DESC:VAGINAL TABLETS OF DYDROGESTERONE

FIELD OF THE INVENTION

The invention relates to a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, along with 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 tablet of dydrogesterone, which are used in the treatment of various diseases.

Dydrogesterone is also known for the treatment of progesterone deficiency such as treatment of threatened abortion and pre-eclampsia. Threatened abortion is defined as pregnancy-related bloody vaginal discharge or frank bleeding during the first half of pregnancy without cervical dilatation. Nearly 25 percent of pregnant women have some degree of vaginal bleeding during the first two trimesters and about 50 percent of these progress to an actual abortion. It is associated with an increased risk of poor obstetric outcomes such as preterm labour, low birth weight, and premature rupture of membranes. It is observed that dydrogesterone was consistently more effective than standard supportive care or placebo, and demonstrated a positive trend towards being more effective than vaginal micronized progesterone in the management of threatened miscarriage. Dydrogesterone helps in relieving lower back pain, abdominal pain, and haemostasis in the threatened abortion, Female infertility, Pain during menstruation, Premenstrual syndrome (PMS), Endometriosis, Heavy menstrual bleeding, pre-eclampsia.

Solid oral formulations of dydrogesterone are known in the art. However, because of the slow gastrointestinal absorption and high hepatic metabolism of dydrogesterone, achieving the desired plasma levels is often slowed, reduced, or is irregular with oral administration. The tablets for insertion into vagina successfully bypass the first-pass effect and provides targeted vaginal delivery that is safe and effective, however, there is currently no commercially available formulation of dydrogesterone for vaginal administration. There is therefore a strong felt need in the art for formulations of dydrogesterone for vaginal use. After extensive experimentation and lots of efforts, the inventors have developed vaginal tablets of dydrogesterone for insertion into vagina which are optimal, stable, safe, and efficacious.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a pharmaceutical composition comprising dispersible tablet of dydrogesterone with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provides a vaginal table of dydrogesterone for the insertion in to vagina, wherein the said tablet further comprises one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provides process of preparation of a pharmaceutical composition of dydrogesterone along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provides a dispersible tablet of dydrogesterone and one more pharmaceutically acceptable excipient, wherein the said tablet is administered for treatment of lower back pain, abdominal pain, and haemostasis in the threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, pre-eclampsia.

SUMMARY OF THE INVENTION

The present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet comprises from about 5 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

According to another aspect, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet comprises about 10 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

According to one aspect, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients selected from the group consisting of diluent(s), disintegrant(s), binder(s), lubricant(s), glidant(s), pH modifier(s), preservative(s), anti-microbial(s), and anti-oxidant(s), or a combination thereof, wherein said vaginal tablet comprises from about 10 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

According to another aspect, the present invention provides a vaginal tablet for insertion into vagina comprising about 5 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof; wherein the vaginal tablet comprises:
1 – 95 % w/w diluent(s),
1 - 50% w/w of disintegrant(s), and
0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet.

According to another aspect, the vaginal tablet of the present invention is a dispersible tablet.

According to another aspect, the present invention provides a dispersible vaginal tablet for insertion into vagina comprising about 10 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof; wherein the vaginal tablet comprises:
25 - 85% w/w diluent(s),
5 - 25% w/w of disintegrant(s),
1 - 10% w/w of binder(s),
0.05 - 5% w/w of pH modifier(s),
0.05-20% w/w of buffering agent(s), and
0.5 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet and optionally a film-coating.

According to another aspect, the present invention provides vaginal tablet for insertion into vagina comprising: (a) a core comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, and (b) optionally, a coating over said core, wherein said coating comprises one or more film forming polymers.

According to one more aspect, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients; wherein the tablet is prepared by direct compression, dry granulation, wet granulation, melt granulation, or melt extrusion process.

According to another aspect, the present invention provides a process for preparation of a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein said process comprises: (a) blending dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients to obtain a blend; (b) optionally granulating and lubricating the blend; (c) compressing the blend or granules to form a tablet.

According to one more aspect, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients; wherein the tablet is administered for treatment of lower back pain, abdominal pain, and haemostasis in the threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, pre-eclampsia.

The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description.

DETAIL DESCRIPTION OF THE INVENTION

The present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients.

As used in this specification, the singular forms “a”, “an”, and “the” include plural references unless the context dictates otherwise. Thus, for example, a reference to “a method” or “a process” includes one or more methods, one or more processes, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

As used herein the term “about” in reference to a numerical value means that variations of 10% above or below the numerical value are within the range described to the specified value.

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, the nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “composition” or “pharmaceutical composition” or “dosage form” or “pharmaceutical formulation” or “formulation” as used herein synonymously include the pharmaceutical compositions in a form suitable for vaginal administration such as but not limited to tablet, dispersible tablet, fast disintegrating tablet, suppository or the like or any other suitable dosage form meant for vaginal administration.

The term “pharmaceutically acceptable” refers to what is physiologically well tolerated by mammals or humans.

In one embodiment vaginal tablet of the present invention is a dispersible tablet or a disintegrating tablet, in particular quick or fast dispersible or disintegrating. The present invention has the advantages that when the quick dispersible or disintegrating tablet in vagina comes in contact with vaginal secretions such tablets quickly disintegrate, disperse or dissolve in vagina; the drug becomes immediately available for action/effect and is absorbed by vaginal mucous membranes to have local treatment action; after that drug enters systemic circulation to produce systemic effect. The application or insertion is convenient without the need of special auxiliary appliances; uncomfortableness is little; the medicine does not spill out of vaginas, the medication is correct, and the compliance of patients is favorable. The preparation method is easy and practical, and the preparing cost is low.

The vaginal tablets of the present invention are fabricated in way that helps them disintegrate, disperse or dissolve in a low volume or amount of vaginal secretions that is available in vagina as compared to oral administration.

The vaginal tablet can have different shapes that facilitates its easy insertion into vagina such as oblong, oval, capsular, circular, diamond, cylindrical, torpedo shaped, bullet shaped and the like.

The “dispersible or disintegrating tablet” as used herein refers to tablet that rapidly or quickly disperses or disintegrates in the vaginal cavity to form a suspension or a solution for example within 10 minutes, preferably within 5 minutes and more preferably within 3 minutes, after insertion into vagina.

The term “impurity A” or “dydrogesterone impurity A” means an impurity with IUPAC name is 9ß, 10a-pregna-4,6, 8-(14)-triene-3, 20-dione. The structure is as follows:

The term “impurity B” or “dydrogesterone impurity B” means an impurity with IUPAC name is pregna-4,6-diene-3, 20-dione. The structure is as follows:

The term “impurity C” or “dydrogesterone impurity C” means an impurity with IUPAC name is 9ß, 10a, 17a-pregna-4,6-diene-3, 20-dione. The structure is as follows:

According to one embodiment, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet comprises from about 5 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

In a preferred embodiment, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet comprises about 10 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

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 such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further include alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like. The term “pharmaceutically acceptable esters” or “esters” is used interchangeably in the context of the present invention.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent(s), disintegrant(s), binder(s), and the like, of a pharmaceutical product. The excipients that are useful in preparing a dosage 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 and are selected from the group comprising of diluent/filler(s), binder(s), surfactant(s), glidant(s), disintegrant(s), pH modifier(s), preservative(s), anti-microbial(s), lubricant(s), anti-oxidant(s), film forming polymer(s), coloring agent/colorant(s), opacifier(s), plasticizer(s) and/or combinations thereof.

Suitable buffering agents include, without limitation, adipic acid, sodium bicarbonate, benzoic acid, sodium meta bisulfite, phosphates, such as sodium phosphate monobasic, sodium phosphate dibasic, phosphoric acid, citric acid, citrates such as sodium citrate, borate, acetic acid, acetates such as sodium acetate, lactic acid, sodium lactate, tartaric acid, sodium tartrate, tartrates, succinates, amino acids such as L-arginine, tromethamine and/or combinations/mixtures thereof.

Suitable stabilizers used for stabilization includes sodium alginate, zinc acetate, ascorbic acid, calcium acetate, Butylated hydroxyanisole, Butylated hydroxytoluene PVP (Povidone), PVA (Polyvinyl alcohol), PEG (Polyethylene glycol), HPMC (Hypromellose), HPC (Hydroxypropyl cellulose), HEC (Hydroxyethyl cellulose), NaCMC (Carboxymethylcellulose sodium), SD (Docusate sodium), SLS (Sodium lauryl sulfate), PEI (Polyehtylene imine), TPGS (D- a - tocopheryl polyethylene glycol succinate), PEO (Polyethylene oxide), PPO (Polypropylene oxide) and/or combinations/mixtures thereof.

Suitable diluent(s) include, without limitation, organic and inorganic diluents such as celluloses and cellulose derivatives, starches and modified starches, polyols, carbohydrates, inorganic phosphates, carbonates, silicates, sulfates etc. In particular, microcrystalline cellulose, silicified microcrystalline cellulose, polyols and sugar alcohols selected from but not limited to alditols, mannitol, D-mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, glycerol, and the like; Carbohydrate selected from but not limited to monosaccharides, oligosaccharides polysaccharides, dextrins, maltodextrin, pullulan, arabinose, dextrose, dextrates, lactose, sucrose, sucralose, saccharin, fructose, maltose, trehalose, psicose, tagatose, sorbose, cellulose derivatives, cellobiose, starches, modified starches, sucrose fatty acid esters, and the like; inorganic diluents selected from but not limited to dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, kaolin, calcium sulfate, and the like; or combinations thereof. Diluents may include co-processed excipients such as microcrystalline cellulose and colloidal silicon dioxide (Prosolve SMCC), D-mannitol and starch (Pearlitol® Flash), lactose and microcrystalline cellulose (Cellactose®), D-mannitol, xylitol, microcrystalline cellulose, Crospovidone, dibasic calcium phosphate anhydrous (F-MELT®, Fujicalin®, Neusilin®) in its tablet. When present, a diluent may be employed in an amount ranging from about 1% to about 95% by weight of the tablet, preferably from about 25% to about 85% by weight of the tablet. According to one embodiment, the filler or diluent used in present invention includes microcrystalline cellulose or lactose.

Suitable binder(s) include, without limitation, natural and synthetic polymers, natural and synthetic gums, hydrocolloids, celluloses and cellulose derivatives, starches and modified starches, carbohydrates, vinyl polymers etc. In particular, polyvinylpyrrolidone (PVP), e.g., PVP K30 or PVP K90, polyvinyl acetate, polyvinyl alcohol, polyethylene glycols (PEG), e.g., PEG 400, PEG 4000, PEG 6000, copolymers of PEG, polyvinyl alcohol, polyvinylacetate, and PVP, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, copovidone, maltodextrins, pregelatinized starch, microcrystalline cellulose, acacia, alginic acid, tragacanth, gelatin, liquid glucose, corn starch, sugars, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium alginate, used either alone or combinations. When present, a binder may be employed in an amount ranging from about 1% to about 20%, preferably from about 1% to about 10% by weight of the tablet. In one embodiment, the binder is polyvinylpyrrolidone (PVP) and is in an amount ranging from 1.0% to 5.0%, by weight of total weight of the tablet.

Suitable disintegrants include, without limitation, natural and synthetic polymers, natural and synthetic gums, celluloses and cellulose derivatives, starches and modified starches etc., 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, maize (corn) starch and guar gum, and/or combinations thereof. In an embodiment, the tablets of present invention employs higher amount of disintegrant(s). The disintegrant is employed in an amount ranging from 1.0% to 50% by weight of the vaginal tablet. In one embodiment, the disintegrant is croscarmellose sodium and is employed in an amount of 5% to 25% by weight of the tablet.

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 5.0%, by weight of the vaginal tablet. In one embodiment, the lubricant is preferably magnesium stearate and is in an amount ranging from 0.5% - 2.5% by weight of total weight of the tablet.

Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (colloidal anhydrous silica), 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 tablet. In one embodiment, the glidant is preferably colloidal silicon dioxide and is in an amount ranging from 0.5% - 2.5% by weight of total weight of the tablet.

The tablets of the present invention may include a preservative or anti-microbial that inhibits the growth of microorganisms such as bacteria and fungi (molds and yeast) in the vagina. Suitable preservatives or anti-microbials include, without limitation, benzalkonium chloride (BAC), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, benzyl alcohol, ethanol, phenylmercury nitrate, phenylmercury acetate, thiomerosal, merthiolate, phenylmercuryborate, methylparaben, propylparaben, sorbic acid, boric acid, sodium borate, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl-p-hydroxybenzoate, chlorobutanol, polyquaternary ammonium compounds, ascorbic acid, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), benzoic acid, citric acid, edetic acid, parabens, phenol, propyl gallate, sodium bisulfite, sodium sulfite, chlorocresol, cresol, dehydroacetic acid, phenol, potassium benzoate, potassium sorbate, sodium dehydroacetate, sodium propionate, thymol, butylparaben, ethylparaben, methylparaben, methylparaben sodium, propylparaben, propylparaben sodium, thimerosal and the various salt forms for these compounds, or combinations thereof. When present, the preservative(s) may be used in an amount of about 0.0001% to about 5.0% by weight of total weight of the tablet.

Suitable antioxidants includes, without limitation, sodium thiosulfate, sodium bisulfite, acetone sodium bisulfite, gentisic acid, gentisic acid ethanolamide, sodium formaldehyde sulfoxylate, thiourea, butylated hydroxyanisole, butylated hydroxy toluene, esters of gallic acid, ascorbic acid, salts of ascorbic acids such as ascorbyl palmitate, tartaric acid, citric acid, fumaric acid, malic acid, sodium ascorbate, retinoids and derivatives of vitamin A, acetylcysteine, thioglycerol, sodium metabisufite, sodium sulphite, sodium pyrosulphate, methionine, glutamine, thiamine, propyl gallate, vitamin C, lutein, beta-carotene, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof

Suitable pH modifier(s) include, without limitation, an acid selected from an organic or inorganic acid such as ascorbic acid, fumaric acid, citric acid, malic acid, succinic acid, adipic acid, maleic acid, lactic acid, sorbic acid, boric acid, sodium borate, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and the like or a base selected from organic bases such as pyridine, alkanamines, such as methylamine, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, pyridine, imidazole, histidine, guanidine, poly ethyleneimine, poly(vinylpyridine), diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane (Tris), sodium glycine, 1-methylimidazole, 2-methylimidazole, and 4(5)-methylimidazole, and 1,2-diaminoethane, 2-(bis(2-hydroxyethyl)amino)-2-(hydroxymethyl)propane-1,3-diol, sodium lysine, sodium histidine, and sodium arginine, polyvinyl imidazole, and copolymers thereof (e.g., a copolymer of poly ethyleneimine and one or more of poly(vinylpyridine) and polyvinylimidazole, or a copolymer of poly(vinylpyridine) with polyvinyl imidazole) or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium citrate, sodium hydroxide, potassium hydroxide, ammonium salts, and the like. In one embodiment, the pH modifier is preferably sorbic acid and is employed in an amount ranging from 0.05% - 1.0% by weight of total weight of the tablet.

In one embodiment, the vaginal tablet is a suppository or a melting tablet that comprises suppository bases that melt at body temperature such as hydrophobic bases, oleaginous or hydrocarbon bases, absorption bases, water removable base and water-soluble base and mixture thereof.

Suitable hydrophobic base(s) include but are not limited to Hydrocarbons such as waxes such as bees wax, carnauba wax etc., petrolatum, paraffins, fatty acids, hard fats, semi-synthetic or synthetic fatty acid glycerides, cocoa butter, Theobroma glycerides, cocoa butter substitutes (primarily vegetable fats), glycerinated gelatin, polyethylene glycols and mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol, such as Witepsol® H-5, Witepsol® H-15 and Witepsol® H-35

According to another aspect, the present invention provides a vaginal tablet for insertion into vagina comprising about 5 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof; wherein the vaginal tablet comprises:
1 – 95 % w/w diluent(s),
1 - 50% w/w of disintegrant(s), and
0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet.

According to another aspect, the present invention provides a dispersible tablet for insertion into vagina comprising about 5 mg to about 40mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof; wherein the vaginal tablet comprises:
25 – 85 % w/w diluent(s),
5- 25% w/w of disintegrant(s),
1 - 10% w/w of binder(s),
0.05 - 5% w/w of pH modifier(s),
0.05-20% w/w of buffering agent(s),
0.5 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet, and
optionally a film-coating.

According to another embodiment, the present invention provides a vaginal tablet for insertion into vagina comprising: (a) a core comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, and (b) optionally, a coating over said core, wherein said coating comprises one or more film forming polymers.

In a specific embodiment, the present invention provides a dispersible vaginal tablet for insertion into vagina comprising about 10 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein said tablet further comprises:
microcrystalline cellulose in an amount of 50%-85% by weight of total weight of the vaginal tablet;
croscarmellose sodium in an amount of 10%-20% by weight of total weight of the vaginal tablet;
polyvinyl pyrrolidone (PVP) as binder in an amount of 1.0%-5% by weight of total weight of the vaginal tablet;
sorbic acid as pH modifier in an amount of 0.05%-1% by weight of total weight of the vaginal tablet; and
magnesium stearate and/or colloidal anhydrous silica in an amount of 1%-5% by weight of total weight of the vaginal tablet.

In a specific embodiment, the present invention provides a dispersible vaginal tablet for insertion into vagina comprising about 10 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein said tablet further comprises:
lactose in an amount of 40%-90% by weight of total weight of the vaginal tablet;
crospovidone in an amount of 1%-20% by weight of total weight of the vaginal tablet;
pregelatinized starch in an amount of 10.0%-50% by weight of total weight of the vaginal tablet;
sodium lauryl sulphate in an amount of 0.05%-2% by weight of total weight of the vaginal tablet; and
magnesium stearate and/or colloidal anhydrous silica in an amount of 1%-5% by weight of total weight of the vaginal tablet.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts or esters thereof is D90 between 5 µm and 100 µm.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts or esters thereof is D50 between 10 µm and 40 µm.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts or esters thereof is D10 between 1.0 µm and 10 µm.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts or esters thereof is D90 less than 50 µm, preferable less than 25 µm, more preferably less than 10 µm.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts or esters thereof is D90 less than 20µm.

Another embodiment of the present invention the particle size of granules of dydrogesterone or pharmaceutically acceptable salts or esters thereof and one or more pharmaceutically acceptable excipients is D90 less than 800 µm, preferably less than 500 µm, more preferably less than 250 µm.

Another embodiment of the present invention the provides a dispersible tablet of dydrogesterone and one or more pharmaceutically acceptable excipients, wherein the total weight of the tablet is about 100mg to 1000mg.

Another embodiment of the present invention the provides a dispersible tablet of dydrogesterone and one or more pharmaceutically acceptable excipients, wherein the total weight of the tablet is about 200mg to about 500mg.

Another embodiment of the present invention the provides a dispersible tablet of dydrogesterone and one or more pharmaceutically acceptable excipients, wherein the total weight of the tablet is about 380mg.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the water/moisture is present in the final composition less than 9%, when measured by KF method.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the water/moisture is present in the final composition about 5.54% after the preparation of composition (at initial), when measured by KF method.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the water/moisture is present in the final composition about 6.92%, after storage for 3 months at 40°C/75%RH, when measured by KF method.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the water/moisture is present in the final composition about 6.43%, after storage for 3 months at 30°C/75%RH (accelerated conditions).

According to one more embodiment, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, one or more disintegrants, and optionally one or more pharmaceutically acceptable excipients; wherein the tablet is administered for treatment of lower back pain, abdominal pain, and haemostasis in the threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, pre-eclampsia.

Another embodiment of the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein the said tablet is used in the treatment of irregular duration of cycles and irregular occurrence and duration of periods caused by progesterone deficiency. Further, the said tablet also used for secondary amenorrhoea, dysfunctional uterine bleeding and post-menopausal complaints where endogenous progesterone deficiency is implicated, in combination with an estrogenic substance.

According to another embodiment, the present invention provides a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients; wherein the tablet is prepared by direct compression, dry granulation, wet granulation process, melt granulation, or melt extrusion process.

According to another embodiment, the present invention provides a process of preparation of a vaginal tablet for insertion into vagina comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, wherein said process comprises: (a) blending dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients to obtain a blend; (b) optionally granulating and lubricating the blend; (c) compressing the blend or granules to form a tablet.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition releases about 95% dydrogesterone from the composition with in 5 minutes and about 100% of dydrogesterone with in 10 minutes from the composition, when measured in 0.3%w/v SLS media; volume 500 mL, RPM 100 Apparatus 2, paddle type dissolution apparatus.

According to another embodiment, the present invention provides a vaginal tablet comprising dydrogesterone, dydrogesterone impurity A, dydrogesterone impurity B, dydrogesterone impurity C and one or more pharmaceutically acceptable excipients, wherein the said composition comprising 10mg of dydrogesterone, wherein the particle size of dydrogesterone in the composition is D90 less than 20µm.

The vaginal tablet of the present is stable. The term “stable or stability or stabilized” means the tablet is stable at 40 °C ± 2 °C and 75% ± 5% RH for a period of six months or 25 °C ± 2 °C ,30? ± 2? , 60% ± 5%, and 75% ± 5% RH for a period of at least 12 months. Further, the total impurity in the tablet is not more than 5% after storing at 40 °C ± 2 °C and 75% ± 5% RH for a period of six months or 25 °C ± 2 °C and 60% ± 5% RH for a period of at least 12 months. Any individual impurity in the tablet is not more than 0.5% after storing at 40 °C ± 2 °C and 75% ± 5% RH for a period of six months or 25 °C ± 2 °C and 60% ± 5% RH for a period of at least 12 months.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition is having total dydrogesterone impurity is less than 1.5%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least three months.

According to another embodiment, the present invention provides a stable pharmaceutical composition comprising dydrogesterone, dydrogesterone impurity A, dydrogesterone impurity B, dydrogesterone impurity C and one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition is having dydrogesterone impurity A is less than 0.5%, preferably less than 0.3%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least three months.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition is having dydrogesterone impurity B is less than 0.5%, preferably less than 0.15%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least three months.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the pharmaceutical composition is having dydrogesterone impurity C is less than 0.5%, preferably less than 0.3%, when stored at 40°C ± 5°C & 75% ± 5% RH for a period of at least three months.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the % assay of dydrogesterone at initial time is about 99.8%.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the % assay of dydrogesterone is about 100.1%, after storage for 3 months at 40°C/75%RH.

According to another embodiment, the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the % assay of dydrogesterone is about 101%, after storage for 3 months at 30°C/75%RH (accelerated conditions).

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

Example 1: Vaginal tablet of Dydrogesterone
S. No. Ingredient Qty/Tablet (mg)
Dry mix
1 Dydrogesterone IP# 10.00
2 Microcrystalline cellulose # 310.50
3 Croscarmellose sodium 48.00
4 Sorbic acid 0.50
Binder
5 Povidone 10.00
6 Purified water** q.s.
Pre-lubrication
7 Colloidal silicon dioxide 5.00
8 Croscarmellose sodium 10.00
Lubrication
9 Magnesium stearate 6.00
** Lost during the process

Process
Dispensing:
Dispensing all the materials as per Bill of Material;
Sifting:
Sifting Dydrogesterone, Microcrystalline Cellulose, Colloidal silicon dioxide, and Croscarmellose sodium through appropriate sieve and collecting separately in double polybag;
Sifting Magnesium stearate through appropriate sieve and keeping separately;
3) Granulation:
a) Binder preparation: Dissolving sorbic acid into hot purified water at temperature 80-90 °C with continuous stirring. Allowing to cool at room temperature and adding Povidone into it with stirring until clear solution will formed;
b) Blending Dydrogesterone, Microcrystalline Cellulose, and Croscarmellose sodium to obtain a blend;
c) Granulating the blend as obtained in the above step using the binder solution to obtain granules;
4) Drying:
Drying the above granules at 60 °C in suitable dryer;
5) Pre-lubrication
Mixing the sifted colloidal silicon dioxide and croscarmellose sodium materials with above dried granules for suitable time into blender;
6) Lubrication
Mixing Magnesium stearate with step 5 material in blender for suitable time;
7) Compressing the lubricated material of step 6 using suitable tooling to obtain tablets;
8) Packing the tablets in approved packing materials.

Example 2: Vaginal tablet of dydrogesterone

S. No. Ingredient Qty./tab. (mg.)
Dry Mixing
1 Dydrogesterone(micronized) IP# 10.000
2 Lactose monohydrate (Flowlac 90) 251.000
3 Crospovidone (Crospovidone XL-10) IP 12.000
4 Pregelatinized Starch (Starch 1500) IP 80.000
5 Sodium lauryl sulphate IP 3.000
Pre-Lubrication
6 Pregelatinized Starch (Starch 1500) 15.000
7 Colloidal silicon dioxide (Aerosil 200) 5.000
Lubrication
8 Magnesium stearate 4.000

Process:
1. Dispensing all the materials as per Bill of Material;
2. Sifting of Dry mixing stage materials:
(a) Sifting Dydrogesterone, Crospovidone XL 10 together through 30 mesh sieve and keeping a side;
Sifting Sodium lauryl sulfate, Lactose monohydrate in equal quantities through 30 mesh sieve and keeping a side;
Passing Safe remaining lactose monohydrate and pregelatinized starch (Starch 1500) together along with sifted materials of Step 2a) & 2b) materials through 30 mesh sieve followed by collecting in a double polybag;
Sifting of Extra-granular mixing
Sifting colloidal silicon dioxide and pre-gelatinized starch together through 30 mesh sieve and collecting in double polybag;
Sifting Magnesium stearate through 60 mesh sieve and keeping separately.
4) Dry mixing: Loading sifted materials of step 2a, 2b, 2c into blender and mixing for 20 min at 10 RPM.
5) Pre-Lubrication: Adding sifted materials of colloidal silicon dioxide and pregelatinized starch (step 2.a) into blender and mixing it for 10 min with the blender as obtained in step 3 at 10 RPM;
6) Lubrication: Adding sifted magnesium stearate with the material as obtained in step 4 and mixing for 5 min at 10 RPM;
7) Compression: Compressing the lubricated blend as obtained in step 5 using suitable oval punch plain on both sides;
8) Packaging: Packing the tablets in approved packing materials with suitable applicator.

The pharmaceutical composition of present invention is prepared and subjected to the access for the release of dydrogesterone from the composition. For the determination of release profile, dissolution is carried out (0.3%w/v SLS; volume 500 mL, RPM 100 Apparatus 2, paddle) for the final composition. The results are given in below table:

Time (min.) % Release of dydrogesterone
5 94
10 100
15 100
30 102
45 103

The pharmaceutical composition of present invention is prepared and subjected to the stability study to access the stability of composition after storage. The composition has prepared and charged into the stability chamber with varying temperature and humidity conditions. The results are given in below table.

Table: Stability study of the composition of Dydrogesterone

Condition Initial 3M-40°C/75%RH 3M-30°C/75%RH
Pack Blister Pack
Average weight(mg) 379.37 386.75 386.73
Assay (%) 99.8 100.1 101.0
Dissolution (%).
100.59 100.61 100.55
Water by KF (wt%) 5.54 6.92 6.43
Related Substance (%w/w by HPLC)
Impurity A BDL BDL BDL
Impurity B BQL BDL BDL
Impurity C 0.15 0.14 0.13
Any unspecified degradation products ND BDL BDL
Total degradation products 0.15 0.14 0.13

Stability is measured in terms of the total impurity. From the above table, it is evident that the composition of dydrogesterone is stable. The total impurity is same or decreases partially after storing 3 months in stability chamber with varying conditions.
,CLAIMS: We Claim:

1. A vaginal tablet comprising dydrogesterone or pharmaceutically acceptable salts or esters thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet comprises from about 5 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts or esters thereof.

2. The vaginal tablet as claimed in claim 1, wherein the said tablet comprises 10mg of dydrogesterone.

3. The vaginal tablet as claimed in claim 1, wherein the said tablet is a dispersible tablet.

4. The vaginal tablet as claimed in claim 1, wherein the vaginal tablet further comprises:
a) 1 – 95 % w/w diluent(s),
b) 1 - 50% w/w of disintegrant(s), and
c) 0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet.

5. The vaginal tablet as claimed in claim 1, wherein the vaginal tablet further comprises:
a) 25 - 85% w/w diluent(s),
b) 5 - 25% w/w of disintegrant(s),
c) 1 - 10% w/w of binder(s),
d) 0.05 - 5% w/w of pH modifier(s),
e) 0.05-20% w/w of buffering agent(s), and
f) 0.5 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the tablet and optionally a film-coating.

6. The vaginal tablet as claimed in claim 1, wherein the vaginal tablet further comprises:
a) lactose in an amount of 40%-90% by weight of total weight of the vaginal tablet;
b) crospovidone in an amount of 1%-20% by weight of total weight of the vaginal tablet;
c) pregelatinized starch in an amount of 10.0%-50% by weight of total weight of the vaginal tablet;
d) sodium lauryl sulphate in an amount of 0.05%-2% by weight of total weight of the vaginal tablet; and
e) magnesium stearate and/or colloidal anhydrous silica in an amount of 1%-5% by weight of total weight of the vaginal tablet.

7. The vaginal tablet as claimed in claim 1, wherein the vaginal tablet release about 95% of dydrogesterone from the composition with in 5 minutes and about 100% of dydrogesterone win in 15 minutes.

8. The vaginal tablet as claimed in claim 1, wherein the particle size of dydrogesterone d90 is less than 20µm.

9. The vaginal tablet as claimed in claim 1, wherein the water/moisture is present in the final composition is less than 9%, when measured by KF method.

10. A vaginal tablet comprising dydrogesterone, dydrogesterone impurity A, dydrogesterone impurity B, dydrogesterone impurity C and one or more pharmaceutically acceptable excipients, wherein the said composition comprising 10mg of dydrogesterone, wherein the particle size of dydrogesterone in the composition is D90 less than 20µm.

Dated this,25th Day of September, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer