CN118019524A

CN118019524A - Dydrogesterone sustained release pharmaceutical composition

Info

Publication number: CN118019524A
Application number: CN202280064294.7A
Authority: CN
Inventors: 奇尚·辛格; K·S·哈琳; 拉什米·兰根·潘达; 奇丹巴拉姆·穆图林加姆; 阿尼尔·库马尔
Original assignee: Manken Pharmaceutical Co ltd
Current assignee: Manken Pharmaceutical Co ltd
Priority date: 2021-09-24
Filing date: 2022-09-20
Publication date: 2024-05-10

Abstract

The invention relates to a slow-release pharmaceutical composition, comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, optionally one or more pharmaceutically acceptable excipients.

Description

Dydrogesterone sustained release pharmaceutical composition

Technical Field

Background

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

Dydrogesterone is a progestogenic drug for the treatment of irregular menstrual cycle duration or irregular menstrual occurrence and duration caused by progesterone deficiency. Furthermore, dydrogesterone, in combination with estrogenic substances, can be used for secondary amenorrhea associated with endogenous progesterone deficiency, dysfunctional uterine bleeding and postmenopausal disorders.

There are several known references describing different dydrogesterone compositions for the treatment of various diseases.

U.S. patent No.7,683,047 discloses a method of treating endometrial hyperplasia in a subject, the method comprising: continuously administering a first dose of a progestin drug to the subject for a first predetermined period of time; and continuously administering a second dose of a progestin drug to the subject for a second predetermined period of time.

U.S. patent publication No.20050020553 A1 discloses a method of inhibiting spontaneous or habitual abortion comprising administering to a female patient in need of such treatment an effective amount of at least one non-endogenous progestogenic compound from the beginning of the ovulatory period.

U.S. patent publication No.20110152840 A1 discloses a method of reducing the occurrence of premature labor, the method comprising: a pharmaceutical composition comprising a steroid hormone is administered to a pregnant female subject having no history of premature birth and one or more risk factors for premature birth.

U.S. patent publication No.20040202713A1 discloses a method of contraception comprising sequentially administering a plurality of dosage units containing a hormone composition to a female having fertility to provide the hormone composition in an amount effective to inhibit ovulation, wherein the hormone composition is a dydrogesterone component or a combination of an estrogen and a dydrogesterone component.

PCT patent publication No.2012055840A1 discloses a pharmaceutical composition comprising a hormonal agent, a biocompatible zinc salt and pharmaceutically acceptable excipients.

PCT patent publication No.2004019954A1 discloses an improved pharmaceutical formulation for administration to women in need of estrogen replacement, comprising a plurality of doses alternating with standard dose estrogen phases and ultra-low dose estrogen phases.

Russian patent No.2289409 discloses a method for rehabilitation after termination of pregnancy with a drug characterized in that on the first day of ovulation, the drug Multi-tabs-intensive is prescribed, 1 tablet per month, from day 16 to day 25, the prescribed drug Dafu Tong (Duphaston) is prescribed 10 mg 2 times per day.

The currently approved dydrogesterone formulation is an immediate release tablet. Patients need to take the dydrogesterone tablet twice a day, i.e. in the morning and evening. The patient may forget to take the dose correctly, i.e. in the morning or evening, which may lead to reduced patient compliance. In contrast, it is convenient for the patient to administer a single dose of the drug that releases the active ingredient over a longer period of time, rather than taking the single dose of the drug multiple times on a regular basis. In sustained release formulations, the dosage form continually provides a drug for absorption into the blood stream, replacing the amount of the dosage form that is eliminated as it passes through the gastrointestinal tract of the patient. In view of the above, it is therefore desirable to provide a sustained release pharmaceutical composition of dydrogesterone that is stable, bioavailable, has a desired release profile, and provides improved patient compliance. In addition, there is a need to develop a process for developing pharmaceutical compositions that is efficient and more economical.

Disclosure of Invention

The invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, and optionally one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, one or more floaters, and optionally one or more pharmaceutically acceptable excipients.

According to another aspect, the present invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, one or more floaters, and optionally one or more pharmaceutically acceptable excipients; wherein the one or more float agents are gas generating 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, or combinations thereof.

According to another aspect, the present invention provides a sustained release pharmaceutical composition comprising: 10mg to 50mg dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers in an amount of 5% to 50% by weight of the total weight of the pharmaceutical composition, and optionally one or more floaters; wherein the total weight of the pharmaceutical composition is between 100mg and 400 mg.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising:

(a) A drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, optionally one or more floaters, and one or more pharmaceutically acceptable excipients;

(b) A coating on the core comprising one or more film-forming polymers.

According to another aspect, the present invention provides a sustained release pharmaceutical composition comprising:

(a) A drug core comprising:

(i) A slow release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, optionally one or more floaters and one or more pharmaceutically acceptable excipients; and

(Ii) An immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients;

(b) A coating on the core, the coating comprising one or more film-forming polymers.

a) A drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof, optionally one or more floaters, and one or more pharmaceutically acceptable excipients; and

B) A coating on the drug core, the coating comprising one or more slow release polymers.

According to another aspect, the present invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation or wet granulation processes.

According to another aspect, the present invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, one or more floaters, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation or wet granulation processes.

According to another aspect, the present invention provides a method of preparing a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the method comprises:

(a) Mixing dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, and optionally one or more floaters to obtain a mixture;

(b) Optionally granulating the mixture;

(c) Lubricating the mixture or particles;

(d) The lubricated mixture or granules are compressed into tablets or filled into capsules.

(a) Preparing a drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof and optionally one or more floaters to obtain a mixture;

(b) Coating the drug core with one or more slow release polymers;

(c) Tabletting the coated drug core of step (b) to form tablets or filling the lubricated mixture or granules in capsules.

(a) A delayed release component comprising:

i) A drug core comprising dydrogesterone or a pharmaceutically acceptable salt 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 a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In another aspect of the present invention, there is provided a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers in an amount of 5 to 50% by weight of the total weight of the pharmaceutical composition, and optionally one or more floaters, wherein the pharmaceutical composition is bioequivalent to an immediate release tablet taken twice daily when taken orally once daily.

In another aspect, the invention provides a sustained release pharmaceutical composition comprising dydrogesterone, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₁₀ is less than 10 μm, D ₅₀ is less than 50 μm, and D ₉₀ is less than 100 μm.

Detailed Description

The invention relates to a slow-release pharmaceutical composition, comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, and optionally one or more pharmaceutically acceptable excipients.

The term "extended release" as used herein refers to the slow release of a drug over a period of time, which may extend from about 2 hours to about 24 hours or more. Sustained release includes, but is not limited to, sustained release (sustained release), controlled release (controlled release), delayed release (DELAYED RELEASE), or modified release forms (modified release form).

The terms "therapeutically effective amount" or "effective amount" are used interchangeably and are defined to mean the amount or quantity of active agent that is sufficient to elicit a perceptible biological response upon administration to a patient. It will be appreciated that the precise therapeutic dosage will depend on the age and condition of the patient, the nature of the condition to be treated, and will ultimately be at the discretion of the attendant physician.

The terms "composition," "solid oral composition," "dosage form," or "pharmaceutical composition" as used herein synonymously include: tablets, such as monolayer tablets, bilayer tablets, trilayer tablets, multilayer tablets, caplets (minitablets) tablets, minitablets (microtablets), capsules, tablets in tablets, tablets in capsules, minitablets in capsules, granules in capsules, pellets in capsules, powders, granules, extrudates, pellets, microbeads or spheres, suspensions or any other suitable dosage form for oral, parenteral, topical, transdermal, mucosal, nasal, buccal or sublingual administration to a patient, preferably oral administration.

The terms "pharmaceutically acceptable salt" or "salt" are used interchangeably in the context of the present invention. As used in the context of the present invention, "pharmaceutically acceptable salts" or "salts" refer to inorganic acids, and inorganic salts may further include alkali and alkaline earth metal salts.

The term "adjuvant" or "pharmaceutically acceptable adjuvant" refers to a pharmacologically inactive ingredient of a pharmaceutical product, such as diluents, disintegrants, carriers, etc. The adjuvants useful in preparing the dosage form are generally safe, non-toxic, and useful for veterinary and human pharmaceutical uses. References to adjuvants include one adjuvant and more than one adjuvant. Pharmaceutically acceptable excipients may include one or more pharmaceutically acceptable excipients selected from diluents/fillers, binders, surfactants, glidants, disintegrants, lubricants, film-forming polymers, colorants/colorants, opacifiers, plasticizers and/or combinations thereof.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein dydrogesterone or a pharmaceutically acceptable salt thereof is entrapped in one or more sustained release polymers.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising a drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the drug core is coated with one or more sustained release polymers.

Another aspect of the invention provides a sustained release pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition comprises from about 10mg to about 50mg dydrogesterone, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof.

In another aspect, the invention provides a sustained release pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition releases less than 85% of dydrogesterone within 2 hours, and releases no less than 75% of dydrogesterone within 16 hours.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₉₀ is less than 100 μm.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₅₀ is less than 50 μm and D ₉₀ is less than 100 μm.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₁₀ is less than 10 μm, D ₅₀ is less than 50 μm and D ₉₀ is less than 100 μm.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₉₀ is between 30 μm and 90 μm, preferably between 65 μm and 85 μm, more preferably between 70 μm and 85 μm.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₅₀ is between 10 μm and 40 μm, preferably between 15 μm and 25 μm, more preferably between 18 μm and 22 μm.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₁₀ is between 1 μm and 10 μm, preferably between 2.0 μm and 5 μm, more preferably between 1.8 μm and 3.0 μm.

Suitable fillers/diluents include, but are not limited to, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose (flowlac a), cellulose derivatives such as silicified microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silicon dioxide, sucrose or other sugars or sugar derivatives, dibasic calcium phosphate, dicalcium phosphate, low substituted hydroxypropylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, and combinations thereof. When present, the filler may be present in an amount of about 10% to about 80%, preferably about 20% to about 80% by weight of the pharmaceutical composition. In one embodiment, the diluent is microcrystalline cellulose in an amount of 40% to about 80% by weight of the pharmaceutical composition.

Suitable binders include, but are not limited to, microcrystalline cellulose, polyvinylpyrrolidone (PVP), such as PVPK30 or PVP 90F, polyethylene glycols (PEG), such as PEG 4000, hydroxypropyl methylcellulose, hydroxypropyl cellulose, both of which are preferably of medium to high viscosity, such as viscosity grades of 3 or 6cps, copovidone, pregelatinized starch, and combinations thereof. When present, the binder may be present in an amount of about 0.1% to about 20%, preferably about 0.5% to about 15%, such as 1% to 10% by weight of the pharmaceutical composition.

Suitable lubricants include, but are not limited to, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silicon dioxide, aluminum or calcium silicate, stearic acid, hydrogenated castor oil (cutina), PEG 4000-8000, talc, and combinations thereof. When present, the lubricant may be present in an amount of about 0.01% to about 10%, preferably about 0.1% to about 5% by weight of the pharmaceutical composition.

Suitable glidants include, but are not limited to, zinc stearate, colloidal silicon dioxide (e.g., aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc, and combinations thereof. When present, glidants may be used in an amount of about 0.01% to about 10%, preferably about 0.1% to about 5% by weight of the pharmaceutical composition.

Suitable disintegrants include, but are not limited to, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g., crospovidone, polyplasdone XL or kollidon CL), crosslinked carboxymethylcellulose sodium, carboxymethyl starch sodium (sodium starch glycolate), polacrilin potassium (polacrillinpotassium), low-substituted hydroxypropylcellulose, 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 is used in an amount of 0.01% to 15%, such as 0.05% to 12%, such as at least 0.1% to 10% by weight of the pharmaceutical composition.

Suitable plasticizers include, but are not limited to, propylene glycol, phthalates, polyethylene glycol, sebacates or citrates, such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate, triethyl citrate, acetyl tributyl citrate, polyethylene glycol.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the composition is free of binders, disintegrants, or both.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the at least one sustained 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 slow release polymers include, but are not limited to, hydrophilic or hydrophobic polymers, including polyvinyl acetate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, fatty acids, fatty acid esters, alkanols, waxes, xanthan gum, gellan gum, shellac, rosin, zein (zein in corn), povidone, kollidon SR (polyvinyl acetate and povidone), poly (meth) acrylate, polyethylene oxide, polyalkollidate, cellulose ether, xanthan gum, tragacanth gum, karaya gum (gum karaya), guar gum, acacia (acacia), gellan gum, carob gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, polyethylene oxide, carbomer homopolymer, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (e.g., HPMC K15M, HPMC K4M), carboxyvinyl polymer, polymeric gelatin, shellac, methacrylic acid copolymer C NF, cellulose phthalate butyrate, cellulose phthalate, polyvinyl acetate phthalate (PVAP), cellulose Acetate (CAP), cellulose Acetate (CAT) cellulose succinate, cellulose acetate (cmm), hydroxypropyl cellulose acetate, cellulose acetate (cas), hydroxypropyl cellulose acetate, hydroxypropyl cellulose (methyl acetate, cellulose acetate, hydroxypropyl cellulose (methyl cellulose acetate), hydroxypropyl cellulose (e), hydroxypropyl cellulose acetate, hydroxypropyl cellulose (e.g., methyl cellulose acetate, hydroxypropyl cellulose (C), hydroxypropyl cellulose acetate, hydroxypropyl cellulose (methyl cellulose acetate), hydroxypropyl cellulose (e), hydroxypropyl cellulose (C), hydroxypropyl cellulose (methyl cellulose acetate), hydroxypropyl cellulose (e), hydroxypropyl cellulose (methyl cellulose acetate), cellulose acetate (C), such as methyl acrylate, ethyl acrylate, methyl methacrylate, and/or copolymers of ethyl methacrylate with acrylic acid and methacrylic acid esters (Eudragit NE, eudragit RL, eudragit RS), carbomers (e.g., carbomer 971P), and the like. The polymer may be used in an amount of 0.1 to 50% by weight of the composition, preferably 10 to 50% by weight of the composition.

According to one embodiment, the sustained release pharmaceutical composition of the present invention comprises: dydrogesterone or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, and optionally one or more pharmaceutically acceptable excipients.

According to another embodiment, the sustained release pharmaceutical composition of the present invention comprises:

(a) A drug core comprising:

(i) A slow release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, hydroxypropyl methylcellulose, optionally one or more floating agents, and one or more pharmaceutically acceptable excipients, and

(Ii) An immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients;

(b) A coating on the drug core, wherein the coating comprises one or more film-forming polymers.

As used herein, "immediate release" refers to the immediate release of a drug, wherein a substantial portion (e.g., substantially all or all) of the pharmaceutically active ingredient is released in a relatively short period of time, such as within 1 hour, preferably within 30 minutes, after oral ingestion.

According to one embodiment, the sustained release pharmaceutical composition of the present invention is in a gastroretentive dosage form. Gastroretentive dosage forms may be swellable or buoyant, or a combination of both.

As used herein, a "floating-type gastroretentive formulation" has a bulk density less than gastric juice. Such dosage forms are "floating" in that they remain buoyant in the gastric fluid of the stomach for a target period of time. The floating dosage form is capable of remaining in the stomach while releasing the active agent. Prolonged gastric retention can improve bioavailability, reduce drug waste, and improve solubility of drugs that are poorly soluble in high pH environments. Gastric retentive delivery systems are designed to remain in the stomach and release their active ingredients for a prolonged period of time, enabling sustained and prolonged drug infusion into the upper part of the gastrointestinal tract (GI).

According to one embodiment, the present invention provides a sustained release pharmaceutical composition comprising: dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, one or more floaters, and optionally one or more pharmaceutically acceptable excipients.

Suitable floaters include, but are not limited to, 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 float produces CO ₂ independent of the individual's fed or fasted state. Sustained release compositions comprising a floating agent provide a gastroretentive dosage form having improved pharmacokinetic properties by retaining the dosage form in the stomach for a prolonged period of time.

As described above, in certain embodiments, the sustained release composition comprises a gas-generating floating agent, such as carbonates and bicarbonates, which generates CO ₂ in the presence of acidic gastric fluids, such as citric acid. In certain embodiments, the drug core further comprises an organic and/or inorganic acid that reacts with the carbonate in an aqueous environment, such as at neutral pH or slightly acidic pH, and generates CO ₂ gas. In other embodiments, the sustained release compositions of the present invention comprising at least one floating agent are stable and provide for the effective delivery of dydrogesterone in the gastrointestinal tract due to the presence of water soluble polymers such as polyethylene oxide, xanthan gum, hydroxypropyl cellulose, carbomers, cross-linked polyvinyl alcohol (PVA), cross-linked polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), polylactic acid (PLA), polyglycolic acid (PGA), polyacrylic acid, tragacanth, methylcellulose, pectin, guar gum, karaya gum, carob gum, and the like, which swells by absorbing water in gastric fluid to (1) increase the size of the composition to promote gastric retention, (2) partially control the release of the drug by encapsulating the drug in the swelled polymer, (3) support the membrane and maintain the integrity of the composition in the swelled state by seal coating and/or by starting at the periphery of the drug composition, and (4) provide buoyancy by encapsulating generated gases (e.g., CO ₂). In other embodiments, the sustained release composition comprises both a gas generant and a water-swellable polymer. In certain embodiments, the sustained-release gastroretentive dosage forms of the present disclosure provide controlled sustained release of the active agent for about 8-16 hours (e.g., about 12 hours) under fed and fasted conditions.

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

According to another embodiment, the present invention provides a sustained release pharmaceutical composition comprising:

(a) A drug core comprising:

(i) A slow release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers, optionally one or more floaters, and one or more pharmaceutically acceptable excipients, and

a) A drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof, optionally one or more floaters, and one or more pharmaceutically acceptable excipients, and

B) A coating on the drug core, wherein the coating comprises one or more slow release polymers.

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

The term "delayed release" as used herein refers to a delay or 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 invention comprises:

B) A coating on the drug core, wherein the coating comprises one or more delayed release polymers.

The "delayed release polymer" is selected such that when the dosage form reaches the small intestine or region of pH greater than 4.5, the therapeutically active agent will be released. Preferred coatings include pH sensitive materials that remain intact in the lower pH environment of the stomach, but disintegrate or dissolve at the pH values common in the patient's small intestine. The delayed release polymer coating material begins to dissolve in an aqueous solution having a pH above 4.5. The pH-solubility behavior of the delayed release polymer of the present invention is such that the delayed release polymer coating does not dissolve significantly before the dosage form is emptied from the stomach. The pH of the small intestine increases gradually from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distal portion of the small intestine (ileum). The lag time between administration and onset of release can be varied by varying the coating material or the amount of coating applied.

Suitable delayed release polymers include, but are not limited to, pH-dependent enteric polymers such as Eudragits, methacrylates, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl methacrylate copolymers, partially neutralized (meth) acrylate copolymers, cellulose phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol-polyethylene glycol graft copolymersVinyl acetate-vinylpyrrolidone copolymer (/ >VA 64), cellulose acetate phthalate, eudragit L, eudragit S,L 100-55、/>L30D-55, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose acetate trimellitate or shellac.

According to one embodiment, the present invention provides a sustained release pharmaceutical composition comprising:

(a) Delayed release component: comprises dydrogesterone or a pharmaceutically acceptable salt thereof, one or more delayed release polymers, and optionally one or more pharmaceutically acceptable excipients, and

According to one embodiment, the sustained release pharmaceutical composition of the present invention comprises:

(a) A delayed release component comprising:

i) A drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients,

Ii) a delayed release layer comprising one or more delayed release polymers,

And

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

According to another embodiment, the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more sustained release polymers, optionally one or more floaters, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is prepared by direct compression, dry granulation, wet granulation, melt granulation or extrusion processes.

According to another aspect, the present invention provides a method of preparing a dydrogesterone sustained release pharmaceutical composition, wherein the method comprises:

(a) Preparing a slow release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers and optionally one or more floaters;

(b) Preparing an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and optionally one or more floating agents;

(c) Pressing the components (a) and (b) to form a bilayer tablet or filling the components (a) and (b) in a capsule.

(a) Preparing a delayed release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more delayed release polymers and optionally one or more pharmaceutically acceptable excipients;

(b) Preparing an immediate release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients;

Another aspect of the invention provides a sustained release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more sustained release polymers in an amount of 5% to 50% by weight based on the total weight of the pharmaceutical composition, and optionally one or more floaters, wherein the total weight of the pharmaceutical composition is between 100mg and 400mg, and the pharmaceutical composition is bioequivalent to an immediate release tablet taken twice daily when taken once daily.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone, wherein the sustained release can be achieved by one or more coatings or embedding in a matrix using hydrophilic or hydrophobic polymers, or by attachment to ion exchange resins. In addition, slow release can be achieved by osmotic oral release techniques.

According to another embodiment, the sustained release pharmaceutical composition of the present invention further comprises a surfactant. Such surfactants include, but are not limited to, anionic, cationic, nonionic, amphoteric, or surfactants known to those skilled in the art. Suitable surface-active substances are poloxamer 188, polysorbate 80, cremophore, soluplus, lecithin and sodium lauryl sulfate.

The pharmaceutical composition of the present invention is stable. The term "stable or stable" means that the dosage form is stable at 40 ℃/75% rh and/or 30 ℃/75% rh for at least six (06) months. In addition, after storage at 40 ℃/75% rh and/or 30 ℃/75% rh for at least six (06) months, the total impurities in the dosage form do not exceed 5%. No single impurity in the dosage form exceeds 0.5% after storage at 40 ℃/75% rh and/or 30 ℃/75% rh for at least six (06) months.

Another embodiment of the present invention provides a sustained release pharmaceutical composition comprising dydrogesterone, wherein the composition is used for treating irregular menstrual cycle duration or irregular menstrual occurrence and duration caused by a progesterone deficiency. In addition, the compositions are also used in combination with estrogenic substances for secondary amenorrhea, dysfunctional uterine bleeding and postmenopausal disorders associated with endogenous progesterone deficiency.

The invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not intended to 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:

The process comprises the following steps:

(a) Dispensing, sieving and mixing dydrogesterone, slow release polymer and one or more pharmaceutically acceptable auxiliary materials.

(B) Lubricating the mixture from step (a) with a lubricant.

(C) The lubricated mixture is pressed with a suitable punch and die.

(D) Coating the pressed mixture obtained in step (c) with a coating liquid.

Dissolution study

In vitro release studies of the pharmaceutical compositions disclosed in example 1 and example 2 were performed in 900mL of 0.2% aqueous sodium dodecyl sulfate, type II USP apparatus at speed 50 RPM. The dissolution data are shown in table 1.

Table 1: release profile of dydrogesterone SR tablet 20mg

The tablets prepared according to example 3 show stability over 3 months. The stability data for the tablets are shown in table 2 below:

Table 2: stability data for dydrogesterone tablets (example 2)

Examples 3 to 7

The process comprises the following steps:

1. All ingredients were accurately weighed.

2. All ingredients were screened through a suitable screen and then mixed in a blender to obtain a mixture.

3. The materials from step2 were placed in a stirrer and mixed for 10 minutes at a suitable speed of 10RPM to obtain a dry mix.

4. The dry blend was pre-lubricated with anhydrous colloidal silica at 10RPM for 10 minutes to obtain a mixture.

5. The pre-lubrication mixture of step 4 was lubricated with magnesium stearate at a speed of 10RPM for 10 minutes.

6. The lubricated mixture is pressed into tablets.

7. And (5) packaging the tablets as required.

Dissolution study

In vitro release studies of the pharmaceutical compositions disclosed in examples 5B, 6,7 and 8 were performed in 900ml of 0.1N HCl containing 0.2% sodium dodecyl sulfate in a type USPI device at 100 RPM. The dissolution data are shown in table 1.

Table 1: comparative Release Curve of dydrogesterone SR tablet 20mg

Examples 8 to 11

The process comprises the following steps:

1. the dydrogesterone, microcrystalline cellulose and hydroxypropyl methylcellulose/carbomer/polyethylene oxide/xanthan gum, sodium bicarbonate, citric acid are sieved through a suitable sieve and then mixed in a blender to give a mixture.

2. The anhydrous colloidal silica is separately sieved through a suitable sieve and mixed with the above mixture.

3. The magnesium stearate is separately sieved through a suitable sieve and mixed with the step 2 material.

4. Compacting to obtain particles of a certain size.

5. The material of step4 is charged into a mixer and mixed at a suitable RPM to obtain a dry mix.

6. The dry mix was pre-lubricated with anhydrous colloidal silica to obtain a mixture.

7. The pre-lubricated mixture of step 6 was lubricated with magnesium stearate.

8. The lubricated mixture is compressed into tablets.

9. And (5) packaging the tablets as required.

Example 12

The process comprises the following steps:

(component-1)

1. All ingredients were sieved through a suitable sieve.

2. The pre-screened dydrogesterone, lactose monohydrate, hypromellose (K100M) and hypromellose (K4M) were added to a suitable mixer and mixed for the appropriate time.

3. The sieved silica is mixed with the material of step 2 in a suitable mixer and for a suitable time. Magnesium stearate was added to give premix-1.

(Component-2)

4. All ingredients were sieved through a suitable sieve.

5. The pre-screened dydrogesterone and lactose monohydrate are added to a suitable mixer and mixed for an appropriate period of time.

6. The sieved silica is mixed with the mass of step 5 in a suitable mixer and for a suitable time. Magnesium stearate was added and mixed again to give premix-2.

7. The lubricated blend of steps 3 and 6 was compressed into bilayer tablets using a suitable tool.

8. Isopropanol was taken and the opadry YS-1-7040 white was added with continuous stirring. Dichloromethane was added with continuous stirring until a uniform coating dispersion was obtained. The dispersion was filtered through 100 mesh nylon cloth and the tablets were coated with the coating dispersion.

9. The tablets are packaged in suitable packages as required.

Example 13

The process comprises the following steps: a pharmaceutical composition was prepared using the procedure described in example 12.

Example 14

The process comprises the following steps:

(drug pellets)

1. All ingredients were sieved through a suitable sieve.

2. Hydroxypropyl methylcellulose was added to the purified water with continuous stirring and allowed to stir until a clear solution formed.

3. Dydrogesterone was added to the isopropyl and added to the mass of step 3 with continuous stirring, allowing it to stir.

4. Talc was added to the material of step4 with continuous stirring and allowed to stir.

5. The dispersion of step 5 above was sieved through a suitable sieve.

6. The dispersion of step 5 was used to coat the drug on the spherical sucrose using a bottom spray technique.

7. The drug coated pellets were dried using bottom spray technique.

8. The drug coated pellets are sieved from a suitable sieve. The residue and fines were discarded and the appropriate size pellets were collected.

(Delayed release drug component)

9. Triethyl citrate was added to purified water under continuous stirring and stirred to prepare a solution.

10. Talc was added to the above solution with continuous stirring.

11. The above dispersion was added to the Eudragit L30D55 dispersion with continuous stirring.

12. The dispersion is sieved through a suitable sieve.

13. Coating the pre-drug coated pellets-1 of step 8 with the dispersion of step 12, and obtaining delayed release pellets using a bottom spray technique.

14. And drying the delayed release pellets by using a bottom spraying technology.

15. The delayed release pellets are sieved from a suitable sieve. The residue and fines were discarded and the appropriate size pellets were collected.

16. Lubricating the delayed release pellet with pulvis Talci.

(Immediate release component)

17. A film coating of a solution of opadry isopropanol and dichloromethane was applied to the pre-drug coated pellet-2 of step 8 using a bottom spray technique.

18. And drying the quick-release pellets by using a bottom spraying technology.

19. The immediate release pellets are sieved from a suitable sieve. The residue and fines were discarded and the appropriate size pellets were collected.

20. Lubricating the quick-release pellets with talcum powder.

(Capsule filling)

21. The lubricated delayed release pellets of step 16 and the immediate release pellets of step 20 are filled in capsules.

Claims

1. A sustained release pharmaceutical composition comprising: dydrogesterone or pharmaceutically acceptable salts thereof, one or more slow release polymers, and one or more pharmaceutically acceptable auxiliary materials.

2. The extended release pharmaceutical composition of claim 1, wherein the composition further comprises a floating 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, and combinations thereof.

3. The extended release pharmaceutical composition according to any one of the preceding claims 1 or 2, wherein the pharmaceutical composition comprises: 10mg to 50mg dydrogesterone or a pharmaceutically acceptable salt thereof, one or more slow release polymers in an amount of 5% to 50% by weight of the total weight of the pharmaceutical composition, and selected from hydrophilic polymers, hydrophobic polymers or combinations thereof; and wherein the total weight of the pharmaceutical composition is between 100mg and 400 mg.

4. A slow release pharmaceutical composition according to any one of the preceding claims 1 to 3 wherein the ratio of slow release polymer to floating agent is 1:1 to 1:10.

5. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 4, wherein the extended release polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, xanthan gum, carbomer, polyethylene oxide, polyvinyl acetate, cellulose acetate butyrate, cellulose acetate propionate, ethylcellulose, xanthan gum, gellan gum, povidone, gellan gum, hydroxyethyl cellulose, carboxyvinyl polymer, cellulose phthalate butyrate, hydrogen cellulose phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methylcellulose acetate succinate, acrylic polymers and copolymers, or combinations thereof.

6. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 5, wherein the extended release pharmaceutical composition comprises a drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof embedded in one or more extended release polymers.

7. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 6, wherein the extended release pharmaceutical composition comprises a drug core comprising dydrogesterone or a pharmaceutically acceptable salt thereof, and wherein the drug core is coated with one or more extended release polymers.

8. The extended release pharmaceutical composition according to any one of the preceding claims i to 7, wherein the extended release pharmaceutical composition comprises:

(a) A drug core comprising:

(i) A sustained release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more sustained release polymers and one or more pharmaceutically acceptable excipients; and

9. The extended release pharmaceutical composition according to any one of the preceding claims l to 8, wherein the extended release pharmaceutical composition comprises:

(a) A delayed release component comprising dydrogesterone or a pharmaceutically acceptable salt thereof, one or more delayed release polymers, and optionally one or more pharmaceutically acceptable excipients; and

10. The extended release pharmaceutical composition according to claim 9, wherein the extended release polymer is selected from the group consisting of methacrylates, methacrylic acid-methyl methacrylate copolymers, methacrylic acid-ethyl methacrylate copolymers, partially neutralized (meth) acrylate copolymers, cellulose phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol-polyethylene glycol graft copolymers, vinyl acetate-vinyl pyrrolidone copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac, or combinations thereof.

11. A slow release pharmaceutical composition according to any one of the preceding claims 1 to 10, wherein the dydrogesterone or a pharmaceutically acceptable salt thereof has a particle size of: d ₉₀ is less than 100 μm.

12. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 11, wherein the extended release pharmaceutical composition releases less than 85% of dydrogesterone within 2 hours and releases not less than 75% of dydrogesterone within 16 hours.

13. A sustained release pharmaceutical composition according to any one of the preceding claims 1 to 12 wherein the one or more pharmaceutically acceptable excipients are selected from diluents, binders, surfactants, glidants, disintegrants, lubricants, film-forming polymers, colorants, opacifiers, plasticizers or combinations thereof.

14. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 13, wherein the extended release pharmaceutical composition comprises dydrogesterone or a pharmaceutically acceptable salt thereof, wherein the composition is free of binders or disintegrants, or neither.

15. The extended release pharmaceutical composition according to any one of the preceding claims 1 to 14, wherein the pharmaceutical composition is bioequivalent to an immediate release tablet taken twice a day when taken orally once a day.

16. A process for preparing a sustained release pharmaceutical composition according to any of the preceding claims 1 to 15, wherein the process comprises:

(b) Optionally granulating the mixture;

(c) Lubricating the mixture or particles;

(c) The lubricated mixture or granules are compressed into tablets or filled into capsules.

17. A process for preparing a sustained release pharmaceutical composition according to any of the preceding claims 1 to 16, wherein the process comprises:

(b) Coating the core with one or more slow release polymers or delayed release polymers;