about 93 ng / mL, preferably about 94 ng / mL, preferably about 95 ng / mL, preferably about 96 ng / mL, preferably about 97 ng / mL, preferably about 98 ng / mL, preferably about 99 ng / mL, preferably about 100 ng / mL, preferably about 101 ng / mL, preferably about 102 ng / mL, preferably about 103 ng / mL, preferably about 104 ng / mL, preferably about 105 ng / mL, preferably about 106 ng / mL, preferably about 107 ng / mL, preferably about 108 ng / mL, preferably about 109 ng / mL, or preferably about 110 ng / mL.

[0110] In one aspect, the AUC(o-24h) and Cmax values provided herein may be measured when a patient is in a fasted state. The “fasted state” as used herein refers to a state where the patient is provided with no food for at least 10 hours prior to dosing.

[0111] The modified release composition may contain one or more pharmaceutically acceptable carriers or excipients as described herein. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0112] The modified release composition preferably comprises lactose as a filler, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 35% to about 55%, preferably about 40% to about 50%, preferably about 41% to about 49%, preferably about 42% to about 48%, and preferably about 43% to about 47%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55%, by weight based on the total weight of the composition.

[0113] The modified release composition preferably comprises colloidal anhydrous silica and / or magnesium stearate as the lubricant / glidant, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1% to about 10%, preferably about 0.5% to about 5%, and preferably about 1 % to about 3%, by weight based on the total weight of the composition.

[0114] The modified release composition may be free from floating agents and / or gas-generating agents as described herein.

[0115] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 2:5 and about 5:6, preferably between about 2:3 and about 4:5 and preferably between about 1 :2 and about 2:3. In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 1 :3 and about 4:5, preferably between about 1 :3 and about 3:5, and preferably between about 2:5 and about 1 :1.

[0116] In an aspect of the present invention, the weight ratio between the filler and the one or more release controlling polymers may be between about 9:10 and about 2:1 , preferably between about 1 :1 and about 3:2, and preferably between about 5:4 and about 4:3.

[0117] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 15% to about 25% by weight based on the total weight of the composition.

[0118] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the one or more release controlling polymers may be present in an amount of about 30% to about 40% by weight based on the total weight of the composition.

[0119] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 1 :2 and about 2:3.

[0120] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the one or more fillers may be present in an amount of about 40% to about 50% by weight based on the total weight of the composition.

[0121] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 2:5 and about 1 :1.

[0122] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between the filler and the one or more release controlling polymers may be between about 5:4 and about 4:3.

[0123] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and lactose, wherein lactose may be present in an amount of about 40% to about 50% by weight based on the total weight of the composition.

[0124] In an aspect of the present invention, there may be provided a modified release composition comprising 15 to 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein 15-70% of dydrogesterone may be released over a period of about 0.5 to about 2 hours, 35-90% of dydrogesterone may be released over about 1 to about 3 hours and 80-100% of dydrogesterone may be released over about 2.5 to about 4 hours.

[0125] In an aspect of the present invention, there may be provided a modified release composition for use in the treatment of endometriosis, comprising, 15 to 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0126] In an aspect of the present invention, there may be provided a modified release composition for use as part of in vitro fertilisation (IVF) treatment, comprising, 15 to 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0127] High Dose Embodiment

[0128] According to an aspect of the present invention, there is provided a modified release composition comprising 26 to 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of 10 to 70 ng*hr / mL. The dydrogesterone may be provided in the composition in a free form or as a pharmaceutically acceptable salt as described herein.

[0129] The dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 10% to about 35%, preferably about 15% to about 35%, preferably about 20% to about 35%, preferably about 25% to about 35%, preferably about 28% to about 32%, and preferably about 30%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof may be present in an amount of about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, by weight based on the total weight of the composition.

[0130] The modified release composition according to the present invention may comprise about 26 to about 35 mg, preferably about 27 to about 34 mg, preferably about 28 to about 33 mg, preferably about 29 to about 32 mg, and preferably about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. In an embodiment, the composition may comprise about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg or about 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the composition comprises 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0131] The modified release composition further comprises one or more release controlling polymers as described herein. In a preferred embodiment, the release controlling polymer is hydroxypropyl methyl cellulose (hypromellose).

[0132] The one or more release controlling polymers may be present in an amount of about 25% to about 40%, preferably about 26% to about 39%, preferably about 27% to about 38%, preferably about 28% to about 37%, and preferably about 29% to about 36% by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition. In the case where the modified release composition comprises two or more release controlling polymers, the weight percentages specified herein refers to the total amount of release controlling polymers present in the modified release composition.

[0133] The modified release composition may provide a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 70 ng*hr / mL, preferably about 15 to about 65 ng*hr / mL, preferably about 20 to about 60 ng*hr / mL, preferably about 25 to about 55 ng*hr / mL, preferably about 30 to about 50 ng*hr / mL, and preferably about 35 to about 45 ng*hr / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dydrogesterone plasma AUC(o- 24h) of about 10 ng*hr / mL, preferably about 11 ng*hr / mL, preferably about 12 ng*hr / mL, preferably about 13 ng*hr / mL, preferably about 14 ng*hr / mL, preferably about 15 ng*hr / mL, preferably about

[0134] 16 ng*hr / mL, preferably about 17 ng*hr / mL, preferably about 18 ng*hr / mL, preferably about 19 ng*hr / mL, preferably about 20 ng*hr / mL, preferably about 21 ng*hr / mL, preferably about 22 ng*hr / mL, preferably about 23 ng*hr / mL, preferably about 24 ng*hr / mL, preferably about 25 ng*hr / mL, preferably about 26 ng*hr / mL, preferably about 27 ng*hr / mL, preferably about 28 ng*hr / mL, preferably about 29 ng*hr / mL, preferably about 30 ng*hr / mL, preferably about 31 ng*hr / mL, preferably about 32 ng*hr / mL, preferably about 33 ng*hr / mL, preferably about 34 ng*hr / mL, preferably 35 ng*hr / mL, preferably about 36 ng*hr / mL, preferably about 37 ng*hr / mL, preferably about 38 ng*hr / mL, preferably about 39 ng*hr / mL, preferably about 40 ng*hr / mL, preferably about 41 ng*hr / mL, preferably about 42 ng*hr / mL, preferably about 43 ng*hr / mL, preferably about 44 ng*hr / mL, preferably about 45 ng*hr / mL, preferably about 46 ng*hr / mL, preferably about 47 ng*hr / mL, preferably about 48 ng*hr / mL, preferably about 49 ng*hr / mL, preferably about 50 ng*hr / mL, preferably about 51 ng*hr / mL, preferably about 52 ng*hr / mL, preferably about 53 ng*hr / mL, preferably about 54 ng*hr / mL, preferably about 55 ng*hr / mL, preferably about 56 ng*hr / mL, preferably about 57 ng*hr / mL, preferably about 58 ng*hr / mL, preferably about 59 ng*hr / mL, preferably about 60 ng*hr / mL, preferably about 61 ng*hr / mL, preferably about 62 ng*hr / mL, preferably about 63 ng*hr / mL, preferably about 64 ng*hr / mL, preferably about 65 ng*hr / mL, preferably about 66 ng*hr / mL, preferably about 67 ng*hr / mL, preferably about 68 ng*hr / mL, preferably about 69 ng*hr / mL or about 70 ng*hr / mL. As used herein, AUC(o-24h) refers to the area under the plasma concentration curve from zero to twenty four hours, as measured using a 30 mg dose of dydrogesterone.

[0135] The modified release composition may provide a mean dydrogesterone plasma Cmax of about 1 .5 to about 7.5 ng / mL, preferably about 2 to about 7 ng / mL, preferably about 3 to about 6 ng / mL and preferably about 4 to about 5 ng / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dydrogesterone plasma Cmax of about 1.5 ng / mL, preferably about 1.6 ng / mL, preferably about 1.7 ng / mL, preferably about 1.8 ng / mL, preferably about 1.9 ng / mL, preferably about 2.0 ng / mL, preferably about 2.1 ng / mL, preferably about 2.2 ng / mL, preferably about 2.3 ng / mL, preferably about 2.4 ng / mL, preferably about 2.5 ng / mL, preferably about 2.6 ng / mL, preferably about 2.7 ng / mL, preferably about 2.8 ng / mL, preferably about 2.9 ng / mL, preferably about 3.0 ng / mL, preferably about 3.1 ng / mL, preferably about 3.2 ng / mL, preferably about 3.3 ng / mL, preferably about 3.4 ng / mL, preferably about 3.5 ng / mL, preferably about 3.6 ng / mL, preferably about 3.7 ng / mL, preferably about 3.8 ng / mL, preferably about 3.9 ng / mL, preferably about 4.0 ng / mL, preferably about 4.1 ng / mL, preferably about 4.2 ng / mL, preferably about 4.3 ng / mL, preferably about 4.4 ng / mL, preferably about 4.5 ng / mL, preferably about 4.6 ng / mL, preferably about 4.7 ng / mL, preferably about 4.8 ng / mL, preferably about 4.9 ng / mL, preferably about 5.0 ng / mL, preferably about 5.1 ng / mL, preferably about 5.2 ng / mL, preferably about 5.3 ng / mL, preferably about 5.4 ng / mL, preferably about 5.5 ng / mL, preferably about 5.6 ng / mL, preferably about 5.7 ng / mL, preferably about 5.8 ng / mL, preferably about 5.9 ng / mL, preferably about 6.0 ng / mL, preferably about 6.1 ng / mL, preferably about 6.2 ng / mL, preferably about 6.3 ng / mL, preferably about 6.4 ng / mL, preferably about 6.5 ng / mL, preferably about 6.6 ng / mL, preferably about 6.7 ng / mL, preferably about 6.8 ng / mL, preferably about 6.9 ng / mL, preferably about 7.0 ng / mL, preferably about 7.1 ng / mL, preferably about 7.2 ng / mL, preferably about 7.3 ng / mL, preferably about 7.4 ng / mL or preferably about 7.5 ng / mL. As used herein, Cmax refers to the maximum observed plasma concentration of dydrogesterone.

[0136] The modified release composition may provide a mean dihydrodydrogesterone plasma AUC(o-24h) of about 400 to about 2200 ng*hr / mL, preferably about 500 to about 2000 ng*hr / mL, preferably about 600 to about 1800 ng*hr / mL, and preferably about 700 to about 1500 ng*hr / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dihydrodydrogesterone plasma AUC(o-24h) of about 400 ng*hr / mL, preferably about 450 ng*hr / mL, preferably about 500 ng*hr / mL, preferably about 550 ng*hr / mL, preferably about 600 ng*hr / mL, preferably about 650 ng*hr / mL, preferably about 700 ng*hr / mL, preferably about 750 ng*hr / mL, preferably about 800 ng*hr / mL, preferably about 850 ng*hr / mL, preferably about 900 ng*hr / mL, preferably about 950 ng*hr / mL, preferably about 1000 ng*hr / mL, preferably about 1050 ng*hr / mL, preferably about 1100 ng*hr / mL, preferably 1150 ng*hr / mL, preferably about 1200 ng*hr / mL, preferably about 1250 ng*hr / mL, preferably about 1300 ng*hr / mL, preferably about 1350 ng*hr / mL, preferably about 1400 ng*hr / mL, preferably about 1450 ng*hr / mL, preferably about 1500 ng*hr / mL, preferably about 1550 ng*hr / mL, preferably about 1600 ng*hr / mL, preferably 1650 ng*hr / mL, preferably about 1700 ng*hr / mL, preferably about 1750 ng*hr / mL, preferably about 1800 ng*hr / mL, preferably about 1850 ng*hr / mL, preferably about 1900 ng*hr / mL, preferably about 1950 ng*hr / mL, preferably about 2000 ng*hr / mL, preferably about 2050 ng*hr / mL, preferably about 2100 ng*hr / mL, preferably 2150 ng*hr / mL or preferably about 2200 ng*hr / mL.

[0137] The modified release composition may provide a mean dihydrodydrogesterone plasma Cmax of about 40 to about 200 ng / mL, preferably about 50 to about 175 ng / mL, preferably about 60 to about 150 ng / mL, and preferably about 70 to about 120 ng / mL. In an embodiment according to the present invention, the modified release composition may provide a mean dihydrodydrogesterone plasma Cmax of about 40 ng / mL, preferably about 45 ng / mL, preferably about 50 ng / mL, preferably about 55 ng / mL, preferably about 60 ng / mL, preferably about 65 ng / mL, preferably about 70 ng / mL, preferably about 75 ng / mL, preferably about 80 ng / mL, preferably about 85 ng / mL, about 90 ng / mL, preferably about 95 ng / mL, preferably about 100 ng / mL, preferably about 105 ng / mL, preferably about 110 ng / mL, preferably about 115 ng / mL, preferably about 120 ng / mL, preferably about 125 ng / mL, preferably about 130 ng / mL, preferably about 135 ng / mL, preferably about 140 ng / mL, preferably about 145 ng / mL, preferably about 150 ng / mL, preferably about 155 ng / mL, preferably about 160 ng / mL, preferably about 165 ng / mL, preferably about 170 ng / mL, preferably about 175 ng / mL, preferably about 180 ng / mL, preferably about 185 ng / mL, preferably about 190 ng / mL, preferably about 195 ng / mL or preferably about 200 ng / mL.

[0138] In one aspect, the AUC(o-24h) and Cmax values provided herein may be measured when a patient is in a fasted state. The “fasted state” as used herein refers to a state where the patient is provided with no food for at least 10 hours prior to dosing.

[0139] The modified release composition may contain one or more pharmaceutically acceptable carriers or excipients as described herein. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0140] The modified release composition preferably comprises lactose as a filler, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 30% to about 65%, preferably about 30% to about 60%, preferably about 30% to about 50%, preferably about 30% to about 45%, and preferably about 30% to about 40%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about

[0141] 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about

[0142] 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about

[0143] 62%, about 63%, about 64%, or about 65%, by weight based on the total weight of the composition.

[0144] The modified release composition preferably comprises colloidal anhydrous silica and / or magnesium stearate as the lubricant / glidant, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1% to about 10%, preferably about 0.5% to about 5%, and preferably about 1 % to about 3%, by weight based on the total weight of the composition.

[0145] The modified release composition may be free from floating agents and / or gas-generating agents as described herein.

[0146] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 1 :4 and about 3:2, preferably between about 2:5 and about 5:4 and preferably between about 1 :2 and about 6:5.

[0147] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 1 :6 and about 6:5, preferably between about 1 :3 and about 6:5, and preferably between about 1 :2 and about 7:6.

[0148] In an aspect of the present invention, the weight ratio between the filler and the one or more release controlling polymers may be between about 3:4 and about 5:2, preferably between about 4:5 and about 5:3, and preferably between about 4:5 and about 4:3.

[0149] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the one or more release controlling polymers may be present in an amount of about 25% to about 40% by weight based on the total weight of the composition. In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers may be between about 1 :2 and about 6:5.

[0150] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the one or more fillers may be present in an amount of about 30% to about 60% by weight based on the total weight of the composition.

[0151] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler may be between about 1 :2 and about 7:6.

[0152] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more fillers, wherein the weight ratio between the filler and the one or more release controlling polymers may be between about 4:5 and about 4:3.

[0153] In an aspect of the present invention, there may be provided a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and lactose, wherein lactose may be present in an amount of about 30% to about 60% by weight based on the total weight of the composition.

[0154] In an aspect of the present invention, there may be provided a modified release composition comprising 26 to 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein 20-30% of dydrogesterone may be released over a period of about 0.5 to about 2 hours, 50-90% of dydrogesterone may be released over about 1 to about 3 hours and 80-100% of dydrogesterone may be released over about 2 to about 4.5 hours. In an aspect of the present invention, there may be provided a modified release composition for use in the treatment of endometriosis, comprising, 26 to 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0155] In an aspect of the present invention, there may be provided a modified release composition for use as part of in vitro fertilisation (IVF) treatment, comprising, 26 to 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers.

[0156] Extended Release and Immediate Release Combination

[0157] In an embodiment according to the present invention, there is provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0158] The dydrogesterone in the extended release component and the immediate release component may be provided in the modified release composition in a free form or as a pharmaceutically acceptable salt as described herein.

[0159] The dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7% to about 25%, and preferably about 8% to about 20%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25%, by weight based on the total weight of the composition.

[0160] The dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 1 % to about 15%, and preferably about 2% to about 10%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%, by weight based on the total weight of the composition.

[0161] The extended release component may comprise about 5 to about 30 mg, and preferably about 10 to about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0162] The immediate release component may comprise about 2 to about 15 mg, preferably about 3 to about 10 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0163] The extended release component further comprises one or more release controlling polymers as described herein. In a preferred embodiment, the release controlling polymer is hydroxypropyl methyl cellulose (hypromellose), and in particular hydroxypropyl methyl cellulose having a viscosity greater than 10 mPa-s (10 cps) in 2% water at 20°C.

[0164] The one or more release controlling polymers in the extended release component may be present in an amount of about 10% to about 40%, preferably about 15% to about 35%, or preferably about 20% to about 35%, by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, or about 35%, by weight based on the total weight of the composition.

[0165] The immediate release component may further comprise one or more coating polymers or film formers. In such an embodiment, the one or more coating polymers or film formers in the immediate release component may be present in an amount of about 1 % to about 15%, and preferably about 2% to about 10%, by weight based on the total weight of the composition. In an embodiment, one or more coating polymers or film formers may be present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the composition.

[0166] The one or more coating polymers or film formers in the immediate release component may preferably be hydroxypropyl methyl cellulose (hypromellose) having a viscosity less than 10 mPa-s (10 cps) in 2% water at 20°C (e.g., hypromellose E5) or Opadry TF. In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the immediate release component may be between about 1 :1 and about 1 :1.4, preferably between about 1 :1 and about 1 :1.3, preferably between about 1 :1 and about 1 :1.2 and preferably about 1 :1.

[0167] In an embodiment of the present invention, the immediate release component may consist of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0168] The modified release composition may contain one or more pharmaceutically acceptable carriers or excipients as described herein. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants, coating polymers or film formers and plasticizers.

[0169] The extended release component preferably comprises lactose as a filler, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 25% to about 60%, and preferably about 30% to about 55%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, or about 55%, by weight based on the total weight of the composition.

[0170] The extended release component preferably comprises colloidal anhydrous silica and / or magnesium stearate as the lubricant / glidant, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1 % to about 5%, preferably about 0.2% to about 5%, and preferably about 0.5% to about 3%, by weight based on the total weight of the composition.

[0171] The modified release composition may be free from floating agents and / or gas-generating agents as described herein. In an embodiment, the modified release composition according to the present invention may be formulated as a single dosage form, preferably as a single tablet, and more preferably as a single oral tablet.

[0172] The modified release composition according to the present invention may be manufactured by a granulation process.

[0173] In an aspect of the present invention, there may be provided a modified release composition comprising:

[0174] (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 25% by weight based on the total weight of the composition; one or more release controlling polymers in an amount of about 10% to about 40% by weight based on the total weight of the composition; one or more fillers in an amount of about 30% to about 55% by weight based on the total weight of the composition; and one or more lubricants or glidants in an amount of about 0.2% to about 5% by weight based on the total weight of the composition, and

[0175] (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 1 % to about 15% by weight based on the total weight of the composition.

[0176] In a preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the immediate release component is between about 1 :1 and about 1 :1.4.

[0177] In a further preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component consisting of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0178] In an aspect of the present invention, there may be provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein 20-65% of dydrogesterone may be released over a period of about 0.25 to about 1 hour, 35-95% of dydrogesterone may be released over about 1 to about 3 hours and 50-100% of dydrogesterone may be released over about 3 to about 5 hours.

[0179] In an aspect of the present invention, there may be provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein said composition releases greater than 30% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0180] In an aspect of the present invention, there may be provided a modified release composition comprising (a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, for use as part of in vitro fertilisation (IVF) treatment.

[0181] Extended Release Core with Immediate Release Outer Layer

[0182] In an embodiment according to the present invention, there is provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0183] The dydrogesterone in the extended release component and the immediate release component may be provided in the modified release composition in a free form or as a pharmaceutically acceptable salt as described herein. The dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7% to about 25%, and preferably about 8% to about 20%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20%, by weight based on the total weight of the composition.

[0184] The dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 1 % to about 15%, and preferably about 2% to about 10%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the composition.

[0185] The extended release component may comprise about 5 to about 30 mg, and preferably about 10 to about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0186] The immediate release component may comprise about 2 to about 15 mg, preferably about 3 to about 10 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0187] The extended release component further comprises one or more release controlling polymers as described herein. In a preferred embodiment, the release controlling polymer is hydroxypropyl methyl cellulose (hypromellose), and in particular hydroxypropyl methyl cellulose having a viscosity greater than 10 mPa-s (10 cps) in 2% water at 20°C.

[0188] The one or more release controlling polymers in the extended release component may be present in an amount of about 10% to about 40%, preferably about 15% to about 35%, or preferably about 20% to about 35%, by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, or about 35%, by weight based on the total weight of the composition. The outer layer may further comprise one or more coating polymers or film formers. In such an embodiment, the one or more coating polymers or film formers in the outer layer may be present in an amount of about 1% to about 15%, and preferably about 2% to about 10%, by weight based on the total weight of the composition. In an embodiment, one or more binders may be present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the composition.

[0189] The one or more coating polymers or film formers in the immediate release component may preferably be hydroxypropyl methyl cellulose (hypromellose) having a viscosity less than 10 mPa-s (10 cps) in 2% water at 20°C (e.g., hypromellose E5) or Opadry TF.

[0190] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the outer layer may be between about 1 :1 and about 1 :1.4, preferably between about 1 :1 and about 1 :1.3, preferably between about 1 :1 and about 1 :1.2 and preferably about 1 :1.

[0191] In an embodiment of the present invention, the outer layer may consist of an immediate release component consisting of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0192] The modified release composition may contain one or more pharmaceutically acceptable carriers or excipients as described herein. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants, coating polymers or film formers and plasticizers.

[0193] The extended release component preferably comprises lactose as a filler, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 35% to about 60%, and preferably about 40% to about 55%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, or about 55%, by weight based on the total weight of the composition. The extended release component preferably comprises colloidal anhydrous silica and / or magnesium stearate as the lubricant / glidant, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1 % to about 5%, preferably about 0.2% to about 5%, and preferably about 0.5% to about 3%, by weight based on the total weight of the composition.

[0194] The modified release composition may be free from floating agents and / or gas-generating agents as described herein.

[0195] In an embodiment, the modified release composition according to the present invention may be formulated as a single dosage form, preferably as a single tablet, and more preferably as a single oral tablet.

[0196] The modified release composition according to the present invention may be manufactured by a granulation process.

[0197] In an aspect of the present invention, there may be provided a modified release composition comprising:

[0198] (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 25% by weight based on the total weight of the composition; one or more release controlling polymers in an amount of about 10% to about 40% by weight based on the total weight of the composition; one or more fillers in an amount of about 35% to about 60% by weight based on the total weight of the composition; and one or more lubricants or glidants in an amount of about 0.2% to about 5% by weight based on the total weight of the composition, and

[0199] (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 2% to about 10% by weight based on the total weight of the composition.

[0200] In a preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the immediate release component is between about 1:1 and about 1 :1.4.

[0201] In a further preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component consisting of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0202] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein 20-65% of dydrogesterone may be released over a period of about 0.25 to about 1 hour, 35-95% of dydrogesterone may be released over about 1 to about 3 hours and 50-100% of dydrogesterone may be released over about 3 to about 5 hours.

[0203] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein said composition releases greater than 35% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0204] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, for use as part of in vitro fertilisation (IVF) treatment.

[0205] Enterically Coated Extended Release Core with Immediate Release Outer Layer

[0206] In another embodiment, there is provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof.

[0207] The dydrogesterone in the extended release component and the immediate release component may be provided in the modified release composition in a free form or as a pharmaceutically acceptable salt as described herein.

[0208] The dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7% to about 25%, preferably about 8% to about 20%, and preferably about 9% to about 17%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the extended release component may be present in an amount of about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, or about 17%, by weight based on the total weight of the composition.

[0209] The dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 2% to about 15%, preferably about 3% to about 10%, and preferably about 5% to about 10%, by weight based on the total weight of the composition. In an embodiment, dydrogesterone or a pharmaceutically acceptable salt thereof in the immediate release component may be present in an amount of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the composition.

[0210] The extended release component may comprise about 10 to about 30 mg, preferably about 15 to about 25 mg, preferably about 20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. The immediate release component may comprise about 5 to about 15 mg, preferably about 10 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0211] The extended release component further comprises one or more release controlling polymers as described herein. In a preferred embodiment, the release controlling polymer is hydroxypropyl methyl cellulose (hypromellose), and in particular hydroxypropyl methyl cellulose having a viscosity greater than 10 mPa-s (10 cps) in 2% water at 20°C.

[0212] The one or more release controlling polymers in the extended release component may be present in an amount of about 10% to about 40%, preferably about 15% to about 35%, or preferably about 20% to about 35%, by weight based on the total weight of the composition. In an embodiment, one or more release controlling polymers may be present in an amount of about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, or about 35%, by weight based on the total weight of the composition.

[0213] The core further comprises an enteric coating over the extended release component. Any suitable material may be used for the enteric coating. Examples of suitable materials include methacrylic acid-ethyl acrylate copolymer (e.g. Kollicoat MAE), polypropylene glycol and combinations thereof. The enteric coating may further comprise talc.

[0214] The enteric coating may be present in amount of about 5% to about 25%, and preferably about 10% to about 20%, by weight based on the total weight of the core. In an embodiment, the coating may be present in an amount of about 10%, about 11 %, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19% or about 20%, by weight based on the total weight of the composition.

[0215] The outer layer may further comprise one or more coating polymers or film formers. In such an embodiment, the one or more coating polymers or film formers in the outer layer may be present in an amount of about 3% to about 15%, preferably about 4% to about 12%, or preferably about 4% to about 10%, by weight based on the total weight of the composition. In an embodiment, one or more coating polymers or film formers may be present in an amount of about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the composition. The one or more coating polymers or film formers in the outer layer may preferably be hydroxypropyl methyl cellulose (hypromellose) having a viscosity less than 10 mPa-s (10 cps) in 2% water at 20°C (e.g., hypromellose E5) or Opadry TF.

[0216] In an aspect of the present invention, the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the outer layer may be between about 1 :1 and about 1 :1.4, preferably between about 1 :1 and about 1 :1.3, preferably between about 1 :1 and about 1 :1.2 and preferably about 1 :1.

[0217] In an embodiment of the present invention, the outer layer consists of an immediate release component consisting of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0218] The modified release composition may contain one or more pharmaceutically acceptable carriers or excipients as described herein. Pharmaceutically acceptable carriers or excipients may include fillers, diluents, binders, lubricants, glidants, disintegrants, coating polymers or film formers and plasticizers.

[0219] The extended release component preferably comprises lactose as a filler, more preferably lactose monohydrate. The one or more fillers may be present in an amount of about 20% to about 50%, preferably about 25% to about 45%, and preferably about 30% to about 40%, by weight based on the total weight of the composition. In an embodiment, the one or more fillers may be present in an amount of about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, by weight based on the total weight of the composition.

[0220] The extended release component preferably comprises colloidal anhydrous silica and / or magnesium stearate as the lubricant / glidant, and more preferably a combination of colloidal anhydrous silica and magnesium stearate. The lubricant / glidant may be present in an amount of about 0.1% to about 5%, preferably about 0.5% to about 5%, and preferably about 1 % to about 3%, by weight based on the total weight of the composition.

[0221] The modified release composition may be free from floating agents and / or gas-generating agents as described herein. In an embodiment, the modified release composition according to the present invention may be formulated as a single dosage form, preferably as a single tablet, and more preferably as a single oral tablet.

[0222] The modified release composition according to the present invention may be manufactured by a granulation process.

[0223] In an aspect of the present invention, there may be provided a modified release composition comprising:

[0224] (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 7% to about 25% by weight based on the total weight of the composition; one or more release controlling polymers in an amount of about 20% to about 35% by weight based on the total weight of the composition; one or more fillers in an amount of about 25% to about 45% by weight based on the total weight of the composition; and one or more lubricants or glidants in an amount of about 0.5% to about 5% by weight based on the total weight of the composition,

[0225] (ii) an enteric coating over the extended release component, and

[0226] (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 2% to about 15% by weight based on the total weight of the composition.

[0227] In a preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers, and wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the immediate release component is between about 1 :1 and about 1 :1.4. In a further preferred embodiment according to the present invention, there may be provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component consisting of dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers.

[0228] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein 20-40% of dydrogesterone may be released over a period of about 0.25 to about 1 hour, 35-55% of dydrogesterone may be released over about 1 to about 3 hours and 45-100% of dydrogesterone may be released over about 3 to about 5 hours.

[0229] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein said composition releases greater than 30% of dydrogesterone in 1 hour and not less than 90% of dydrogesterone within 5 hours.

[0230] In an aspect of the present invention, there may be provided a modified release composition comprising (a) a core comprising (i) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers, and (ii) an enteric coating over the extended release component and (b) an outer layer over said core, wherein said outer layer comprises an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, for use as part of in vitro fertilisation (I VF) treatment. Dosage Form

[0231] According to a further aspect of the present invention, there is provided a dosage form comprising a modified release composition as described herein. The dosage form may comprise: (a) a core comprising dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, and b) a coating over said core, wherein said coating comprises one or more film forming polymers. Any suitable film forming polymer may be used for the coating. Examples of suitable film forming polymers include cellulose acetate, ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin and combinations thereof.

[0232] The coating may be present in amount of about 1 % to about 10%, preferably about 2% to about 8%, and preferably about 2% to about 5%, by weight based on the total weight of the core. In an embodiment, the coating may be present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the core. Unless specifically stated otherwise, where the dosage form is coated, it is to be understood that a reference to % weight of the various components of the modified release composition refers to the amount excluding the coating.

[0233] The total weight of the dosage form may be from about 100 mg to about 350 mg, preferably from about 100 mg to about 300 mg, preferably from about 100 mg to about 250 mg, preferably from about 100 mg to about 200 mg, preferably from about 100 mg to about 150 mg.

[0234] In an aspect of the present invention, the dosage form may be formulated as a single unit dosage form.

[0235] The modified release composition may also be formulated for administration once daily.

[0236] The modified release composition according to the present invention may be formulated for oral administration. The composition may be formulated as a tablet such as mono-layered tablets, bilayered tablets, trilayered tablet, multilayer tablet, caplets, minitablets, microtablets, capsules, tablet in tablet, tablets in a capsule, microtablets in a capsule, minitablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, extrudes, pellets, beads or spheroids, suspension or any other suitable dosage form meant for oral administration to a patient. Medical Treatment

[0237] The composition according to the present invention as described herein may be used to treat various indications including gynaecological disorders, infertility, prevention of miscarriages and as a component of menopausal hormone therapy. In an aspect of the present invention, the modified release composition may be used in the treatment of infertility and / or prevention of miscarriages. The composition may specifically be used in the treatment of infertility due to luteal insufficiency, threatened miscarriage, habitual or recurrent miscarriage during pregnancy, menstrual disorders, dysfunctional bleeding, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, as part of in vitro fertilisation (IVF) treatment and / or as a component of menopausal hormone therapy. In a preferred aspect of the present invention, the modified release composition may be used in the treatment of endometriosis or as part of in vitro fertilisation (IVF) treatment.

[0238] In a further aspect of the present invention, provided herein is a method of treating infertility and / or preventing miscarriages in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a modified release composition as described herein. In a preferred aspect of the present invention, provided herein is a method of treating endometriosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a modified release composition as described herein. In yet a further preferred aspect of the present invention, provided herein is a method of administering to the patient a therapeutically effective amount of a modified release composition as described herein as part of in vitro fertilisation (IVF) treatment.

[0239] The present invention also relates to the use of a modified release composition as described herein, for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of infertility and / or preventing miscarriages.

[0240] As used herein, the terms “treating” and “treatment” and like terms refer to the administration of dydrogesterone or a pharmaceutically acceptable salt thereof in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and / or to prolong the survival of the patient being treated. In some cases, dydrogesterone or a pharmaceutically acceptable salt thereof may be used in combination (for example, in a composition as described herein) with one or more pharmaceutically active compounds.

[0241] As used herein, the term “therapeutically effective” or "effective amount" indicates that dydrogesterone or a pharmaceutically acceptable salt thereof when administered is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of a disease, disorder or medical condition being treated, and / or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disease, disorder or condition and its severity and the age, weight, etc., of the patient to be treated.

[0242] In an aspect of the present invention, the modified release composition may be administered as a single dosage form. The modified release composition may also be administered once daily.

[0243] The modified release composition according to the present invention may be administered by oral administration.

[0244] Method of Manufacture

[0245] According to a further aspect of the present invention, there is provided a method of manufacturing a modified release composition comprising the steps of:

[0246] 1) providing a dry mixture of dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers and one or more pharmaceutically acceptable excipients;

[0247] 2) adding water to said dry mixture;

[0248] 3) performing a granulation step to provide a granulated mixture; and

[0249] 4) drying said mixture to remove the water.

[0250] The method of manufacturing the modified release composition may comprise one or more of the following steps: (1) Dry Mixing, (2) Granulation, (3) Drying, (4) Dry Sizing, (5) Blending, (6) Lubrication, (7) Compression and (8) Coating.

[0251] Dry Mixing A dry mixing step may be performed to produce a homogenous powder mixture of drug substance and excipients. In an aspect of the present invention, dydrogesterone, one or more release controlling polymers (e.g. hypromellose) and a filler (e.g. lactose) may be placed into a rapid mixer granulator, and mixed for a duration of 5 minutes (± 5 seconds) at 124 rpm (121 - 127 rpm).

[0252] Granulation

[0253] Granulation may be performed in a high-shear granulator. More specifically, when dry mixing is completed, granulation may be carried out by addition of water to the dry powder mixture, at a rate between 0.689 to 1.172 kg / minute (target: 1.03 kg / minute) using a peristaltic pump with spray gun 8.0 mm nozzle by keeping impeller at 124 ± 3 rpm (121 - 127 rpm) and chopper at 950 rpm (947 - 953 rpm). Granulation may be continued until the addition of water has been completed, and wet granules are obtained.

[0254] Drying

[0255] Once the granulation step has been completed, a drying process of the wet granules may be carried out at a temperature of about 55°C (target 45°C ± 5°C). The drying process may be continued until the loss on drying (LOD) of the granules is between 2.2 - 3.6 % w / w (target: 3.0 % w / w).

[0256] Dry Sizing

[0257] A sizing step may be performed to produce a granulate with the desired flow and compaction properties for downstream processing. More specifically, the granules obtained from the drying step may be sifted through a mesh (1.25 mm) by using a vibratory sifter, and milled using a multimill through 2.50 mm or 1.50 mm screen with impact forward direction at 2500 ± 150 rpm.

[0258] Blending and Lubrication

[0259] The blending and lubrication may take place in a bin blender (filling level max. 2 / 3). The milled granules from the dry sizing step may first be blended with an excipient (e.g. silica, colloidal anhydrous) at about 12 rpm for about 4 min. Afterwards one or more additional glidants / lubricants (e.g. magnesium stearate) may be added and the mixture may be blended at about 12 rpm for about 2 to 3 mins. Tableting

[0260] The lubricated tablet blend may be compressed into about 20 or 30 mg tablets according to the following process parameters:

[0261] Press speed: 50 rpm / 20 - 60 rpm

[0262] Feeder speed: 20 rpm

[0263] Filling depth: 1 .3 - 1.5 mm I NMT 1.7 mm

[0264] Pre-compression force: 0.1 - 0.2 kN

[0265] Main compression force: 9 - 11 kN / N LT 5 kN

[0266] Ejection force: 70 - 100 N

[0267] Coating

[0268] A film-coating suspension may be prepared by mixing purified water and coating powder in a liquid manufacturing tank. The tablet core may be coated with the suspension in a perforated pan coater (O’Hara Labcoat M) having about 12.0 inch pan and about 1.2 mm nozzle.

[0269] Process parameters of coating:

[0270] Inlet air temperature: 52 °C

[0271] Inlet air volume: 180 m3 / h

[0272] Pan differential pressure: -0.2 mbar

[0273] Bed temperature: 38 - 40 °C / 36 - 44 °C

[0274] Pan speed: 12 - 14 rpm / NLT 10 rpm

[0275] Spray rate: 3 - 4 g / min / 1 - 9 g / min

[0276] Atomizing air pressure: 0.7 - 1.0 bar I NLT 0.7 bar

[0277] Pattern air pressure: 0.7 - 0.9 bar

[0278] The tablets may be dried intermittently during spraying. The coating process may be controlled for weight gain, 2 - 5 % of tablet core weight (target about 3 %).

[0279] Below, there is provided a non-exhaustive list of non-limiting embodiments. Any one or more of the features of these embodiments may be combined with any one or more features of another embodiment or aspect described herein. Embodiment 1 : a modified release composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 20% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

[0280] Embodiment 2: the composition according to Embodiment 1 , wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 10% to about 40%, preferably about 15% to about 40%, preferably about 15% to about 35%, preferably about 16% to about 35%, preferably about 17% to about 34%, preferably about 18% to about 33%, and preferably about 18% to about 32%, by weight based on the total weight of the composition.

[0281] Embodiment 3: the composition according to Embodiment 2, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition.

[0282] Embodiment 4: the composition according to any one of Embodiments 1 to 3, wherein the dydrogesterone is in a free form.

[0283] Embodiment 5: the composition according to any one of Embodiments 1 to 4, wherein the composition comprises about 10 mg or more, preferably greater than 10 mg, preferably about 15 to about 40 mg, preferably about 20 to about 40 mg, and preferably about 20 to about 30 mg, and preferably about 20 mg or about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0284] Embodiment 6: the composition according to Embodiment 5, wherein the composition comprises about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg, of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0285] Embodiment 7: the composition according to any one of Embodiments 1 to 6, wherein the one or more release controlling polymers is selected from the group consisting of hydrophilic or hydrophobic polymers comprising one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose (hypromellose) (e.g., type 2208, type 2910, methocel K15M, methocel E15LV), carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C - NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers such as methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS), Carbomer (e.g., Carbomer 971 P) and combinations thereof.

[0286] Embodiment 8: the composition according to Embodiment 7, wherein the one or more release controlling polymers is hydroxypropyl methyl cellulose (hypromellose).

[0287] Embodiment 9: the composition according to any one of Embodiments 1 to 8, wherein the composition contains more than one type of release controlling polymer.

[0288] Embodiment 10: the composition according to any one of Embodiments 1 to 9, wherein the composition contains two different types of release controlling polymers.

[0289] Embodiment 11 : the composition according to Embodiment 10, wherein the composition contains two different types of hydroxypropyl methyl cellulose (hypromellose) polymers, for example, a combination of methocel K15M and methocel E15LV.

[0290] Embodiment 12: the composition according to any one of Embodiments 1 to 11 , wherein the one or more release controlling polymers is present in an amount of about 20% to about 60%, preferably about 25% to about 60%, preferably about 25% to about 55%, preferably about 28% to about 50%, preferably about 30% to about 40%, preferably about 30% to about 35%, or preferably about 25% to about 35%, by weight based on the total weight of the composition.

[0291] Embodiment 13: the composition according to Embodiment 12, wherein the one or more release controlling polymers is present in an amount of about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% by weight based on the total weight of the composition.

[0292] Embodiment 14: the composition according to any one of Embodiments 1 to 13, wherein the modified release composition provides a mean dydrogesterone plasma AUC(o-24h) value relative to that of an immediate release formulation comprising dydrogesterone, of at least about 1.0, or at least about 1.05, or at least about 1.1 , or at least about 1.2, or at least about 1.3, or at least about 1 .4, or at least about 1.5, or at least about 2.0, or at least about 2.5, or at least about 3.0, where the AUC(o-24h) values may be determined under similar conditions, preferably wherein the immediate release formulation comprising dydrogesterone is a commercially available Duphaston® tablet.

[0293] Embodiment 15: the composition according to any one of Embodiments 1 to 13, wherein the modified release composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to at least two immediate release formulations each comprising 10 mg of dydrogesterone, preferably whrerein the modified release composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to 2 to 4, for example 2, 3 or 4 immediate release formulations each comprising 10 mg of dydrogesterone.

[0294] Embodiment 16: the composition according to Embodiment 15, wherein the modified release composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to 2 or 3 immediate release formulations each comprising 10 mg of dydrogesterone.

[0295] Embodiment 17: the composition according to any one of Embodiments 14 to 16, wherein the immediate release formulation comprising 10 mg of dydrogesterone refers to an immediate release product containing 10 mg of dydrogesterone, such as duphaston®. Embodiment 18: the composition according to any one of Embodiments 14 to 17, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to two immediate release formulations each comprising 10 mg of dydrogesterone, such as duphaston®.

[0296] Embodiment 19: the composition according to any one of Embodiments 14 to 17, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to three immediate release formulations each comprising 10 mg of dydrogesterone, such as duphaston®.

[0297] Embodiment 20: the composition according to any one of Embodiments 1 to 19, wherein the one or more pharmaceutically acceptable excipients is selected from the group consisting of fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0298] Embodiment 21 : the composition according to Embodiment 20, wherein the filler or diluent is selected from the group consisting of starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, lactose monohydrate, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, and combinations thereof.

[0299] Embodiment 22: the composition according to Embodiment 21 , wherein the filler is lactose, preferably lactose monohydrate.

[0300] Embodiment 23: the composition according to any one of Embodiments 20 to 22, wherein the filler is present in an amount of about 20% to about 65%, preferably about 20% to about 60%, preferably about 25% to about 60%, preferably about 30% to about 60%, preferably about 30% to about 55%, and preferably about 30% to about 50%, by weight based on the total weight of the composition.

[0301] Embodiment 24: the composition according to Embodiment 23, wherein the filler is present in an amount of about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59% or about 60%, by weight based on the total weight of the composition. Embodiment 25: the composition according to Embodiment 20 wherein the binder is selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP 90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropyl cellulose, copovidone, and combinations thereof.

[0302] Embodiment 26: the composition according to Embodiment 20 or 25, wherein the binder is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0303] Embodiment 27: the composition according to Embodiment 20 wherein the lubricant or glidant is selected from the group consisting of zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silicon dioxide (e.g., Aerosil 200), colloidal anhydrous silica, aluminum or calcium silicate, stearic acid, cutina, magnesium trisilicate, powdered cellulose, talc and combinations thereof.

[0304] Embodiment 28: the composition according to Embodiment 27 wherein the lubricant or glidant is colloidal anhydrous silica and / or magnesium stearate.

[0305] Embodiment 29: the composition according to Embodiment 28 wherein the lubricant or glidant is a combination of colloidal anhydrous silica and magnesium stearate.

[0306] Embodiment 30: the composition according to any one of Embodiments 20 or 27 to 29, wherein the lubricant or glidant is present in an amount of about 0.1% to about 10%, preferably about 0.5% to about 5%, and preferably about 1% to about 3%, by weight based on the total weight of the composition.

[0307] Embodiment 31 : the composition according to Embodiment 20, wherein the disintegrant is selected from the group consisting of carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (pirimojel and explotab) and / or combinations thereof. Embodiment 32: the composition according to Embodiment 20 or 31 , wherein the disintegrant is present in an amount of about 0.01 % to about 15%, preferably about 0.05% to about 12%, and preferably about 0.1% to about 10%, by weight based on the total weight of the composition.

[0308] Embodiment 33: the composition according to Embodiment 20, wherein the plasticizer is selected from the group consisting of propylene glycol, phthalates, polyethylene glycols, sebacates, or citrates such as dibutyl phthalate, diethyl phthalate, dibutyl sebecate, triethyl citrate, acetyl tributyl citrate and polyethylene glycol.

[0309] Embodiment 34: the composition according to Embodiment 20 or 33, wherein the plasticizer is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0310] Embodiment 35: the composition according to any one of Embodiments 1 to 34, wherein the composition is free from floating agents.

[0311] Embodiment 36: the composition according to Embodiment 35, wherein the floating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate, adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, sodium citrate and citric acid.

[0312] Embodiment 37: the composition according to any one of Embodiments 1 to 36, wherein the composition is free from gas-generating agents.

[0313] Embodiment 38: the composition according to Embodiment 37, wherein the gas-generating agent is selected from the group consisting of carbonate and bicarbonate salts, that generate CO2 in the presence of acidic gastric fluid such as citric acid.

[0314] Embodiment 39: the composition according to any one of Embodiments 1 to 38, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers is between about 1 :6 and about 2:1 , preferably between about 1 :4 and about 3:2, preferably between about 1 :2 and about 4:3 and preferably between about 1 :2 and about 1 :1. Embodiment 40: the composition according to any one of Embodiments 20 to 24 or 35 to 39, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler is between about 1 :6 and about 2:1 , preferably between about 1 :4 and about 3:2, preferably between about 1 :3 and about 2:1 , and preferably between about 1 :3 and about 1 :1.

[0315] Embodiment 41 : the composition according to any one of Embodiments 20 to 24 or 35 to 40, wherein the weight ratio between the filler and the one or more release controlling polymers is between about 1 :3 and about 5:2, preferably between about 1 :2 and about 7:3, preferably between about 3:4 and about 2:1 , and preferably between about 4:5 and about 5:3.

[0316] Embodiment 42: the composition according to any one of Embodiments 1 to 41 , wherein the composition is manufactured by a granulation process.

[0317] Embodiment 43: a modified release composition comprising 15 to 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of 10 to 25 ng*hr / mL.

[0318] Embodiment 44: the composition according to Embodiment 43, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 15% to about 25%, preferably about 16% to about 24%, preferably about 17% to about 23%, preferably about 18% to about 22%, preferably about 19% to about 21 %, and preferably about 20%, by weight based on the total weight of the composition.

[0319] Embodiment 45, the composition according to Embodiment 44, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24% or about 25%, by weight based on the total weight of the composition.

[0320] Embodiment 46: the composition according to any one of Embodiments 43 to 45, wherein the dydrogesterone is in a free form.

[0321] Embodiment 47: the composition according to any one of Embodiments 43 to 46, wherein the composition comprises about 15 to about 25 mg, preferably about 16 to about 24 mg, preferably about 17 to about 23 mg, preferably about 18 to about 22 mg, preferably about 19 to about 21 mg and preferably about 20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof. Embodiment 48: the composition according to Embodiment 47, wherein the composition comprises about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg or about 25 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0322] Embodiment 49: the composition according to Embodiment 48, wherein the composition comprises 20 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0323] Embodiment 50: the composition according to any one of Embodiments 43 to 49, wherein the one or more release controlling polymers is selected from the group consisting of hydrophilic or hydrophobic polymers comprising one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose (hypromellose) (e.g., type 2208, type 2910, methocel K15M, methocel E15LV), carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C - NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers such as methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS), Carbomer (e.g., Carbomer 971 P) and combinations thereof.

[0324] Embodiment 51 : the composition according to Embodiment 50, wherein the one or more release controlling polymers is hydroxypropyl methyl cellulose (hypromellose). Embodiment 52: the composition according to any one of Embodiments 43 to 51 , wherein the composition contains more than one type of release controlling polymer.

[0325] Embodiment 53: the composition according to any one of Embodiments 43 to 52, wherein the composition contains two different types of release controlling polymers.

[0326] Embodiment 54: the composition according to Embodiment 53, wherein the composition contains two different types of hydroxypropyl methyl cellulose (hypromellose) polymers, for example, a combination of methocel K15M and methocel E15LV.

[0327] Embodiment 55: the composition according to any one of Embodiments 43 to 54, wherein the one or more release controlling polymers is present in an amount of about 30% to about 40%, preferably about 31% to about 39%, preferably about 32% to about 38%, preferably about 33% to about 37%, and preferably about 34 to about 36% by weight based on the total weight of the composition.

[0328] Embodiment 56: the composition according to Embodiment 55, wherein the one or more release controlling polymers is present in an amount of about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition.

[0329] Embodiment 57: the composition according to any one of Embodiments 43 to 56, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 25 ng*hr / mL, preferably about 10 to about 20 ng*hr / mL, preferably about 15 to about 20 ng*hr / mL and preferably about 15 to about 19 ng*hr / mL.

[0330] Embodiment 58: the composition according to Embodiment 57, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 ng*hr / mL, preferably about 11 ng*hr / mL, preferably about 12 ng*hr / mL, preferably about 13 ng*hr / mL, preferably about 14 ng*hr / mL, preferably about 15 ng*hr / mL, preferably about 16 ng*hr / mL, preferably about 17 ng*hr / mL, preferably about 18 ng*hr / mL, preferably about 19 ng*hr / mL, preferably about 20 ng*hr / mL, preferably about 21 ng*hr / mL, preferably about 22 ng*hr / mL, preferably about 23 ng*hr / mL, preferably about 24 ng*hr / mL or preferably 25 ng*hr / mL. Embodiment 59: the composition according to any one of Embodiments 43 to 58, wherein the composition provides a mean dydrogesterone plasma Cmax of about 2 to about 5 ng / mL, preferably about 2 to about 4 ng / mL, preferably about 2 to about 3 ng / mL, and preferably about 2.5 to about 3 ng / mL.

[0331] Embodiment 60: the composition according to Embodiment 59, wherein the composition provides a mean dydrogesterone plasma Cmax of about 2 ng / mL, preferably about 2.1 ng / mL, preferably about 2.2 ng / mL, preferably about 2.3 ng / mL, preferably about 2.4 ng / mL, preferably about 2.5 ng / mL, preferably about 2.6 ng / mL, preferably about 2.7 ng / mL, preferably about 2.8 ng / mL, preferably about 2.9 ng / mL, preferably about 3.0 ng / mL, preferably about 3.1 ng / mL, preferably about 3.2 ng / mL, preferably about 3.3 ng / mL, preferably about 3.4 ng / mL, preferably about 3.5 ng / mL, preferably about 3.6 ng / mL, preferably about 3.7 ng / mL, preferably about 3.8 ng / mL, preferably about 3.9 ng / mL, preferably about 4.0 ng / mL, preferably about 4.1 ng / mL, preferably about 4.2 ng / mL, preferably about 4.3 ng / mL, preferably about 4.4 ng / mL, preferably about 4.5 ng / mL, preferably about 4.6 ng / mL, preferably about 4.7 ng / mL, preferably about 4.8 ng / mL, preferably about 4.9 ng / mL, or preferably about 5.0 ng / mL.

[0332] Embodiment 61 : the composition according to any one of Embodiments 43 to 60, wherein the composition provides a mean dihydrodydrogesterone plasma AUC(o-24h) of about 350 to about 750 ng*hr / mL, preferably about 400 to about 700 ng*hr / mL, preferably about 450 to about 650 ng*hr / mL, preferably about 500 to about 600 ng*hr / mL, and preferably about 500 to about 550 ng*hr / mL.

[0333] Embodiment 62: the composition according to Embodiment 61 , wherein the composition provides a mean dihydrodydrogesterone plasma AUC(o-24h) of about 350 ng*hr / mL, preferably about 360 ng*hr / mL, preferably about 370 ng*hr / mL, preferably about 380 ng*hr / mL, preferably about 390 ng*hr / mL, preferably about 400 ng*hr / mL, preferably about 410 ng*hr / mL, preferably about 420 ng*hr / mL, preferably about 430 ng*hr / mL, preferably about 440 ng*hr / mL, preferably about 450 ng*hr / mL, preferably about 460 ng*hr / mL, preferably about 470 ng*hr / mL, preferably about 480 ng*hr / mL, preferably about 490 ng*hr / mL, preferably about 500 ng*hr / mL, preferably about 510 ng*hr / mL, preferably about 520 ng*hr / mL, preferably about 530 ng*hr / mL, preferably about 540 ng*hr / mL, preferably about 550 ng*hr / mL, preferably about 560 ng*hr / mL, preferably about 570 ng*hr / mL, preferably about 580 ng*hr / mL, preferably about 590 ng*hr / mL, preferably 600 ng*hr / mL, preferably about 610 ng*hr / mL, preferably about 620 ng*hr / mL, preferably about 630 ng*hr / mL, preferably about 640 ng*hr / mL, preferably about 650 ng*hr / mL, preferably about 660 ng*hi7mL, preferably about 670 ng*hr / mL, preferably about 680 ng*hr / mL, preferably about 690 ng*hr / mL, preferably 700 ng*hr / mL, preferably about 710 ng*hr / mL, preferably about 720 ng*hr / mL, preferably about 730 ng*hr / mL, preferably about 740 ng*hr / mL, or preferably about 750 ng*hr / mL.

[0334] Embodiment 63: the composition according to any one of Embodiments 43 to 62, wherein the composition provides a mean dihydrodydrogesterone plasma Cmax of about 50 to about 110 ng / mL, preferably about 55 to about 105 ng / mL, preferably about 60 to about 100 ng / mL, preferably about 65 to about 95 ng / mL, preferably about 70 to about 90 ng / mL, and preferably about 75 to about 85 ng / mL.

[0335] Embodiment 64: the composition according to Embodiment 63, wherein the composition provides a mean dihydrodydrogesterone plasma Cmax of about 50 ng / mL, preferably about 51 ng / mL, preferably about 52 ng / mL, preferably about 53 ng / mL, preferably about 54 ng / mL, preferably about 55 ng / mL, preferably about 56 ng / mL, preferably about 57 ng / mL, preferably about 58 ng / mL, preferably about 59 ng / mL, preferably about 60 ng / mL, preferably about 61 ng / mL, preferably about 62 ng / mL, preferably about 63 ng / mL, preferably about 64 ng / mL, preferably about 65 ng / mL, preferably about 66 ng / mL, preferably about 67 ng / mL, preferably about 68 ng / mL, preferably about 69 ng / mL, preferably about 70 ng / mL, preferably about 71 ng / mL, preferably about 72 ng / mL, preferably about 73 ng / mL, preferably about 74 ng / mL, preferably about 75 ng / mL, preferably about 76 ng / mL, preferably about 77 ng / mL, preferably about 78 ng / mL, preferably about 79 ng / mL, preferably about 80 ng / mL, preferably about 81 ng / mL, preferably about 82 ng / mL, preferably about 83 ng / mL, preferably about 84 ng / mL, preferably about 85 ng / mL, preferably about 86 ng / mL, preferably about 87 ng / mL, preferably about 88 ng / mL, preferably about 89 ng / mL, preferably about 90 ng / mL, preferably about 91 ng / mL, preferably about 92 ng / mL, preferably about 93 ng / mL, preferably about 94 ng / mL, preferably about 95 ng / mL, preferably about 96 ng / mL, preferably about 97 ng / mL, preferably about 98 ng / mL, preferably about 99 ng / mL, preferably about 100 ng / mL, preferably about 101 ng / mL, preferably about 102 ng / mL, preferably about 103 ng / mL, preferably about 104 ng / mL, preferably about 105 ng / mL, preferably about 106 ng / mL, preferably about 107 ng / mL, preferably about 108 ng / mL, preferably about 109 ng / mL, or preferably about 110 ng / mL.

[0336] Embodiment 65: the composition according to any one of Embodiments 43 to 64, wherein the AUC(o-24h) and / or Cmax values are measured when a patient is in a fasted state. Embodiment 66: the composition according to Embodiment 65, wherein the fasted state refers to a state where the patient is provided with no food for at least 10 hours prior to dosing.

[0337] Embodiment 67: the composition according to any one of Embodiments 43 to 66, wherein the composition further comprises one or more pharmaceutically acceptable carriers or excipients.

[0338] Embodiment 68: the composition according to Embodiment 69, wherein the one or more pharmaceutically acceptable carriers or excipients is selected from the group consisting of fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0339] Embodiment 69: the composition according to Embodiment 68, wherein the filler or diluent is selected from the group consisting of starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, lactose monohydrate, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, and combinations thereof.

[0340] Embodiment 70: the composition according to Embodiment 69, wherein the filler is lactose, preferably lactose monohydrate.

[0341] Embodiment 71 : the composition according to any one of Embodiments 68 to 70, wherein the filler is present in an amount of about 35% to about 55%, preferably about 40% to about 50%, preferably about 41% to about 49%, preferably about 42% to about 48%, and preferably about 43% to about 47%, by weight based on the total weight of the composition.

[0342] Embodiment 72: the composition according to Embodiment 71 , wherein the filler is present in an amount of about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51 %, about 52%, about 53%, about 54%, or about 55%, by weight based on the total weight of the composition.

[0343] Embodiment 73: the composition according to Embodiment 68 wherein the binder is selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP 90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropyl cellulose, copovidone, and combinations thereof. Embodiment 74: the composition according to Embodiment 68 or 73, wherein the binder is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0344] Embodiment 75: the composition according to Embodiment 68 wherein the lubricant or glidant is selected from the group consisting of zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silicon dioxide (e.g., Aerosil 200), colloidal anhydrous silica, aluminum or calcium silicate, stearic acid, cutina, magnesium trisilicate, powdered cellulose, talc and combinations thereof.

[0345] Embodiment 76: the composition according to Embodiment 75 wherein the lubricant or glidant is colloidal anhydrous silica and / or magnesium stearate.

[0346] Embodiment 77: the composition according to Embodiment 76 wherein the lubricant or glidant is a combination of colloidal anhydrous silica and magnesium stearate.

[0347] Embodiment 78: the composition according to any one of Embodiments 68 or 75 to 77, wherein the lubricant or glidant is present in an amount of about 0.1% to about 10%, preferably about 0.5% to about 5%, and preferably about 1% to about 3%, by weight based on the total weight of the composition.

[0348] Embodiment 79: the composition according to Embodiment 68, wherein the disintegrant is selected from the group consisting of carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (pirimojel and explotab) and / or combinations thereof.

[0349] Embodiment 80: the composition according to Embodiment 68 or 79, wherein the disintegrant is present in an amount of about 0.01 % to about 15%, preferably about 0.05% to about 12%, and preferably about 0.1% to about 10%, by weight based on the total weight of the composition. Embodiment 81 : the composition according to Embodiment 68, wherein the plasticizer is selected from the group consisting of propylene glycol, phthalates, polyethylene glycols, sebacates, or citrates such as dibutyl phthalate, diethyl phthalate, dibutyl sebecate, triethyl citrate, acetyl tributyl citrate and polyethylene glycol.

[0350] Embodiment 82: the composition according to Embodiment 68 or 81 , wherein the plasticizer is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0351] Embodiment 83: the composition according to any one of Embodiments 43 to 82, wherein the composition is free from floating agents.

[0352] Embodiment 84: the composition according to Embodiment 83, wherein the floating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate, adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, sodium citrate and citric acid.

[0353] Embodiment 85: the composition according to any one of Embodiments 43 to 84, wherein the composition is free from gas-generating agents.

[0354] Embodiment 86: the composition according to Embodiment 85, wherein the gas-generating agent is selected from the group consisting of carbonate and bicarbonate salts, that generate CO2 in the presence of acidic gastric fluid such as citric acid.

[0355] Embodiment 87: the composition according to any one of Embodiments 43 to 86, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers is between about 2:5 and about 5:6, preferably between about 2:3 and about 4:5 and preferably between about 1 :2 and about 2:3.

[0356] Embodiment 88: the composition according to any one of Embodiments 68 to 70 or 83 to 87, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler is between about 1 :3 and about 4:5, preferably between about 1 :3 and about 3:5, and preferably between about 2:5 and about 1 :1. Embodiment 89: the composition according to any one of Embodiments 68 to 70 or 83 to 88, wherein the weight ratio between the filler and the one or more release controlling polymers is between about 9:10 and about 2:1 , preferably between about 1 :1 and about 3:2, and preferably between about 5:4 and about 4:3.

[0357] Embodiment 90: the composition according to any one of Embodiments 43 to 89, wherein the composition is manufactured by a granulation process.

[0358] Embodiment 91 : the composition according to any one of Embodiments 43 to 90, wherein 15- 70% of dydrogesterone is released over a period of about 0.5 to about 2 hours, 35-90% of dydrogesterone is released over about 1 to about 3 hours and 80-100% of dydrogesterone is released over about 2.5 to about 4 hours.

[0359] Embodiment 92: a modified release composition comprising 26 to 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof; and one or more release controlling polymers, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of 10 to 70 ng*hr / mL.

[0360] Embodiment 93: the composition according to Embodiment 92, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 10% to about 35%, preferably about 15% to about 35%, preferably about 20% to about 35%, preferably about 25% to about 35%, preferably about 28% to about 32%, and preferably about 30%, by weight based on the total weight of the composition.

[0361] Embodiment 94: the composition according to Embodiment 93, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, or about 35%, by weight based on the total weight of the composition.

[0362] Embodiment 95: the composition according to any one of Embodiments 92 to 94, wherein the dydrogesterone is in a free form.

[0363] Embodiment 96: the composition according to any one of Embodiments 92 to 95, wherein the composition comprises about 26 to about 35 mg, preferably about 27 to about 34 mg, preferably about 28 to about 33 mg, preferably about 29 to about 32 mg, and preferably about 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0364] Embodiment 97: the composition according to Embodiment 96, wherein the composition comprises about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg or about 35 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0365] Embodiment 98: the composition according to Embodiment 97, wherein the composition comprises 30 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

[0366] Embodiment 99: the composition according to any one of Embodiments 92 to 98, wherein the one or more release controlling polymers is selected from the group consisting of hydrophilic or hydrophobic polymers comprising one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, xanthan gum, gellan gum, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR (polyvinyl acetate and povidone), a poly(meth)acrylate, poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose (hypromellose) (e.g., type 2208, type 2910, methocel K15M, methocel E15LV), carboxyvinyl polymers, polymerized gelatin, shellac, methacrylic acid copolymer type C - NF, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydrogenated castor oil, stearic acid, hydrogenated vegetable oil, glyceryl behenate, glyceryl monostearate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and acrylic acid polymers and copolymers such as methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS), Carbomer (e.g., Carbomer 971 P) and combinations thereof.

[0367] Embodiment 100: the composition according to Embodiment 99, wherein the one or more release controlling polymers is hydroxypropyl methyl cellulose (hypromellose). Embodiment 101 : the composition according to any one of Embodiments 92 to 100, wherein the composition contains more than one type of release controlling polymer.

[0368] Embodiment 102: the composition according to any one of Embodiments 92 to 101 , wherein the composition contains two different types of release controlling polymers.

[0369] Embodiment 103: the composition according to Embodiment 102, wherein the composition contains two different types of hydroxypropyl methyl cellulose (hypromellose) polymers, for example, a combination of methocel K15M and methocel E15LV.

[0370] Embodiment 104: the composition according to any one of Embodiments 92 to 103, wherein the one or more release controlling polymers is present in an amount of about 25% to about 40%, preferably about 26% to about 39%, preferably about 27% to about 38%, preferably about 28% to about 37%, and preferably about 29% to about 36% by weight based on the total weight of the composition.

[0371] Embodiment 105: the composition according to Embodiment 104, wherein the one or more release controlling polymers is present in an amount of about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31 %, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40%, by weight based on the total weight of the composition.

[0372] Embodiment 106: the composition according to any one of Embodiments 92 to 105, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 70 ng*hr / mL, preferably about 15 to about 65 ng*hr / mL, preferably about 20 to about 60 ng*hr / mL, preferably about 25 to about 55 ng*hr / mL, preferably about 30 to about 50 ng*hr / mL, and preferably about 35 to about 45 ng*hr / mL.

[0373] Embodiment 107: the composition according to Embodiment 106, wherein the composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 ng*hr / mL, preferably about 11 ng*hr / mL, preferably about 12 ng*hr / mL, preferably about 13 ng*hr / mL, preferably about 14 ng*hr / mL, preferably about 15 ng*hr / mL, preferably about 16 ng*hr / mL, preferably about 17 ng*hr / mL, preferably about 18 ng*hr / mL, preferably about 19 ng*hr / mL, preferably about 20 ng*hr / mL, preferably about 21 ng*hr / mL, preferably about 22 ng*hr / mL, preferably about 23 ng*hi7mL, preferably about 24 ng*hr / mL, preferably about 25 ng*hr / mL, preferably about 26 ng*hr / mL, preferably about 27 ng*hr / mL, preferably about 28 ng*hr / mL, preferably about 29 ng*hr / mL, preferably about 30 ng*hr / mL, preferably about 31 ng*hr / mL, preferably about 32 ng*hr / mL, preferably about 33 ng*hr / mL, preferably about 34 ng*hr / mL, preferably 35 ng*hr / mL, preferably about 36 ng*hr / mL, preferably about 37 ng*hr / mL, preferably about 38 ng*hr / mL, preferably about 39 ng*hr / mL, preferably about 40 ng*hr / mL, preferably about 41 ng*hr / mL, preferably about 42 ng*hr / mL, preferably about 43 ng*hr / mL, preferably about 44 ng*hr / mL, preferably about 45 ng*hr / mL, preferably about 46 ng*hr / mL, preferably about 47 ng*hr / mL, preferably about 48 ng*hr / mL, preferably about 49 ng*hr / mL, preferably about 50 ng*hr / mL, preferably about 51 ng*hr / mL, preferably about 52 ng*hr / mL, preferably about 53 ng*hr / mL, preferably about 54 ng*hr / mL, preferably about 55 ng*hr / mL, preferably about 56 ng*hr / mL, preferably about 57 ng*hr / mL, preferably about 58 ng*hr / mL, preferably about 59 ng*hr / mL, preferably about 60 ng*hr / mL, preferably about 61 ng*hr / mL, preferably about 62 ng*hr / mL, preferably about 63 ng*hr / mL, preferably about 64 ng*hr / mL, preferably about 65 ng*hr / mL, preferably about 66 ng*hr / mL, preferably about 67 ng*hr / mL, preferably about 68 ng*hr / mL, preferably about 69 ng*hr / mL or about 70 ng*hr / mL.

[0374] Embodiment 108: the composition according to any one of Embodiments 92 to 107, wherein the composition provides a mean dydrogesterone plasma Cmax of about 1.5 to about 7.5 ng / mL, preferably about 2 to about 7 ng / mL, preferably about 3 to about 6 ng / mL and preferably about 4 to about 5 ng / mL.

[0375] Embodiment 109: the composition according to Embodiment 108, wherein the composition provides a mean dydrogesterone plasma Cmax of about 1.5 ng / mL, preferably about 1.6 ng / mL, preferably about 1.7 ng / mL, preferably about 1.8 ng / mL, preferably about 1.9 ng / mL, preferably about 2.0 ng / mL, preferably about 2.1 ng / mL, preferably about 2.2 ng / mL, preferably about 2.3 ng / mL, preferably about 2.4 ng / mL, preferably about 2.5 ng / mL, preferably about 2.6 ng / mL, preferably about 2.7 ng / mL, preferably about 2.8 ng / mL, preferably about 2.9 ng / mL, preferably about 3.0 ng / mL, preferably about 3.1 ng / mL, preferably about 3.2 ng / mL, preferably about 3.3 ng / mL, preferably about 3.4 ng / mL, preferably about 3.5 ng / mL, preferably about 3.6 ng / mL, preferably about 3.7 ng / mL, preferably about 3.8 ng / mL, preferably about 3.9 ng / mL, preferably about 4.0 ng / mL, preferably about 4.1 ng / mL, preferably about 4.2 ng / mL, preferably about 4.3 ng / mL, preferably about 4.4 ng / mL, preferably about 4.5 ng / mL, preferably about 4.6 ng / mL, preferably about 4.7 ng / mL, preferably about 4.8 ng / mL, preferably about 4.9 ng / mL, preferably about 5.0 ng / mL, preferably about 5.1 ng / mL, preferably about 5.2 ng / mL, preferably about 5.3 ng / mL, preferably about 5.4 ng / mL, preferably about 5.5 ng / mL, preferably about 5.6 ng / mL, preferably about 5.7 ng / mL, preferably about 5.8 ng / mL, preferably about 5.9 ng / mL, preferably about 6.0 ng / mL, preferably about 6.1 ng / mL, preferably about 6.2 ng / mL, preferably about 6.3 ng / mL, preferably about 6.4 ng / mL, preferably about 6.5 ng / mL, preferably about 6.6 ng / mL, preferably about 6.7 ng / mL, preferably about 6.8 ng / mL, preferably about 6.9 ng / mL, preferably about 7.0 ng / mL, preferably about 7.1 ng / mL, preferably about 7.2 ng / mL, preferably about 7.3 ng / mL, preferably about 7.4 ng / mL or preferably about 7.5 ng / mL.

[0376] Embodiment 110: the composition according to any one of Embodiments 92 to 109, wherein the composition provides a mean dihydrodydrogesterone plasma AUC(o-24h) of about 400 to about 2200 ng*hr / mL, preferably about 500 to about 2000 ng*hr / mL, preferably about 600 to about 1800 ng*hr / mL, and preferably about 700 to about 1500 ng*hr / mL.

[0377] Embodiment 111 : the composition according to Embodiment 110, wherein the composition provides a mean dihydrodydrogesterone plasma AUC(o-24h) of about 400 ng*hr / mL, preferably about 450 ng*hr / mL, preferably about 500 ng*hr / mL, preferably about 550 ng*hr / mL, preferably about 600 ng*hr / mL, preferably about 650 ng*hr / mL, preferably about 700 ng*hr / mL, preferably about 750 ng*hr / mL, preferably about 800 ng*hr / mL, preferably about 850 ng*hr / mL, preferably about 900 ng*hr / mL, preferably about 950 ng*hr / mL, preferably about 1000 ng*hr / mL, preferably about 1050 ng*hr / mL, preferably about 1100 ng*hr / mL, preferably 1150 ng*hr / mL, preferably about 1200 ng*hr / mL, preferably about 1250 ng*hr / mL, preferably about 1300 ng*hr / mL, preferably about 1350 ng*hr / mL, preferably about 1400 ng*hr / mL, preferably about 1450 ng*hr / mL, preferably about 1500 ng*hr / mL, preferably about 1550 ng*hr / mL, preferably about 1600 ng*hr / mL, preferably 1650 ng*hr / mL, preferably about 1700 ng*hr / mL, preferably about 1750 ng*hr / mL, preferably about 1800 ng*hr / mL, preferably about 1850 ng*hr / mL, preferably about 1900 ng*hr / mL, preferably about 1950 ng*hr / mL, preferably about 2000 ng*hr / mL, preferably about 2050 ng*hr / mL, preferably about 2100 ng*hr / mL, preferably 2150 ng*hr / mL or preferably about 2200 ng*hr / mL.

[0378] Embodiment 112: the composition according to any one of Embodiments 92 to 111 , wherein the composition provides a mean dihydrodydrogesterone plasma Cmax of about 40 to about 200 ng / mL, preferably about 50 to about 175 ng / mL, preferably about 60 to about 150 ng / mL, and preferably about 70 to about 120 ng / mL. Embodiment 113: the composition according to Embodiment 112, wherein the composition provides a mean dihydrodydrogesterone plasma Cmax of about 40 ng / mL, preferably about 45 ng / mL, preferably about 50 ng / mL, preferably about 55 ng / mL, preferably about 60 ng / mL, preferably about 65 ng / mL, preferably about 70 ng / mL, preferably about 75 ng / mL, preferably about 80 ng / mL, preferably about 85 ng / mL, about 90 ng / mL, preferably about 95 ng / mL, preferably about 100 ng / mL, preferably about 105 ng / mL, preferably about 110 ng / mL, preferably about 115 ng / mL, preferably about 120 ng / mL, preferably about 125 ng / mL, preferably about 130 ng / mL, preferably about 135 ng / mL, preferably about 140 ng / mL, preferably about 145 ng / mL, preferably about 150 ng / mL, preferably about 155 ng / mL, preferably about 160 ng / mL, preferably about 165 ng / mL, preferably about 170 ng / mL, preferably about 175 ng / mL, preferably about 180 ng / mL, preferably about 185 ng / mL, preferably about 190 ng / mL, preferably about 195 ng / mL or preferably about 200 ng / mL.

[0379] Embodiment 114: the composition according to any one of Embodiments 92 to 113, wherein the composition further comprises one or more pharmaceutically acceptable carriers or excipients.

[0380] Embodiment 115: the composition according to Embodiment 114, wherein the one or more pharmaceutically acceptable carriers or excipients is selected from the group consisting of fillers, diluents, binders, lubricants, glidants, disintegrants and plasticizers.

[0381] Embodiment 116: the composition according to Embodiment 115, wherein the filler or diluent is selected from the group consisting of starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, lactose monohydrate, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, and combinations thereof.

[0382] Embodiment 117: the composition according to Embodiment 116, wherein the filler is lactose, preferably lactose monohydrate.

[0383] Embodiment 118: the composition according to any one of Embodiments 115 to 117, wherein the filler is present in an amount of about 30% to about 65%, preferably about 30% to about 60%, preferably about 30% to about 50%, preferably about 30% to about 45%, and preferably about 30% to about 40%, by weight based on the total weight of the composition. Embodiment 119: the composition according to Embodiment 118, wherein the filler is present in an amount of about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41 %, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61 %, about 62%, about 63%, about 64%, or about 65%, by weight based on the total weight of the composition.

[0384] Embodiment 120: the composition according to Embodiment 115 wherein the binder is selected from the group consisting of microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP 90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropyl cellulose, copovidone, and combinations thereof.

[0385] Embodiment 121 : the composition according to Embodiment 115 or 118, wherein the binder is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0386] Embodiment 122: the composition according to Embodiment 115 wherein the lubricant or glidant is selected from the group consisting of zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silicon dioxide (e.g., Aerosil 200), colloidal anhydrous silica, aluminum or calcium silicate, stearic acid, cutina, magnesium trisilicate, powdered cellulose, talc and combinations thereof.

[0387] Embodiment 123: the composition according to Embodiment 122 wherein the lubricant or glidant is colloidal anhydrous silica and / or magnesium stearate.

[0388] Embodiment 124: the composition according to Embodiment 123 wherein the lubricant or glidant is a combination of colloidal anhydrous silica and magnesium stearate.

[0389] Embodiment 125: the composition according to any one of Embodiments 115 or 122 to 124, wherein the lubricant or glidant is present in an amount of about 0.1 % to about 10%, preferably about 0.5% to about 5%, and preferably about 1% to about 3%, by weight based on the total weight of the composition. Embodiment 126: the composition according to Embodiment 115, wherein the disintegrant is selected from the group consisting of carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), carboxymethyl starch-Na (pirimojel and explotab) and / or combinations thereof.

[0390] Embodiment 127: the composition according to Embodiment 115 or 126, wherein the disintegrant is present in an amount of about 0.01 % to about 15%, preferably about 0.05% to about 12%, and preferably about 0.1% to about 10%, by weight based on the total weight of the composition.

[0391] Embodiment 128: the composition according to Embodiment 115, wherein the plasticizer is selected from the group consisting of propylene glycol, phthalates, polyethylene glycols, sebacates, or citrates such as dibutyl phthalate, diethyl phthalate, dibutyl sebecate, triethyl citrate, acetyl tributyl citrate and polyethylene glycol.

[0392] Embodiment 129: the composition according to Embodiment 115 or 128, wherein the plasticizer is present in an amount of about 0.1 % to about 20%, preferably about 0.5% to about 15%, and preferably about 1 % to about 10%, by weight based on the total weight of the composition.

[0393] Embodiment 130: the composition according to any one of Embodiments 92 to 129, wherein the composition is free from floating agents.

[0394] Embodiment 131 : the composition according to Embodiment 130, wherein the floating agent is selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate, adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, sodium citrate and citric acid.

[0395] Embodiment 132: the composition according to any one of Embodiments 92 to 131 , wherein the composition is free from gas-generating agents.

[0396] Embodiment 133: the composition according to Embodiment 132, wherein the gas-generating agent is selected from the group consisting of carbonate and bicarbonate salts, that generate CO2 in the presence of acidic gastric fluid such as citric acid. Embodiment 134: the composition according to any one of Embodiments 92 to 133, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more release controlling polymers is between about 1 :4 and about 3:2, preferably between about 2:5 and about 5:4 and preferably between about 1 :2 and about 6:5.

[0397] Embodiment 135: the composition according to any one of Embodiments 115 to 119 or 130 to

[0398] 134, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler is between about 1 :6 and about 6:5, preferably between about 1 :3 and about 6:5, and preferably between about 1 :2 and about 7:6.

[0399] Embodiment 136: the composition according to any one of Embodiments 115 to 119 or 130 to

[0400] 135, wherein the weight ratio between the filler and the one or more release controlling polymers is between about 3:4 and about 5:2, preferably between about 4:5 and about 5:3, and preferably between about 4:5 and about 4:3.

[0401] Embodiment 137: the composition according to any one of Embodiments 92 to 136, wherein the composition is manufactured by a granulation process.

[0402] Embodiment 138: the composition according to any one of Embodiments 92 to 137, wherein 20- 30% of dydrogesterone is released over a period of about 0.5 to about 2 hours, 50-90% of dydrogesterone is released over about 1 to about 3 hours and 80-100% of dydrogesterone is released over about 2 to about 4.5 hours.

[0403] Embodiment 139: A dosage form comprising (a) a core comprising the composition according to any one of Embodiments 1 to 138 and b) a coating over said core, wherein said coating comprises one or more film forming polymers.

[0404] Embodiment 140: the dosage form according to Embodiment 139, wherein the film forming polymer is selected from the group consisting of cellulose acetate, ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin and combinations thereof.

[0405] Embodiment 141 : the dosage form according to Embodiment 139 or 140, wherein the coating is present in amount of about 1 % to about 10%, preferably about 2% to about 8%, and preferably about 2% to about 5%, by weight based on the total weight of the core. Embodiment 142: the dosage form according to Embodiment 141 , wherein the coating is present in an amount of about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, by weight based on the total weight of the core.

[0406] Embodiment 143: the dosage form according to any one of Embodiments 139 to 142, wherein the total weight of the dosage form is from about 100 mg to about 350 mg, preferably from about 100 mg to about 300 mg, preferably from about 100 mg to about 250 mg, preferably from about 100 mg to about 200 mg, preferably from about 100 mg to about 150 mg.

[0407] Embodiment 144: the dosage form according to any one of Embodiments 139 to 143, wherein the dosage is be formulated as a single unit dosage form, preferably as a single tablet, and more preferably as a single oral tablet.

[0408] Embodiment 145: the dosage form according to any one of Embodiments 139 to 144, wherein the dosage is be formulated for administration once daily.

[0409] Embodiment 146: the dosage form according to any one of Embodiments 139 to 145, wherein the dosage form is formulated for oral administration.

[0410] Embodiment 147: the dosage form according to Embodiment 146, wherein the dosage form is formulated as a tablet such as mono-layered tablets, bilayered tablets, trilayered tablet, multilayer tablet, caplets, minitablets, microtablets, capsules, tablet in tablet, tablets in a capsule, microtablets in a capsule, minitablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, extrudes, pellets, beads or spheroids, suspension or any other suitable dosage form meant for oral administration to a patient.

[0411] Embodiment 148: the composition or dosage form according to any one of Embodiments 1 to 147, for use in the treatment of gynaecological disorders, infertility, prevention of miscarriages and as a component of menopausal hormone therapy.

[0412] Embodiment 149: the composition or dosage form according to Embodiment 148, for use in the treatment of infertility and / or prevention of miscarriages. Embodiment 150: the composition or dosage form according to Embodiment 148 or 149, for use in the treatment of infertility due to luteal insufficiency, threatened miscarriage, habitual or recurrent miscarriage during pregnancy, menstrual disorders, dysfunctional bleeding, dysmenorrhea, endometriosis, secondary amenorrhea, irregular cycles, premenstrual syndrome, as part of in vitro fertilisation (IVF) treatment and / or as a component of menopausal hormone therapy.

[0413] Embodiment 151 : the composition or dosage form according to Embodiment 150, for use in the treatment of endometriosis or as part of in vitro fertilisation (IVF) treatment.

[0414] Embodiment 152: a method of treating infertility and / or preventing miscarriages in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the composition or dosage form according to any one of embodiments 1 to 147.

[0415] Embodiment 153: the method according to Embodiment 152, wherein the method is for treating endometriosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the composition or dosage form according to any one of embodiments 1 to 147.

[0416] Embodiment 154: a method of administering to the patient a therapeutically effective amount of the composition or dosage form according to any one of embodiments 1 to 147, as part of in vitro fertilisation (IVF) treatment.

[0417] EXAMPLES

[0418] Example 1

[0419] Example 2

[0420] Example 3 Example 4

[0421] Example 5

[0422] Example 6 Example 7

[0423] Example 8 - Clinical Study of Composition 1

[0424] STUDY OBJECTIVES

[0425] Primary Objective: to study the pharmacokinetic profile and assess bioequivalence of single dose of Dydrogesterone Modified Release Tablet 20 mg (Once in a day), (Test) and Duphaston® Tablets 10 mg (Twice in a day) (Reference) in healthy, adult, women subjects under fasting conditions.

[0426] Secondary Objective: to monitor the safety and tolerability of single dose of Dydrogesterone Modified Release Tablet 20 mg (Once in a day), (Test) and Duphaston® Tablets 10 mg (Twice in a day) (Reference) in healthy, adult, women subjects under fasting conditions.

[0427] OVERALL STUDY DESIGN AND PLAN DESCRIPTION

[0428] This was an open-label, balanced, randomized, two treatment, two sequence, two period, two way cross-over, oral dose, bioequivalence study of single dose of Dydrogesterone Modified Release Tablet 20 mg, and Duphaston® Tablets 10 mg administered twice daily in healthy, adult, women subjects under fasting conditions.

[0429] Methodology

[0430] Based on pre-study examinations performed within 21 days prior to check-in and verification of compliance with the inclusion and exclusion criteria, eligible subjects were checked into the clinical pharmacology unit (CPU) and were given dinner. Thereafter, subjects were fasted for at least 10.00 hours prior to dosing.

[0431] Dosing activity for test product (A), which corresponds to Composition 1 of Example 1 and reference product (B) was as follows:

[0432] For administration of test product (A) and first dose of reference product (B):

[0433] Following an overnight fast of at least 10.00 hours, subjects were orally administered one tablet of either test product (A) or first dose of reference product (B) with 240 ± 2 mL of drinking water at ambient temperature in an upright sitting position as per the randomization schedule.

[0434] For administration of second dose of reference product (B):

[0435] Following a fast of at least 2.00 hours and after maintaining an interval of 12.00 hours from first dose, subjects were orally administered one tablet of second dose of reference product (B) with 240 ± 2 mL of drinking water at ambient temperature in an upright sitting position as per the randomization schedule.

[0436] A total of 52 blood samples (4.0 mL each) were collected during the study from each subject.

[0437] Table 1 : Mode of administration

[0438] Table 2: Identity of investigational products (IPs)

[0439] The PK parameters described in Table 3 below were assessed for each subject per treatment. Table 3: PK parameters assessed

[0440] The PK parameters were calculated using a non-compartmental analysis model using Phoenix® WinNonlin® - Software, Version 8.3.5 (Certara USA, Inc.) for PK analysis of Dydrogesterone and Dihydrodydrogesterone.

[0441] Statistical analysis was performed using SAS® (SAS Institute Inc., USA) Version 9.4.

[0442] The statistical analysis included: a) two one-sided ANOVA test; b) power analysis; c) ratio analysis d) acceptance criteria for bioequivalence.

[0443] Consistent with Schuirmann’s two one-sided tests procedure for bioequivalence, ANOVA was performed at 5% level of significance on natural In-transformed PK parameters AUCo-t and AUCo- tau to determine whether the average values for these PK measures determined after administration of the test and reference products are comparable. This involved the calculation of 90% Cl for the ratio of the averages (population geometric least square means) of the measures for test and reference products. The ANOVA model included sequence subject nested within the sequence, period and treatment as fixed effects factors. The significance of the sequence effect was tested using the subject nested within the sequence as the error term. Each ANOVA testing also included calculation of LSM, adjusted differences between formulation means and the standard error associated with these differences.

[0444] Geometric least square mean values were reported for In-transformed primary PK parameters of Dydrogesterone and Dihydrodydrogesterone on which Cl is based. Ratios of geometric least square means are expressed as a percentage of the LSM for the test and reference products.

[0445] Test product was considered bioequivalent to reference product, if 90% Cis for ratio (test / reference) of geometric least square means based on In-transformed primary PK parameters - ALICo-t and AUCo-tau fall within acceptable BE limits of 80.00% to 125.00% for Dydrogesterone.

[0446] Data of Dihydrodydrogesterone was provided as supportive evidence.

[0447] Pharmacokinetic Results

[0448] The mean PK parameters for the test product (Composition 1) and the reference product of Dydrogesterone and Dihydrodydrogesterone are presented in Tables 4 and 5.

[0449] Table 4: Mean Pharmacokinetic Parameters of Dydrogesterone (N=26)

[0450] N: Number of evaluated subjects; *Median (Range) is provided Table 5: Mean Pharmacokinetic Parameters of Dihydrodydrogesterone (for supportive information) (N=26)

[0451] N: Number of evaluated subjects; *Median (Range) is provided

[0452] Evaluation of Bioequivalence

[0453] The Ln-transformed primary PK parameters of Dydrogesterone and Dihydrodydrogesterone were evaluated for bioequivalence and the results are presented in Tables 6 and 7.

[0454] Table 6: Bioequivalence Assessment of Dydrogesterone (N=26)

[0455] 1 . For loge-transformed results (Ln), value is the least-squares geometric mean.

[0456] 2. Ratio% of geometric least-squares means for loge-transformed results.

[0457] 3. ISCV% = %lntra-subject coefficient of variation calculated from the mean square term of the ANOVA.

[0458] 4. Confidence interval on ratio. Table 6: Bioequivalence Assessment of Dihydrodydrogesterone (for supportive information) (N=26)

[0459] 1 . For loge-transformed results (Ln), value is the least-squares geometric mean.

[0460] 2. Ratio% of geometric least-squares means for loge-transformed results.

[0461] 3. ISCV% = %lntra-subject coefficient of variation calculated from the mean square term of the ANOVA.

[0462] 4. Confidence interval on ratio.

[0463] Bioequivalence Conclusions

[0464] The 90% confidence intervals for the ratio (test / reference) of geometric least square means based on Ln-transformed primary PK parameter AUCo-tau and AllCo-t were found within the acceptable bioequivalence limits of 80.00% to 125.00% for Dydrogesterone.

[0465] The results of the study demonstrated that the test product Dydrogesterone Modified Release Tablets 20 mg, was bioequivalent to the reference product Duphaston® Tablets 10 mg under fasting condition.

[0466] There were no SAEs observed during the study and no unresolved AEs with either the test product or the reference product. Both the test product and the reference product were well tolerated during the study.

[0467] Dissolution Data

[0468] The dissolution data for the release of dydrogesterone are provided in Tables 7 and 8 below, with the percentage LC released and relative standard deviation (RSD). Table 7: Dissolution profile for 20 mg dydrogesterone MR tablet

[0469] Table 8: Dissolution profile for 30 mg dydrogesterone MR tablet (Composition 5)

[0470]

[0471] Example 9 - Efficacy and Safety Study of 20 mg dydrogesterone MR tablet

[0472] A Phase III prospective, randomized, single-blind, single-dummy, two-arm, multicentric study was carried out to assess the efficacy and safety of dydrogesterone modified release tablets 20 mg OD compared to dydrogesterone 10 mg IR (BID) in the management of endometriosis. The treatment was conducted over 3 months.

[0473] Both dydrogesterone treatment regimens - modified release tablets 20 mg OD and immediate release 10 mg BID - demonstrated to have a positive benefit-risk profile for management of endometriosis-related chronic pelvic pain and improving HR-QoL of patients. The 20 mg once- daily modified release formulation could be a suitable alternate treatment option to the twice-daily 10 mg immediate release formulation, offering comparable efficacy with a convenient once daily dosing schedule. The safety profile observed in this study under 20 mg once-daily modified release formulation for treatment of endometriosis can be considered similar to the safety profile under twice-daily 10 mg immediate release formulation.

[0474] Example 10 - Extended Release and Immediate Release Combination

[0475] A dual immediate release I extended release tablet (composition 8) was prepared with the components as set out below: Composition 8

[0476] Process Details

[0477] A tablet according to composition 8 was prepared according to the following method.

[0478] Sieving: the ingredients were separately weighted and then hypromellose K15M, E15LV, dydrogesterone micronised and lactose were passed through a 1000 pm sieve and placed in a granulator (298 g, 70% fill).

[0479] Granulation: the powder blend was mixed at 500 rpm impeller speed for 5 min. The impeller speed was increased to 750 rpm and the chopper speed was set to 1500 rpm, when the addition of the granulation liquid (2% w / v HPMC E15 solution in water) was started (dropwise addition). A total of 100 g granulation liquid was added in 10 min (10 g / min) and then granulation was continued for another 10 min under the same conditions. The LOD of the wet mass was 24% corresponding well with the added amount of water (24.7% based on total weight).

[0480] Wet sieving: the wet mass was passed through a 2000 pm sieve.

[0481] Drying: the drying was performed at 40°C for 24 hours. Sieving: the dried granules (LOD: 1.3%) were passed through a 710 pm sieve.

[0482] Tableting: compaction at 20 kN lead to hardness of 55-60 N.

[0483] Tablet coating: the extended release component was coated with the immediate release component using a dydrogesterone : HPMC E5 1:1 solution in a side vented pan coater to obtain the targeted 10% weight gain.

[0484] Process parameters are summarized below:

[0485] Dissolution Data

[0486] A dissolution experiment was performed for the tablet according to composition 8 over 12 hours (basket at 150 rpm, 0.3% SDS, 37°C) with UV-detection. The results are presented below.

[0487]

[0488] The immediate release component of the tablet dissolved within the first 15 minutes. Thereafter the extended release component released about 80% of the loading over about 3.5 - 4 hours.

[0489] The immediate release I extended release combination was feasibly formulated and the formulation of the extended release core tablet and the immediate release component showed appropriate tablet properties.

[0490] Example 11 - Enterically Coated Extended Release and Immediate Release Combination

[0491] A dual immediate release I extended release tablet (composition 9) was prepared with the components as set out below: Composition 9

[0492] Process Details

[0493] A tablet according to composition 9 was prepared according to the following method.

[0494] Sieving: the ingredients were separately weighted and then hypromellose E15LV, dydrogesterone micronised and lactose were passed through a 1000 pm sieve and placed in a granulator.

[0495] Granulation: the powder blend was mixed at 500 rpm impeller speed for 5 min. The impeller speed was increased to 750 rpm and the chopper speed was set to 1500 rpm, when the addition of the granulation liquid (2% w / v HPMC E15 solution in water) was started (dropwise addition). Granulation liquid was added in 8:23 min (10 g / min) and then granulation was continued for another 5 min under the same conditions. The LOD of the wet mass was 21 % corresponding well with the added amount of water (21 .5% based on total weight).

[0496] Wet sieving: the wet mass was passed through a 2000 pm sieve. Drying: the drying was performed at 40°C for 16 hours.

[0497] Sieving: the dried granules (LOD: 2.2%) were passed through a 710 pm sieve.

[0498] Tableting: compaction was performed at 20 kN, which led to hardness of 45-52 N.

[0499] Tablet enteric coating: the tablet cores were coated with an enteric coating layer based on Kollicoat MAE 30 DP.

[0500] Tablet outer coating: the enterically coated extended release component was coated with the immediate release component using a dydrogesterone : HPMC E5 1:1 solution in a side vented pan coater to obtain the targeted weight gain.

[0501] Process parameters are summarized below:

[0502] Dissolution Data

[0503] A dissolution experiment was performed for the tablet according to composition 9 over 6 hours (basket at 150 rpm, 37°C) with UV-detection. The release medium (500 ml) consisted of sodium lauryl sulfate (0.3%) dissolved in 0.1 N HCI during a 2-hour acid stage and it was exchanged with 500 ml of sodium lauryl sulfate (0.3%) dissolved in 50 mM sodium phosphate buffer pH 6.8 thereafter. The results are presented below.

[0504] Drug release occurred over about 4.5 hours and showed two distinct release phases due to the immediate release component released during the acid stage and the extended release component released within 2.5 hours in the buffer stage.

[0505] Example 12 - Extended Release and Immediate Release Combination

[0506] A dual immediate release I extended release tablet (composition 10) was prepared with the components as set out below:

[0507] Composition 10

[0508] Process Details

[0509] A tablet according to composition 10 was prepared according to the following method.

[0510] Dydrogesterone micronised and excipients were each screened through a 1000 pm sieve and loaded into the HS mixer and mixed for 5 min. Granulation liquid was then pumped into the bed at 9-10 g / min per peristaltic pump. The amount of water added as granulation liquid corresponded to 28% w / w of total solids in the powder blend (dydrogesterone micronised, HPMCs and lactose). Granulation was continued for 5 min (total granulation time: 15 min) under the same conditions after which the material was unloaded, wet screened (1000 pm) and dried overnight at 40°C.

[0511] Tablet compression: granules and colloidal silica were each screened through a 1000 pm sieve, loaded (about 70% fill) into a mixer and mixed for 10 minutes at 49 rpm. Magnesium stearate was screened through a 180 pm sieve, added to the granule blend and mixed (lubrication) in a blender for 3 min at 49 rpm.

[0512] Tablets were compressed with an instrumented single punch tableting machine.

[0513] Drug-Layered SR tablets: tablet cores were layered with drug:HPMC E5 1 :1 (7.14% solids content) using a drum coater with perforated pan.

[0514] Process parameters are summarized below:

[0515] Dissolution Data

[0516] A dissolution experiment was performed for the tablet according to composition 10 over 6 hours.

[0517] The results are presented below.

[0518] Example 13 - Extended Release and Immediate Release Combination

[0519] A dual immediate release I extended release tablet (composition 11) was prepared with the components as set out below:

[0520] Composition 11

[0521] Process Details

[0522] A tablet according to composition 11 was prepared according to the following method.

[0523] Sifting: the Hypromellose (Methocel K15) 2208, Hypromellose (Methocel E15LV) 2910 and Lactose monohydrate were sifted through #20 mesh using vibratory sifter and collected separately in a double lined polythene bag in a HDPE container.

[0524] Dry mixing: the sifted Lactose monohydrate was loaded into the RMG and Dydrogesterone and was added, then sifted Hypromellose (Methocel K15) 2208 and Hypromellose (Methocel EI5LV) 2910 were added into the RMG and mixed for 5 mins (±5 seconds) at impeller speed of 124 rpm (121 - 127 rpm) and chopper off. Binder addition: the Purified water was taken in dried SS vessel.

[0525] Wet granulation: Purified water was added into the RMG at a rate of by using a peristaltic pump with Spray by keeping impeller at 124rpm (121 - 127 rpm) & Chopper at 950 rpm (947 - 953 rpm). The materials were wet mixed for about 5 mins (±5 seconds) by keeping the impeller at 133 rpm (130 -136) and chopper at 950 rpm (947 - 953 rpm). The materials were unloaded in FBD bowl with suitable impeller RPM.

[0526] Drying: the FBD bowl was attached to the FBD and the drying process was started with inlet temperature of NMT 55°C (Target 45°C ± 5°C) and suitable air flow. The product temperature was NMT 45°C. Drying was continued until the Loss on Drying reached in between 2.2 - 3.6 % w / w at 105°C with 3 g sample.

[0527] Sizing: the dried granules were milled through 62 G (Grater sieve) using Co-mill at speed of 2500 rpm ± 100 rpm. Before milling the screen impeller distance was adjusted with proper spacer. The milled granules were collected in a double lined LDPE bags (inner clear and outer black) placed inside clean and fared HDPE container labelled with proper status label. The weight was recorded and the containers lid was sealed tightly.

[0528] Extra granular dispensing: the same dispensed quantity of extra granular material was used, if the batch yield of sifted granules was 98.0 % and above. Otherwise, the extra granular material was dispensed based on the batch yield of sifted granules, if the batch yield was less than 98. 0 %.

[0529] Extra granular sifting: Colloidal silica Aerosil 200 was sifted through #20 mesh and Magnesium Stearate was sifted through #40 mesh by using vibratory sifter and collected separately in a double lined polythene bag in a container.

[0530] Pre-lubrication: the half-sized granules quantity was added into the blender and sifted Colloidal silica Aerosil 200. The remaining half quantity of sized granules were added and blend for 4 mins at 12 rpm.

[0531] Lubrication: the sifted Magnesium Stearate was added into the blender and mixed for 3 mins at 12 rpm. The final blend was collected in double-lined (inner clear & outer black) LDPE bags placed inside a clean and fared HDPE container. Compression stage: the final blend was compressed into the tablets by using a compression machine.

[0532] Coating stage: Purified Water was collected in a clean, dry Stainless Steel vessel. Opadry TF 265F280007-CN was added under stirring condition and after addition, the stirring process was continued for 15 minutes. Dydrogesterone was slowly added into this dispersion under stirring condition. The stirring process was continued after addition for 60 minutes. The suspension was filtered through #100 mesh and the suspension weight after filtration was noted down. The compressed tablets were coated by using 36-inch coating pan.

[0533] Dissolution Data

[0534] A dissolution experiment was performed for the tablet according to composition 11 over 5 hours. The results are presented below.

Claims

CLAIMS1 . A modified release composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof; one or more release controlling polymers; and one or more pharmaceutically acceptable excipients, wherein said composition releases greater than 20% of dydrogesterone in 1 hour and not less than 80% of dydrogesterone within 5 hours.

2. The composition according to Claim 1 , wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) value relative to that of an immediate release formulation comprising dydrogesterone, of at least about 1 .0, or at least about 1.05, or at least about 1.1 , or at least about 1.2, or at least about 1 .3, or at least about 1.4, or at least about 1.5, or at least about 2.0, or at least about 2.5, or at least about 3.0, where the AUC(o-24h) values may be determined under similar conditions.

3. The composition according to Claim 1 or Claim 2, comprising: dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of 10% to 40%; one or more release controlling polymers in an amount of 20 to 60%; and one or more pharmaceutically acceptable excipients.

4. The composition according to any preceding claim, comprising: dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of 10% to 40%; one or more release controlling polymers in an amount of 20 to 60%; one or more fillers in an amount of 20% to 65%; and one or more lubricants and / or glidants in an amount of 0.1% to 10%.

5. The composition according to any preceding claim, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and said one or more release controlling polymers is between 1 :6 and 2:1.

6. The composition according to any preceding claim, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the filler is between 1 :6 and 2:1.

7. The composition according to any preceding claim, wherein the weight ratio between the filler and the one or more release controlling polymers is between 1 :3 and 5:2.

8. The composition according to any preceding claim, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof is present in an amount of 10% to 40%, preferably 15% to 35%, by weight based on the total weight of the composition.

9. The composition according to any preceding claim, wherein the composition comprises 15 to 50 mg of dydrogesterone or a pharmaceutically acceptable salt thereof.

10. The composition according to any preceding claim, wherein said one or more release controlling polymers is present in an amount of 20 to 60%, preferably 30 to 40% by weight based on the total weight of the composition.

11. The composition according to any preceding claim, wherein said one or more release controlling polymers is hydroxypropyl methylcellulose.

12. The composition according to any preceding claim, wherein said filler is present in an amount of 20% to 65%, preferably 30% to 60%, by weight based on the total weight of the composition.

13. The composition according to any preceding claim, wherein said filler is lactose, and more preferably lactose monohydrate.

14. The composition according to any preceding claim, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to 2 immediate release formulations each comprising 10 mg of dydrogesterone.

15. The composition according to Claim 14, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 25 ng*hr / mL.

16. The composition according to any one of Claims 1 to 13, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) equivalent to 3 immediate release formulations each comprising 10 mg of dydrogesterone.

17. The composition according to Claim 16, wherein said composition provides a mean dydrogesterone plasma AUC(o-24h) of about 10 to about 70 ng*hr / mL.

18. The composition according to any preceding claim, wherein said composition is free from floating agents and / or gas-generating agents.

19. The composition according to any preceding claim for use in the treatment of gynaecological disorders, menstrual disorders, infertility, prevention of miscarriages, as part of in vitro fertilisation (IVF) treatment or as a component of menopausal hormone therapy.

20. The composition according to Claim 19 for use in the treatment of endometriosis or as part of in vitro fertilisation (IVF) treatment.

21. The composition or composition for use according to any preceding claim, wherein said composition is administered once daily.

22. A method of manufacturing the modified release composition according to any one of Claims 1 to 21, comprising the steps of:1) providing a dry mixture of dydrogesterone or a pharmaceutically acceptable salt thereof, one or more release controlling polymers and one or more pharmaceutically acceptable excipients;2) adding water to said dry mixture;3) performing a granulation step to provide a granulated mixture; and4) drying said mixture to remove the water.

23. A modified release composition comprising:(a) an extended release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more release controlling polymers; and(b) an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more coating polymers or film formers, wherein the weight ratio between dydrogesterone or a pharmaceutically acceptable salt thereof and the one or more coating polymers or film formers in the immediate release component is between about 1:1 and about 1:1.4.

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