FIELD OF THE INVENTION

The invention relates to an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, optionally one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Dydrogesterone, also known as 6-dehydro-9ß,10a-progesterone or as 9ß,10a-pregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone and retroprogesterone (9ß,10a-progesterone) having formula I.

Dydrogesterone is a progestin medication which is used for treatment of irregular duration of cycles and irregular occurrence and duration of periods caused by progesterone deficiency. Further, combined with an estrogenic substance, dydrogesterone can be applied in secondary amenorrhoea, dysfunctional uterine bleeding and post-menopausal complaints where endogenous progesterone deficiency is implicated.

There are several references known in the literature, which describe the different composition of dydrogesterone, which are used in the treatment of various diseases.

US Patent No. 7,683,047 disclose a method of treating endometrial hyperplasia in a subject, said method comprising: administering continuously and uninterruptedly for a first predetermined time period a first dose of a progestin agent to said subject; and administering continuously and uninterruptedly for a second predetermined time period a second dose of a progestin agent to said subject.

US Patent Publication No. 20050020553 A1 disclose a method of inhibiting spontaneous or habitual miscarriage, said method comprising administering to a female patient in need of such treatment an effective amount of at least one non-endogenous gestagen compound from the moment of ovulation on.

US Patent Publication No. 20110152840 A1 disclose a method for reducing the occurrence of preterm delivery, the method comprising: administering a pharmaceutical composition comprising a steroid hormone to a pregnant female subject having no history of preterm delivery and exhibiting one or more risk factors for preterm delivery.

US Patent Publication No. 20040202713 A1 disclose a contraceptive method comprising sequentially administering a plurality of dosage units containing a hormone composition to a female of childbearing capability so as to provide the hormone composition in an amount which is effective to inhibit ovulation, wherein the hormone composition is dydrogesterone component or a combination of estrogen and dydrogesterone component.

PCT Patent Publication No. 2012055840 A1 disclose a pharmaceutical composition comprising a hormonal agent, a biocompatible zinc salt, and pharmaceutical acceptable excipients.

PCT Patent Publication No. 2004019954 A1 disclose an improved pharmaceutical preparation, for administration to a female in need of estrogen replacement, comprising a plurality of doses arranged in alternating standard dose estrogen phases and ultra-low dose estrogen phases.

Russian Patent No. 2289409 disclose a method of rehabilitation after medical termination of pregnancy, characterized in that on the first day from the moment of expulsion of the ovum, the drug Multi-tabs-intensive is prescribed, 1 tablet for a month, from the 16th to the 25th day, the drug Duphaston is prescribed 10 mg 2 times a day.

Currently approved formulation of dydrogesterone is in the form of immediate release tablet. Patients need to take tablets of dydrogesterone two times a day, i.e., in morning and evening. There are chances that patient may forget to take dose properly, i.e., either morning or evening dose, which can lead to decrease in patient compliance. In contrast, administering a single dose of medication which releases active ingredient over an extended period of time as opposed to the administration of a number of single doses at regular intervals is convenient for patients. In extended release preparations, the dosage form continuously provide drug for absorption into the blood stream to replace the amount eliminated while the dosage form is passing through the gastrointestinal tract of the patient. In view of the above, it is therefore, desirable to provide an extended release pharmaceutical composition of Dydrogesterone which is stable, have desired release profile, and improves patient compliance. Furthermore, there exists a need to develop a process for the preparation of pharmaceutical composition which is robust and economical.

SUMMARY OF THE INVENTION

The present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymers, and optionally one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymers, one or more floating agents, and optionally one or more pharmaceutically acceptable excipients.

According to one more aspect, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymers, one or more floating agents, and optionally one or more pharmaceutically acceptable excipients, wherein the one or more floating agents is a gas generating agent 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, citric acid, or a combination thereof.

According to another aspect, the present invention provides an extended release pharmaceutical composition comprising from 10mg to 50mg of dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer in an amount from 5% to 50% by weight of total weight of the pharmaceutical composition, and optionally one or more floating agents; wherein the total weight of the pharmaceutical composition is between 100 mg to 400mg.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising (a) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients; (b) a coating over said core which comprises one or more film forming polymer.

According to another aspect, the present invention provides an extended release pharmaceutical composition comprising: (a) a core comprising: i) an extended release component comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and (ii) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; b) a coating over said core, wherein said coating comprises one or more film forming polymers.

According to one more aspect, the present invention provides an extended release pharmaceutical composition comprising: a) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and b) a coating over said core, wherein said coating comprises one or more extended release polymers.

According to one more aspect, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, or wet granulation process.

According to one more aspect, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, one or more floating agents, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, or wet granulation process.

According to another aspect, the present invention provides a process of preparation of an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein said process comprises: (a) blending dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and optionally one or more floating agents to obtain a blend; b) optionally granulating the blend; (c) lubricating the blend or granules; (d) compressing the lubricated blend or granules to form a tablet or filling the lubricated blend or granules in a capsule.

According to another aspect, the present invention provides a process of preparation of an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein said process comprises: (a) preparing a core comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more floating agents to obtain a blend; b) coating the core with one or more extended release polymer; (c) compressing the coated core of step b) to form a tablet or filling the lubricated blend or granules in a capsule.

According to another aspect, the present invention provides an extended release pharmaceutical composition comprising: (a) a delayed release component comprising: i) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients, and ii) a delayed release layer comprising one or more delayed release polymers, and b) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

Another aspect of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer in an amount from 5% to 50% by weight of total weight of the pharmaceutical composition, and optionally one or more floating agents, wherein the pharmaceutical composition when taken orally once-a-day is bioequivalent to the immediate release tablet taken twice daily.

In one another aspect, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone, wherein said dydrogesterone or pharmaceutically acceptable salts thereof, has a particle size of D10 less than 10 microns, D50 less than 50 microns, D90 less than 100 microns.

DESCRIPTION OF THE INVENTION
This is a cognate application of first application numbered IN 202111043335 filed on September 24, 2021 and second application numbered IN 202211007938 filed on Feb 15, 2022.

Accordingly the present invention relates to an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and optionally one or more pharmaceutically acceptable excipients.

The term ‘extended release’ as used herein refers to release of drug over an extended period of time i.e. from about 2 hours to about 24 hours. The extended release includes but is not limited to sustained release, controlled release, delayed release, or modified release form or combination thereof.

The term “therapeutically effective amount” or “effective amount” used interchangeably, is defined to mean the amount or quantity of the active drug, which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “composition” or “solid oral composition” or “dosage form” or “pharmaceutical composition” as used herein synonymously include 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, parenteral, topical, transdermal, mucosal, nasal, buccal, or sublingual administration to a patient, preferably oral.

The term “pharmaceutically acceptable salt” or “salt” is used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids and inorganic salts may further includes alkali metal and alkaline earth metal salts.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent, disintegrant, carrier, and the like, of a pharmaceutical product. The excipients that are useful in preparing a dosages form are generally safe, non-toxic, and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one excipient and more than one excipient. The pharmaceutically acceptable excipients may include one or more pharmaceutically acceptable excipients are selected from the group comprising of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the dydrogesterone or pharmaceutically acceptable salts thereof is embedded in one or more extended release polymer.

Another embodiment of the present invention provides an extended release pharmaceutical composition that comprises a core comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the core is coated with one or more extended release polymer.

Another aspect of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition comprising about 10mg to about 50mg of dydrogesterone or pharmaceutically acceptable salts, ester, solvates, polymorphs thereof.

Another aspect of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone, wherein said pharmaceutical composition releases less than 85% of dydrogesterone within 2 hours and not less than 75% of dydrogesterone is released within 16 hours.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D90 less than 100 microns.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D50 less than 50 microns and D90 less than 100 microns.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D10 less than 10 microns, D50 less than 50 microns and D90 less than 100 microns.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D90 between 30µm and 90µm; preferably between 65 µm and 85 µm, more preferably between 70 µm and 85 µm.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D50 between 10µm and 40µm; preferably between 15 µm and 25 µm, more preferably between 18 µm and 22 µm.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D10 between 1µm and 10µm; preferably between 2.0 µm and 5 µm, more preferably between 1.8 µm and 3.0 µm.

Suitable fillers/ diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose (flowlac 90), 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, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof. When present, a filler may be employed in an amount ranging from about 10% to about 80%, preferably from about 20% to about 80% by weight of the pharmaceutical composition. In one embodiment, the diluent is microcrystalline cellulose in an amount ranging from 40% to about 80% by weight of the pharmaceutical composition.

Suitable binders include, without limitation, microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K 30 or PVP90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, copovidone, pregelatinized starch and combinations thereof. When present, a binder may be employed in an amount ranging from about 0.1% to about 20%, preferably from about 0.5% to about 15%, such as 1% to 10%, by weight of the pharmaceutical composition.

Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical composition.

Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical composition.

Suitable disintegrants include, without limitation, 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. A disintegrant is employed in an amount of 0.01 to 15%, such as of 0.05 to 12%, such as at least 0.1 to 10%, by weight of the pharmaceutical composition.

Suitable plasticizers include, without limitation, propylene glycol, phthalates, polyethylene glycols, sebacates, or citrates such as dibutyl phthalate, diethyl phthalate, dibutyl sebecate, triethyl citrate, acetyl tributyl citrate, polyethylene glycol.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the composition is free of binder, disintegrant, or both.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the at least one extended release polymer is selected from the group consisting of water insoluble polymers, water soluble polymers, pH dependent polymers, pH independent polymers and mixtures thereof.

Suitable extended release polymer, without limitation includes hydrophilic or hydrophobic polymers comprise 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 (e.g., HPMC K15M, HPMC K4M), 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 like 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 971P) and the like. Polymer may be used from 0.1- 50% by weight of the composition, preferably 10-50% by weight of the composition.

According to one embodiment the extended release pharmaceutical composition of the present invention comprises dydrogesterone or pharmaceutically acceptable salts thereof, hydroxypropyl methyl cellulose, and optionally one or more pharmaceutically acceptable excipients.

According to another embodiment the extended release pharmaceutical composition of the present invention comprises: (a) a core comprising: i) an extended release component comprising dydrogesterone or pharmaceutically acceptable salts thereof, hydroxypropyl methyl cellulose, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and (ii) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; b) a coating over said core, wherein said coating comprises one or more film forming polymers.

The ‘immediate release” as used herein refers to immediate release of drug is where the majority (e.g., substantially all or all) of the pharmaceutically active ingredient is released within a relatively short time, for example within 1 hour, preferably within 30 minutes, after oral ingestion.

According to one embodiment the extended release pharmaceutical composition of present invention is a gastroretentive dosage form. Gastroretentive dosage form can be swellable or floating or combination of both.

As used herein, a “floating gastroretentive dosage form” has a bulk density less than gastric fluids. Such dosage forms are “floating” in that they remain buoyant in the gastric fluids of the stomach for a targeted period of time. The floating dosage form is able to be retained in the stomach, while releasing an active agent. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves solubility of drugs that are less soluble in a high pH environment. Gastro retentive delivery systems are designed to be retained in the stomach for a prolonged time and release their active ingredients and thereby enable sustained and prolonged input of the drug to the upper part of the gastrointestinal (GI) tract.

According to one embodiment, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymers, one or more floating agents, and optionally one or more pharmaceutically acceptable excipients.

Suitable floating agents, without limitation includes 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. In certain embodiments, the floating agent generates CO2 independent of a fed or fasted state of an individual. The extended release composition comprising floating agent provides a gastroretentive dosage form that possess improved pharmacokinetic profile by retaining the dosage form in the stomach for a prolonged period of time.

As noted above, in certain embodiments, the extended release composition comprises gas-generating floating agents, e.g., carbonate and bicarbonate salts, that generate CO2 in presence of acidic gastric fluid such as citric acid. In certain embodiments, the core further comprises organic and/or inorganic acids that react with carbonate salts in an aqueous environment, e.g., at neutral pH or at a weakly acidic pH, and generate CO2 gas. In other embodiments, the extended release composition of the present invention comprising at least one floating agent are stable, and provide efficient delivery of dydrogesterone in the GI tract due to the presence of a water-soluble polymer such as polyethylene oxide, xanthan gum, hydroxypropyl cellulose, carbopol, Cross-linked polyvinyl alcohol (PVA), Cross-linked polyvinyl pyrrolidone (PVP), Polyvinylpyrrolidone (PVP), Hydroxypropyl methyl cellulose (HPMC), Polylactic acid (PLA), Polyglycolic acid (PGA), Polyacrylic acid, Tragacanth, Methyl cellulose, Pectin, Guar gum, Karaya gum, Locust bean gum, etc., that swells via imbibition of water from gastric fluid to (1) increase the size of the composition to promote gastric retention, (2) partially control the release of drug by entrapping the drug in the swollen polymer, (3) support the membrane and maintain the integrity of the composition in a swollen state with a seal coat and/or by forming a layer beginning at the periphery of the pharmaceutical composition, and (4) entrap generated gas (e.g., CO2) to provide buoyancy. In other embodiments the extended release composition comprises both gas generating agents and water swellable polymers. In certain embodiments, the extended release gastroretentive dosage form of the present disclosure provides a controlled sustained release of the active agent for a period of about 8-16 hours, e.g., about 12 hours, under fed and fasted conditions.

According to another embodiment, the ratio of extended release polymer and floating agent is 1:1 to 1:10.

According to another embodiment, the present invention provides an extended release pharmaceutical composition comprising: (a) a core comprising: i) an extended release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof, one or more extended release polymer, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and (ii) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; b) a coating over said core, wherein said coating comprises one or more film forming polymers.

According to another embodiment, the present invention provides an extended release pharmaceutical composition comprising: a) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and b) a coating over said core, wherein said coating comprises one or more extended release polymers.

According to one embodiment the extended release pharmaceutical composition of present invention is a delayed release pharmaceutical composition.

The term ‘delayed release’ as used herein refers to a delay or a time lag of 2 hours to 12 hours before the active ingredient is released from the composition after administration.

According to another embodiment, the delayed release pharmaceutical composition of the present invention comprises: a) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and b) a coating over said core, wherein said coating comprises one or more delayed release polymers.

The “delayed release polymer” is selected such that the therapeutically active agent will be released when the dosage form reaches the small intestine or a region in which the pH is greater than pH 4.5. Preferred coating includes pH-sensitive materials, which remain intact in the lower pH environment of the stomach, but which disintegrate or dissolve at the pH commonly found in the small intestine of the patient. The delayed release polymer coating material begins to dissolve in an aqueous solution at pH above 4.5. The pH-solubility behavior of the delayed release polymers of the present invention are such that significant dissolution of the delayed release polymer coating will not occur until the dosage form has emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal portions of the small intestine (ileum). The lag time between the administration and the onset of the release can be modified by altering the coating materials or the amount of coat applied.

Suitable delayed release polymers, without limitation includes pH dependent enteric polymers such as Eudragits, methacrylates, methacrylic acid-methylmethacrylate copolymers, methacrylic acid-ethylmethacrylate copolymers, partially neutralized (meth)acrylate copolymer, cellulose phthalates, Hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol-polyethylene glycol graft copolymers (Kollicoat®), vinyl acetate-vinylpyrrolidone copolymer (Kollidon® VA64), cellulose acetate phthalate, Eudragit L, Eudragit S, Eudragit® L 100-55, Eurdragit® L30 D-55, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose acetate trimellitate or shellac.

According to one embodiment, the present invention provides an extended release pharmaceutical composition comprising: (a) a delayed release component comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more delayed release polymers, and optionally one or more pharmaceutically acceptable excipients, and b) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

According to one embodiment, the extended release pharmaceutical composition of the present invention comprises: (a) a delayed release component comprising: i) a core comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients, and ii) a delayed release layer comprising one or more delayed release polymers, and b) an immediate release component comprising dydrogesterone or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

The term “component” as used herein refers to a part or portion of the pharmaceutical composition.

According to another embodiment, the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, optionally one or more floating agents, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, wet granulation process, melt granulation, or extrusion process.

According to another aspect, the present invention provides a process of preparation of extended release pharmaceutical composition of dydrogesterone, wherein said process comprises:
(a) preparing an extended release component comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and optionally one or more floating agent;
(b) preparing immediate release component comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more floating agent;
(c) compressing the components a) and b) to form a bilayer tablet or filling the components a) and b) in a capsule.

According to another aspect, the present invention provides a process of preparation of an extended release pharmaceutical composition of dydrogesterone, wherein said process comprises:
(a) preparing a delayed release component comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more delayed release polymer, and optionally one or more pharmaceutically acceptable excipients;
(b) preparing an immediate release component comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients;
(c) compressing the components a) and b) to form a bilayer tablet or filling the components a) and b) in a capsule.

Another aspect of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer in an amount from 5% to 50% by weight of total weight of the pharmaceutical composition, and optionally one or more floating agents, wherein the total weight of the pharmaceutical composition is between 100mg to 400mg and the pharmaceutical composition when taken orally once-a-day is bioequivalent to the immediate release tablet taken twice daily.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone, wherein the extended release may be achieved by one or more of coating or embedding in matrix using hydrophilic or hydrophobic polymers or by attachment to ion-exchange resins. Further, extended release may be achieved by osmotic oral release technology also.

According to another embodiment the extended release pharmaceutical composition of the present invention further comprises a surfactant. The surfactants include but are not limited to anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Suitable surface active are poloxamer 188, polysorbate 80, Cremophore, Soluplus, lecithin and sodium lauryl sulfate.

The pharmaceutical composition of the present is stable. The term “stable or stability or stabilized” means the dosages form is stable under 40°C/75% RH and/or 30°C/75% RH for at least six (06) months. Further, the total impurity in the dosage form is not more than 5% after storing at 40°C/75% RH and/or 30°C/75% RH for at least six (06) months. Any individual impurity in the dosage form is not more than 0.5% after storing at 40°C/75% RH and/or 30°C/75% RH for at least six (06) months.

Another embodiment of the present invention provides an extended release pharmaceutical composition comprising dydrogesterone, wherein the said composition is used in the treatment of irregular duration of cycles and irregular occurrence and duration of periods caused by progesterone deficiency. Further, the said composition also used for secondary amenorrhoea, dysfunctional uterine bleeding and post-menopausal complaints where endogenous progesterone deficiency is implicated, in combination with an estrogenic substance.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don’t limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:
S. No. Ingredient Qty/Tablet (mg)
Dry mix Exp. 1 Exp. 2
1 Dydrogesterone 20.000 20.000
2 Lactose monohydrate 136.000 136.000
3 Hydroxypropyl methyl cellulose K100M 15.000 25.000
4 Hydroxypropyl methyl cellulose K4M 25.000 15.000
Pre-lubrication
5 Colloidal anhydrous silica 1.000 1.000
Lubrication
6 Magnesium stearate 3.000 3.000
Film coating
7 Hydroxypropyl methyl cellulose 0.1-10 0.1-10
8 Macrogol 0.1-10 0.1-10
9 Titanium Dioxide 0.1-10 0.1-10
10 Talc 0.1-10 0.1-10
11 Isopropyl Alcohol q.s. q.s.
12 Methylene chloride q.s. q.s.

Process:
(a) Dispense, sift and blend the dydrogesterone, extended release polymer and one or more pharmaceutically acceptable excipients.
(b) Lubricate the blend obtained from step (a) with lubricants.
(c) Compress the lubricated blend using suitable punches and dies.
(d) Coat the compress mixture obtained in step (c) with coating solution.

Dissolution Study
The in vitro release study for the pharmaceutical composition disclosed in Example 1 and 2 was carried out in 900ml of 0.2% sodium lauryl sulfate in water, USP Type II apparatus at a speed of 50RPM. The dissolution data is given in Table 1.

Table 1: Release Profile of Dydrogesterone SR Tablets 20 mg
Time (Hr.) 0.2% SLS in Water
% Drug release (Example 1) % Drug release (Example 2)
1 12 14
2 16 20
4 34 37
6 53 58
8 69 76
10 81 86
12 91 93
16 101 101
20 105 104
24 105 105

Tablets prepared according to example 3 shows stability over a period of 3 months. The stability data of tablets is shown in the Table-2 as follows:

Table 2: Stability Data of dydrogesterone tablets (Example 2)
S. No. Tests Initial 3 Month
(40°C & 75%RH) 3 Month
(30°C & 75%RH) Specification
1. Water determination (wt% by KF) 5.3 5.5 5.51 NMT 10.0 %
2 Dydrogesterone IP 20 mg 20.08 mg
(100.4%) 20.04mg
(100.2%) 20.10mg
(100.5%) 18.50 to 21.50 mg
92.5% to 107.5%
3 ? 8-14 triene dydrogesterone 0.06 0.06 0.06 NMT 0.5 %
4 Dydrogesterone Impurity A (6- Dehydrogesterone ) 0.05 0.04 0.04 NMT 0.5 %
5 Dydrogesterone Impurity B (17-@ Dydrogestrone) 0.09 0.08 0.08 NMT 0.5 %
6 Each unidentified degradation product 0.01 0.02 0.01 NMT 0.2 %
7 Total Impurity 0.22 0.20 0.19 NMT 1.0 %

Examples 3-7
S. No. Ingredient Qty/Tablet (mg)
Exp. 3 Exp. 4 Exp. 5 Exp. 6 Exp. 7
Dry Granulation (Compaction)
1 Dydrogesterone 20.00 20.00 20.00 20.00 20.00
2 Microcrystalline cellulose 106.00 85.00 - - 37.500
3 Lactose Monohydrate - - 125.00 75.00 37.500
5 Hydroxypropyl methylcellulose K4M 30.00 50.00 - 50.00 50.00
6 Xanthan Gum - - 10.00 10.00 10.00
7 Sodium bicarbonate 40.00 40.00 40.00 40.00 40.00
8 Citric acid 20.00 40.00 40.00 40.00 40.00
Pre-lubrication before compaction
9 Colloidal anhydrous silica 2.00 3.00 3.00 3.00 3.00
Lubrication before compaction
10 Magnesium stearate 3.00 2.00 2.00 2.00 2.00

Process:
1. All ingredients are weighed accurately.
2. All ingredients were sifted through appropriate sieves followed by mixing in a blender to get a blend.
3. Loaded the material of step 2 in a blender and mixed at suitable 10 RPM for 10 minutes to get a dry mix.
4. Pre-lubricated the dry mix for 10 minutes at 10 RPM with colloidal anhydrous silica to get a blend.
5. Lubricated the pre-lubricated blend of step 4 with magnesium stearate for 10 minutes at 10 RPM.
6. Compressed the lubricated blend into tablets.
7. Packed the tablets as per requirement.

Dissolution Study
The in vitro release study for the pharmaceutical composition disclosed in Example 5B, 6, 7, and 8 was carried out in 900 ml of 0.1N HCl containing 0.2% sodium lauryl sulfate, USP Type I apparatus at a speed of 100 RPM. The dissolution data is given in Table 1.

Table 1: Comparative Release Profile of Dydrogesterone SR Tablets 20 mg
Time (Hr.) 0.1 N HCl + 0.2% SLS; 900 mL, 100 RPM, USP I (Basket)
% Drug release (Example 4) % Drug release (Example 5) % Drug release (Example 6) % Drug release (Example 7)
1 34 37 25 51
2 51 55 35 77
4 64 74 47 95
6 70 82 56 97
8 73 87 63 99
10 75 91 71 101
12 77 93 77 102
16 79 95 86 103
20 80 97 91 104
24 83 98 96 105

Example 8-11
S. No. Ingredient Qty/Tablet (mg)
Dry Granulation (Compaction) Exp. 8 Exp. 9 Exp. 10 Exp. 11
1 Dydrogesterone 20.000 20.000 20.000 20.000
2 Microcrystalline cellulose 116.000 116.000 116.000 116.000
3 Hydroxypropyl methylcellulose K15M 20 - - -
3 Polyethylene oxide - 20.000 - -
4 Carbomer homopolymer 971P - - 20.000 -
5 Xanthan Gum - - - 20.000
6 Sodium bicarbonate 40.000 40.000 40.000 40.000
7 Citric acid 20.000 20.000 20.000 20.000
Pre-lubrication before compaction
8 Colloidal anhydrous silica 1.000 1.000 1.000 1.000
Lubrication before compaction
9 Magnesium stearate 1.000 1.000 1.000 1.000
Pre-Lubrication after compaction
10 Colloidal anhydrous silica 1.000 1.000 1.000 1.000
Lubrication after compaction
11 Magnesium stearate 2.000 2.000 2.000 2.000

Process:
1. Sifted Dydrogesterone, Microcrystalline cellulose and Hydroxypropyl methylcellulose /Carbomer/Polyethylene oxide/Xanthan gum, Sodium bicarbonate, citric acid through appropriate sieves followed by mixing in a blender to get a blend.
2. Separately sifted colloidal anhydrous silica through appropriate sieve and mixed with above blend.
3. Separately sifted Magnesium stearate through appropriate sieve and mixed with step 2.
4. Compacted to get sized granules.
5. Loaded the material of step 4 in a blender and mixed at suitable RPM to get a dry mix.
6. Pre-lubricated the dry mix with colloidal anhydrous silica to get a blend.
7. Lubricated the pre-lubricated blend of step 6 with magnesium stearate.
8. Compressed the lubricated blend into tablets.
9. Packed the tablets as per requirement.

Example 12
S. No. Ingredient Qty/Tablet
(mg)
Dry mix (Component-1) – Extended Release Component
1. Dydrogesterone 10.000
2. Lactose monohydrate 105.000
3. Hypromellose (K100M) 15.000
4. Hypromellose (K4M) 5.000
Pre-lubrication
5. Colloidal anhydrous silica 1.000
Lubrication
6. Magnesium stearate 2.000
Dry mix (Component-2) – Immediate Release Component
7. Dydrogesterone 10.000
8. Lactose monohydrate 50.000
Pre-lubrication
9. Colloidal anhydrous silica 1.000
Lubrication
10. Magnesium stearate 1.000
Film coating
11. Opadry white (YS-1-7040) 6.000
12. Isopropyl Alcohol q.s.
13. Methylene chloride q.s.
Coated tablet weight 206.000

Process:
(Component -1)
1. Sifted all the ingredients through appropriate sieves.
2. Added pre-sifted Dydrogesterone, Lactose monohydrate, Hypromellose
(K100M) and Hypromellose (K4M) in a suitable blender and mixed for suitable time.
3. Mixed the sifted silicon dioxide with step 2 in a suitable blender and mixed for suitable time. Added magnesium stearate to get Premix-1.
(Component -2)
4. Sifted all the ingredients through appropriate sieves.
5. Added pre-sifted Dydrogesterone and Lactose monohydrate in a suitable blender and mixed for suitable time.
6. Mixed the sifted silicon dioxide with step 5 in a suitable blender and mixed for suitable time. Added magnesium stearate and mixed again to get Premix-2.
7. Compressed the lubricated blend of step 3 and step 6 into bilayer tablets using suitable tools.
8. Took Isopropyl alcohol and added Opadry YS-1-7040 white under continuous stirring. Added methylene chloride (dichloromethane) under continuous stirring till homogeneous coating dispersion was obtained. Filtered the dispersion through 100 mesh nylon cloth and coated the tablets with the coating dispersion.
9. Packed the tablets in suitable packs as per the requirement.

Example 13
S. No. Ingredient Qty/Tablet
(mg)
Dry mix (Component-1) – Extended Release Layer
1. Dydrogesterone (Unmicronised)* 10.000
2. Lactose monohydrate (flowlac 90)# 105.000
3. Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) (Eudragit L100 55) 20.000
Pre-lubrication
4. Colloidal anhydrous silica 1.000
Lubrication
5. Magnesium stearate 2.000
Dry mix (Component-2) – Immediate Release Layer
6. Dydrogesterone (Unmicronised)* 10.000
7. Lactose monohydrate (flowlac 90)# 50.000
Pre-lubrication
8. Colloidal anhydrous silica 1.000
Lubrication
9. Magnesium stearate 1.000
Film coating
10. Opadry white (YS-1-7040) 6.000
11. Isopropyl Alcohol q.s.
12. Methylene chloride q.s.
Coated tablet weight 206.000

Process: The pharmaceutical composition was prepared by the process as described in Example 12.

Example 14
S. No. Ingredient Qty/Capsule
(mg)

1. Sugar Spheres 70.00
Drug Coated Pellets
2. Dydrogesterone (Unmicronised)* 20.00
3. Hydroxypropyl methylcellulose 30.00
4. Talc 6.80
5. Isopropyl Alcohol q.s
6. Water q.s.
Total Drug Pellets 126.80
Delayed Release (DR) Component
7. Drug coated pellets-1 63.40
8. Methacrylic Acid-Ethyl Acrylate Copolymer (1:1) (Eudragit L100 55) 4.500
9. Triethyl citrate 0.85
10. Talc 0.85
11. Water q.s.
Lubrication
12. Talc 1.20
Total Delayed Release Pellets 70.80
Immediate Release Component
13. Drug coated pellets-2 63.40
Film coating
14. Opadry white (YS-1-7040) 4.50
15. Isopropyl Alcohol q.s.
16. Methylene chloride q.s.
Lubrication
17. Talc 1.10
Total Immediate Release (IR) Pellets 69.00
Capsule filling (DR + IR) Pellets 139.80

Process:
(Drug Pellets)
1. Sifted all the ingredients through appropriate sieves.
2. Add Hydroxypropyl methylcellulose to purified water under continuous stirring. Allow to stir to form clear solution.
3. Add Dydrogestrone to Isopropyl and add to step 3 under continuous stirring. Allow it to stir.
4. Add talc to step 4 under continuous stirring. Allow it to stir.
5. Sift above dispersion of step 5 through suitable sieve.
6. Dispersion of step 5 was used for drug coating on sugar spheres using bottom spray technique.
7. Dry the drug coated pellets using bottom spray technique.
8. Sift the drug coated pellets from suitable sieves. Discard the retentions and fines and collect the pellets of suitable size.
(Delayed Release Component)
9. Add Triethyl citrate to purified Water under continuous stirring. Allow to stir to make solution.
10. Add Talc to above Solution under continuous stirring.
11. Add above dispersion to the Eudragit L30D55 dispersion under continuous stirring.
12. Sift above dispersion through suitable sieve.
13. Dispersion of step 12 was used to coat the previously drug coated pellets-1 of step 8, using bottom spray technique to obtain Delayed Release pellets.
14. Dry the Delayed Release pellets using bottom spray technique.
15. Sift the Delayed Release pellets from suitable sieves. Discard the retentions and fines and collect the pellets of suitable size.
16. Lubricate above Delayed Release pellets with talc.
(Immediate Release Component)
17. Coat the previously drug coated pellets-2 of step 8, with film coating of Opadry in Isopropyl Alcohol and Methylene Chloride using bottom spray technique.
18. Dry the Immediate Release pellets using bottom spray technique.
19. Sift the Immediate Release pellets from suitable sieves. Discard the retentions and fines and collect the pellets of suitable size.
20. Lubricate above Immediate Release pellets with talc.
(Capsule filling)
21. Filling the lubricated Delayed Release pellets of step 16 and Immediate Release pellets of step 20 in capsules.

WE CLAIM

1. An extended release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and one or more pharmaceutically acceptable excipients.

2. The extended release pharmaceutical composition as claimed in claim 1, wherein the composition further comprises floating agents selected from sodium carbonate, sodium bicarbonate, calcium carbonate, adipic acid, malic acid, tartaric acid, ascorbic acid, fumaric acid, maleic acid, succinic acid, sodium citrate, citric acid, combinations thereof.

3. The extended release pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition comprises from 10mg to 50mg of dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer in an amount from 5% to 50% by weight of total weight of the pharmaceutical composition and is selected from hydrophilic polymers, hydrophobic polymers, or combinations thereof, and wherein the total weight of the pharmaceutical composition is between 100 mg to 400mg.

4. The extended release pharmaceutical composition as claimed in claim 1, wherein the extended release pharmaceutical composition comprises a core comprising dydrogesterone or pharmaceutically acceptable salts thereof embedded in one or more extended release polymer.

5. The extended release pharmaceutical composition as claimed in claim 1, wherein the extended release pharmaceutical composition comprises a core comprising dydrogesterone or pharmaceutically acceptable salts thereof and wherein the core is coated with one or more extended release polymer.

6. The extended release pharmaceutical composition as claimed in claim 1, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D90 less than 100 microns.

7. The extended release pharmaceutical composition as claimed in claim 1, wherein the extended release composition releases less than 85% of dydrogesterone within 2 hours and not less than 75% of dydrogesterone is released within 16 hours.

8. The extended release pharmaceutical composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of diluents, binders, surfactants, glidants, disintegrants, lubricants, film forming polymers, coloring agents, opacifiers, plasticizers, or combinations thereof.

9. A process for preparing the extended release pharmaceutical composition as claimed in claim 1, wherein the process comprises: (a) blending dydrogesterone or pharmaceutically acceptable salts thereof, one or more extended release polymer, and optionally one or more floating agent to obtain a blend; (b) optionally granulating the blend; (c) lubricating the blend or granules; (c) compressing the lubricated blend or granules to form a tablet or filling the lubricated blend or granules in a capsule.

10. A process for preparing the extended release pharmaceutical composition as claimed in claim 1, wherein the process comprises: (a) preparing a core comprising dydrogesterone or pharmaceutically acceptable salts thereof and optionally one or more floating agents to obtain a blend; (b) coating the core with one or more extended release polymer or delayed release polymer; (c) compressing the coated core of step (b) to form a tablet or filling the lubricated blend or granules in a capsule.