DESC:TOPICAL COMPOSITIONS OF DYDROGESTERONE

FIELD OF THE INVENTION

The present invention relates to a topical pharmaceutical composition comprising dydrogesterone, and one or more pharmaceutically acceptable excipients. Moreover, the present invention also relates to the process for the preparation of the topical pharmaceutical composition.

BACKGROUND OF THE INVENTION

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

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

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

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

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

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

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

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

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

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. Dydrogesterone has consistently proved to be 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.

The aforementioned publications disclose or suggest solid oral formulations of dydrogesterone. However, because of the slow gastrointestinal absorption and high hepatic metabolism of dydrogesterone, achieving the desired plasma levels is often difficult with oral administration. The topical pharmaceutical compositions successfully bypass the first-pass effect and provides targeted vaginal delivery. Attempts have been made to provide optimal, stable topical pharmaceutical compositions of dydrogesterone, however, there is currently no commercially available formulation of dydrogesterone for topical administration.

There is therefore a strong felt need in the art for topical pharmaceutical compositions of dydrogesterone. After extensive experimentation and lots of efforts, the inventors have developed topical pharmaceutical composition of dydrogesterone which is optimal, stable, safe and efficacious.

OBJECTIVES OF THE INVENTION

The principal objective of the present invention is to provide a topical pharmaceutical composition comprising of therapeutically effective amount of dydrogesterone, and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a process for the preparation of the topical pharmaceutical composition.

Another objective of the present invention is to provide a topical pharmaceutical composition comprising effective amount of dydrogesterone and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of cream, foam, ointment, aqueous gel or emulgel.

Another objective of the present invention is to provide a topical pharmaceutical composition of dydrogesterone which is optimal, stable, safe and efficacious.

Another objective of the present invention is to provide a topical pharmaceutical composition for the treatment of progesterone deficiency, threatened abortion, pre-eclampsia, pre-menstrual syndrome (PMS), Post-menopausal complaints, female infertility, pain during menstruation, endometriosis, irregular duration and occurrence of menstrual cycles, dysfunctional uterine bleeding, and heavy menstrual bleeding.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a topical pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, and one or more pharmaceutically acceptable excipients.

According to one aspect, the present invention provides a topical pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone; and one or more pharmaceutically acceptable excipients selected from hydrophobic cream base(s), gelling agent(s), viscosity modifier(s), lipid(s), emulsifier(s), co-emulsifier(s), surfactant(s), solubilizing agent(s), humectant(s), pH adjusting agent(s), antimicrobial agent(s), buffering agent(s), antioxidant(s), humectant(s), chelating agent(s), stabilizer(s), preservative(s), solvent(s), and co-solvent(s), wherein the composition is a cream, foam, ointment, lotion, aqueous gel or emulgel .

According to another aspect, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the composition is a cream, foam, ointment, lotion, aqueous gel or emulgel having a pH in a range of 1 to 7.

According to another aspect, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the topical pharmaceutical composition is a vaginal gel having pH in the range of 1 to 5.

According to another aspect, the present invention provides a topical pharmaceutical composition comprising about 1 mg to about 100 mg of dydrogesterone, gelling agent(s) in an amount of about 0.1% w/w to about 25% w/w, solubilizing agent(s) in an amount of about 0.01% w/w to about 80 % w/w, and one or more pharmaceutically acceptable excipients selected form the group comprising one or more co-solvent(s) in an amount of about 0.01% w/w to about 50 % w/w, viscosity modifier(s) in an amount of about 0.01% w/w to about 20 % w/w; buffering agent(s) in an amount of about 0.01% w/w to about 20 % w/w; preservative(s) in an amount of about 0.001% w/w to about 20% w/w; chelating agent(s) in an amount of about 0.001% w/w to about 10% w/w; antioxidant(s) in an amount of about 0.001% w/w to about 10% w/w; pH adjusting agent(s); based on the total weight of the composition, wherein the composition is a cream, foam, ointment, lotion, aqueous gel or emulgel and is having a pH in a range of 1 to 5.

According to another embodiment, the present invention provides a process of preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises:
- Collecting water in a suitable vessel;
- Adding solubilizing agent(s), optionally cosolvent(s), and dydrogesterone, simultaneously or one after the other to water obtain a clear solution;
- Adding gelling agent(s) and optionally, one or more other pharmaceutically acceptable excipients to the above solution;
- Optionally, adjusting the pH;
- Making up the volume to 100% batch size with water,
wherein the composition is an aqueous gel and is having a pH in a range of 1 to 7.

According to another embodiment, the present invention provides a process of preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises:
- preparing water phase comprising gelling agent(s) and one or more pharmaceutically acceptable excipients;
- preparing oil phase comprising dydrogesterone and lipids or hydrophobic liquids or hydrophobic semisolids selected from one or more of mono-, di-, or tri- glycerides, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil, palm seed oil, mineral oil, silicone oil, petrolatum, or lanolin;
- mixing water phase and oil phase.
wherein the composition is an emulgel and is having a pH in a range of 1 to 7.

According to another aspect, the present invention provides a topical pharmaceutical composition comprising about 1 mg to about 100 mg of dydrogesterone, gelling agent(s) in an amount of about 0.1% w/w to about 25% w/w, and one or more pharmaceutically acceptable excipients selected form the group comprising one or more humectant(s) in an amount of about 10% w/w to about 80 % w/w, one or more hydrophobic base(s) in an amount of about 5% w/w to about 40 % w/w; one or more preservative(s) in an amount of about 0.001% w/w to about 20% w/w; one or more emulsifier(s) in an amount of about 0.01% w/w to about 20% w/w; wherein the composition is a cream, foam, ointment, lotion, aqueous gel or emulgel and is having a pH in a range of 1 to 5.

According to one more aspect, the topical pharmaceutical composition of the present invention comprising a therapeutically effective amount of dydrogesterone is a vaginal gel and is applied for treatment of progesterone deficiency, threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, and/or 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 topical pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, 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 clearly 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.

The term “formulation” or “pharmaceutical formulation” “topical pharmaceutical composition” or “topical composition” “topical formulation” or “dosage form” as used herein synonymously include the pharmaceutical formulations in a form suitable for topical administration such as but not limited to include solution, suspension, gel, gel forming suspension (in-situ gels), cream, ointment, lotion, or any other suitable dosage form meant for topical application, preferable for vaginal application. Preferably, composition is a cream, a gel, or a gel forming suspension.

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 ascribed 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, i.e., Dydrogesterone or pharmaceutically acceptable salts thereof, 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 “dydrogesterone” “dydrogesterone or pharmaceutically acceptable salts thereof” or “dydrogesterone salt” are used interchangeably, is defined to mean that the “dydrogesterone or pharmaceutically acceptable salts thereof”.

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

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 “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component. As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulation in many different ways, e.g., solubilisation, dilution, thickening, stabilization, and preservation. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, ease of administration, and stability of the dosage form. Due to the varying properties of the active drug substance to be formulated, dosage forms typically require pharmaceutical excipients that are uniquely tailored for the active drug substance in order to achieve advantageous physical and pharmaceutical properties.

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

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.

According to one embodiment, the present invention provides a topical pharmaceutical composition comprising from about 1 mg to about 100 mg of dydrogesterone, or about 5 mg to about 50 mg of dydrogesterone, or about 1 mg of dydrogesterone, or about 5 mg of dydrogesterone, about 10 mg of dydrogesterone, or about 20 mg of dydrogesterone, or about 50 mg of dydrogesterone, and one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone in an amount of about 0.1% w/w to about 10% w/w, preferably about 0.1% w/w to about 5% w/w, specifically 0.5% w/w, 1% w/w, 2% w/w, 5% w/w.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising about 1% w/w of dydrogesterone, about 3.375% w/w of gelling agent(s), about 0.09% w/w of preservative(s), about 14.51 % w/w of humectant(s), about 4.725 % w/w of hydrophobic base(s), about 1.125 %w/w of emulsifier(s) and one or more pharmaceutically acceptable excipients.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising about 1% w/w of dydrogesterone, about 3.375% w/w of gelling agent(s), about 0.09% w/w of preservative(s), about 14.51 % w/w of humectant(s), about 4.725 % w/w of hydrophobic base(s), about 1.125 %w/w of emulsifier(s) and one or more pharmaceutically acceptable excipients, wherein the composition is in the form of cream, foam, ointment, lotion, aqueous gel or emulgel.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising about 1% w/w of dydrogesterone, about 3.375% w/w of gelling agent(s) selected from the group comprising polycarbophil, carbomer or combination thereof, about 0.09% w/w of sorbic acid, about 14.51 % w/w of glycerine, about 4.725 % w/w of liquid paraffin, about 1.125 %w/w of hydrogenated palm oil glyceride and one or more pharmaceutically acceptable excipients.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone and one or more gelling agent(s), wherein the dydrogesterone and gelling agent(s) is present in ratio of 1:30 to 30:1.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone and one or more humectant(s), wherein the dydrogesterone and humectant (s) is present in ratio of 1:70 to 1:1.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, one or more gelling agent(s) and one or more humectant(s), wherein the gelling agent(s) and humectant(s) is present in ratio of 1:10 to 10:1.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the topical pharmaceutical composition is a vaginal gel.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the topical pharmaceutical composition is a vaginal gel and having a pH about 2.5 ± 0.5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the topical pharmaceutical composition is a vaginal gel and having a pH about 3.0 ± 0.5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the compositions is having a pH in the range of 1 to 7.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the compositions is having a pH in the range of 1 to 5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the compositions is having a pH in the range of 2.5 to 3.5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the compositions is having a pH about 2.5 ± 0.5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the compositions is having a pH about 3.0 ± 0.5.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the viscosity of composition is about 7000 cps to about 20000 cps.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the viscosity of composition is about 10000 cps to about 15000 cps.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the viscosity of composition is about 10000 cps to about 11000 cps.

According to another one embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone; and one or more pharmaceutically acceptable excipients, wherein the viscosity of composition is about 10000 cps to about 13000 cps.

According to another embodiment, the present invention provides a topical 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 topical 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 stable topical pharmaceutical composition comprising dydrogesterone, one or more of dydrogesterone impurity selected from the group comprising dydrogesterone impurity A, dydrogesterone impurity B, dydrogesterone impurity C or combinations thereof and one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone, wherein the composition is having dydrogesterone impurity A is less than 0.5%, preferably less than 0.1%, more preferably less than 0.08%, 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 topical pharmaceutical composition comprising dydrogesterone, wherein the composition is having dydrogesterone impurity B is less than 0.5%, preferably less than 0.05%, 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 topical pharmaceutical composition comprising dydrogesterone, wherein the composition is having dydrogesterone impurity C is less than 0.5%, preferably less than 0.1%, more preferably less than 0.06%, 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 topical pharmaceutical composition comprising about 1 mg to about 100 mg of dydrogesterone, gelling agent(s) in an amount of about 0.1% w/w to about 25% w/w, solubilizing agent(s) in an amount of about 0.01% w/w to about 80 % w/w, and one or more pharmaceutically acceptable excipients selected form the group comprising one or more co-solvent(s) in an amount of about 0.01% w/w to about 50 % w/w, viscosity modifier(s) in an amount of about 0.01% w/w to about 20 % w/w; buffering agent(s) in an amount of about 0.01% w/w to about 20 % w/w; preservative(s) in an amount of about 0.001% w/w to about 20% w/w; tonicity agent(s) in an amount of about 0.01% w/w to about 10% w/w; chelating agent(s) in an amount of about 0.001% w/w to about 10% w/w; antioxidant(s) in an amount of about 0.001% w/w to about 10% w/w; pH adjusting agent(s); based on the total weight of the composition, wherein the composition is in the form of cream, foam, ointment, lotion, aqueous gel or emulgel and is having a pH in a range of 1 to 5.

According to another embodiment, the present invention provides a topical pharmaceutical composition comprising about 1 mg to about 50 mg of dydrogesterone; carboxyvinyl polymer, cellulosic polymer, or combination thereof as gelling agent in an amount of about 0.1% w/w to about 25% w/w; Hydroxypropyl-ß-cyclodextrin as solubilizing agent(s) in an amount of about 0.01% w/w to about 80 % w/w; and one or more pharmaceutically acceptable excipients, wherein the composition is an aqueous gel and is having a pH in a range of 1 to 5.

According to another embodiment, the present invention provides a topical pharmaceutical composition comprising about 1 mg to about 50 mg of dydrogesterone; carboxyvinyl polymer, cellulosic polymer, or combination thereof as gelling agent in an amount of about 0.1% w/w to about 25% w/w; lipids or hydrophobic liquids or hydrophobic semisolids selected from one or more of mono-, di-, or tri- glycerides, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil, palm seed oil, mineral oil, silicone oil, petrolatum, or lanolin as solubilizing agent(s) in an amount of about 0.01% w/w to about 80 % w/w; and one or more pharmaceutically acceptable excipients, wherein the composition is an emulgel and is having a pH in a range of 1 to 5.

According to another embodiment, the present invention provides a process of preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises:
- Collecting water in a suitable vessel;
- Adding solubilizing agent(s), optionally cosolvent(s), and dydrogesterone, simultaneously or one after the other to water obtain a clear solution;
- Adding gelling agent(s) and optionally, one or more other pharmaceutically acceptable excipients to the above solution;
- Optionally, adjusting the pH;
- Making up the volume to 100% batch size with water,
wherein the composition is an aqueous gel and is having a pH in a range of 1 to 7.

According to another embodiment, the present invention provides a process for preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises the following steps:
- Collecting water in a suitable vessel;
- Adding Hydroxypropyl-ß-cyclodextrin and Dydrogesterone, in water;
- Adding benzalkonium chloride and stirring to obtain clear solution;
- Heating the solution at 70-80 ºC and adding gelling agent selected from carboxyvinyl polymer, cellulosic polymer, or combination thereof, under stirring;
- Optionally, cooling and adjusting the pH;
- Making up volume up to 100% batch size.
wherein the composition is an aqueous gel and is having a pH in a range of 1 to 5.

According to another embodiment, the present invention provides a process of preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises:
- preparing water phase comprising gelling agent(s) and one or more pharmaceutically acceptable excipients;
- preparing oil phase comprising dydrogesterone and lipids or hydrophobic liquids or hydrophobic semisolids selected from one or more of mono-, di-, or tri- glycerides, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil, palm seed oil, mineral oil, silicone oil, petrolatum, or lanolin;
- mixing water phase and oil phase.
wherein the composition is an emulgel and is having a pH in a range of 1 to 7.

According to another embodiment, the present invention provides a process of preparation of a topical pharmaceutical composition comprising dydrogesterone, wherein said process comprises the following steps:
- Collecting water in a suitable vessel;
- adding gelling agent selected from carboxyvinyl polymer, cellulosic polymer, or combination thereof, in water, followed by adding sorbic acid, to obtain water phase;
- heating liquid paraffin at 60-70 ºC and dispersing Dydrogesterone under stirring, followed by adding glycerin and hydrogenated palm oil;
- mixing the water phase and oil phase,
wherein the composition is a emulgel and is having a pH in a range of 1 to 5.

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

According to another embodiment, the present invention provides a topical pharmaceutical composition comprising dydrogesterone and one or more pharmaceutically acceptable excipients; wherein the composition is applied for the treatment of progesterone deficiency, threatened abortion, pre-eclampsia, pre-menstrual syndrome (PMS), post-menopausal complaints, female infertility, pain during menstruation, endometriosis, irregular duration and occurrence of menstrual cycles, dysfunctional uterine bleeding and/or heavy menstrual bleeding.

The pharmaceutical composition of the present is stable. The term “stable or stability or stabilized” means the dosages form is stable under 40 °C/75% RH and/or 30 °C/75% RH for at least six (6) months. Further, the total impurity in the dosage form is not more than 5% after storing at 40 °C/75% RH and/or 30 °C/75% RH for at least six (6) months. Any individual impurity in the dosage form is not more than 0.5% after storing at 40 °C/75% RH and/or 30 °C/75% RH for at least six (6) months.

According to another embodiment provides a topical pharmaceutical composition of dydrogesterone and one or more pharmaceutically acceptable excipients, wherein the one or more pharmaceutically acceptable excipients is selected from the group comprising hydrophobic cream base(s), gelling agent(s), viscosity modifier(s), lipid(s), emulsifier(s), co-emulsifier(s), surfactant(s), solubilizing agent(s), humectant(s), tonicity agent(s), pH adjusting agent(s), antimicrobial agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), preservative(s), solvent(s), co-solvent(s), or combinations thereof.

According to another embodiment, the present invention describes a topical cream formulation using a hydrophobic cream base. A topical formulation in hydrophobic cream base is particularly advantageous as it provides an emollient action and soothes the skin. Dydrogesterone is mixed with hydrophobic cream base or mixture of hydrophobic cream base(s), selected from following classes such as Oleaginous bases, Absorption bases, Water removable base and Water-soluble base and mixture thereof.

‘Oleaginous Bases’ are also termed as Hydrocarbon bases. On application to the skin, have an emollient effect and as occlusive dressing, can remain on the skin for prolonged periods of time without drying out.

‘Absorption Bases’ are of two types: (i) those that permit the incorporation of aqueous solutions resulting in the formation of water-in-oil emulsions, (ii) those that are water-in-oil emulsions (i.e., emulsion bases) and permit the incorporation of additional quantities of aqueous solutions.

‘Water-Removable Bases’ are oil-in-water emulsions resembling creams in appearance. Because the external phase of the emulsion is aqueous, they are easily washed from skin and are often called “water-washable” bases.

‘Water-Soluble Bases’ do not contain oleaginous components. They are completely water-washable and often referred to as “greaseless” Because they soften greatly with the addition of water; large amounts of aqueous solutions are not effectively incorporated into these bases. They mostly are used for the incorporation of solid substances.

Suitable hydrophobic cream base(s) include but are not limited to Hydrocarbons such as Liquid petrolatum (mineral oil, liquid paraffin, paraffin oil), White petrolatum (petroleum jelly, Vaseline), Yellow petrolatum (petroleum jelly) Squalane (perhydrosqualene, spinacane); Silicones such as Liquid polydimethylsiloxanes (dimethicone, silastic, medical grade silicone oil); Alcohols such as Lauryl alcohols (1-dodecanol, dodecyl alcohols), Myristyl alcohols (tetradecanol, tetradecyl alcohols), Cetyl alcohols (hexadecanol, ethal, palmityl alcohols), Stearyl alcohols (stenol, cetosteryl alcohols), Oleyl alcohols (ocenol) Sterols; sterol esters: Lanolin (hydrous wool fat, lanum), Anhydrous lanolin (wool fat, anhydrous lanum, agnin), Semi synthetic lanolin’s; Carboxylic Acids such as Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid Esters; polyesters: Cholesterol esters (stearate), Ethylene glycol monoesters, Propylene glycol monoesters, Glyceryl monoesters, Glyceryl monostearate, Sorbitol monoesters, Sorbitain monoesters, Sorbitol diesters, Sorbitan polyesters (spans, arlacels), Glyceryl tristearate, Lard, Almond oil, Corn oil, Caster oil, Cottonseed oil, Olive oil, Soyabean oil, Hydrogenated oils, Sulfated oils, Isopropyl myristate, Isopropyl palmitate. Ethers; polyethers: Polyethylene-polypropylene glycols (pluronics).

According to another embodiment, the present invention provides a topical gel formulation using a gel base. A topical formulation in gel base is particularly advantageous as it provides a soothing and hydrant action. Dydrogesterone is mixed with gelling agent or mixture of gelling agent(s) to form a topical gel. Gelling agents are the gel-forming agents when dissolved in a liquid phase as a colloidal mixture forms a weakly cohesive internal structure. They are organic hydrocolloids or hydrophilic inorganic substances. The gel is an aqueous gel or an emulgel. The aqueous gel is pure water based, emulgel contains both water and lipid and/or hydrophobic liquid/semisolid.

Suitable gelling agent(s) include, without limitation, synthetic, semisynthetic, natural gelling agents, or mixtures thereof. Examples include but not limited to gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, and hyaluronic acid derivatives, cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyl ethyl cellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), carboxymethyl cellulose, carboxymethylcellulose, hydroxypropylmethyl cellulose, a carboxyvinyl polymer such as polycarbophil, cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross- linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), poly(N-isopropylacrilamide), poly(N-isopropylacrilamide) monomer crosslinked with N,N'-methylenebisacrylamide, polyethylene glycol (PEG)-conjugated- poly(N-isopropylacrilamide), poly(hydroxyethylmethacrylate)- conjugated- poly(N-isopropylacrilamide), poly(N-isopropylacrilamide)-block-poly(methyl methacrylate)-(poly (acrylic acid)), polyvinylacetal diethylaminoacetate, poly(2-hydroxyethylmethacrylate-co-2-(diisopropylamino)ethyl methacrylate), Poly(2-hydroxyethyl methacrylate), gelatine methacrylate (GelMA), PLGA-PEG-PLGA triblock copolymer hydrogels, poly(ethylene glycol) acrylate, poly(ethylene glycol) diacrylate, poly(ethylene glycol) methacrylate, polycaprolactone-polylactic acid, hydroxyethyl methacrylate-methacrylic acid, Polyvinyl alcohol (PVA) and Polyvinylpyrrolidone (PVP), poly(amino acids), methyl methacrylate cross-linked poly (vinyl alcohol), Polyglycolic acid-polycaprolactone-polyethylene glycol-polycaprolactone-polyglycolic acid (PGA-PCL-PEG-PCL-PGA), polylactic acid-polycaprolactone-polyethyleneglycol-polycaprolactone-polylactic acid (PLA-PCL-PEG-PCL-PLA), poly(N-isopropylacrylamide)-poly(ethylene glycol)- poly(e-caprolactone), poly (N,N-diethylacrylamide) and poly (N-isopropylacrylamide), poly (N-n-propylacrylamide), ethylene vinyl acetate polymer , polyalkyl cyanoacrylate, hydroxypropyl methacrylate mixture of tocopheryl acetate:medium-chain triglycerides, polyoxyethylene hydrogenated castor oil, or combinations thereof. When present, gelling agent(s) may be employed in an amount ranging from about about 0.05% w/w to about 50% w/w, of the pharmaceutical composition.

Suitable solubilizing agents include, without limitation, emulsifier, co-emulsifiers, surfactants, lipids, hydrophobic liquids/semi-solids, cyclic oligosaccharides/ cyclodextrins, phospholipids, or mixtures thereof. The solubilizing agent(s) may be employed in an amount ranging from about 0.01% w/w to about 80% w/w of the pharmaceutical formulation. Solubilizing agents are used to either increase the solubility of dydrogesterone or act as dispersion medium to uniformly dispersion the drug with in the gel or both.

As used herein, the term “emulsifier” and “co-emulsifier” represents suitable agents that aids emulsification and surfactants that may be included in the formulations of the invention. Suitable emulsifiers, co-emulsifiers, and surfactants include, without limitation, ionic, non-ionic, amphiphilic, amphoteric emulsifiers, co-emulsifiers, and surfactants such as sodium docusate, sodium lauryl sulfate, naturally occurring phospholipids extracted from egg yolk or soybean, synthetic phosphatidyl cholines or purified phosphatidyl cholines from vegetable origin, hydrogenated derivatives can also be used, such as phosphatidylcholine hydrogenated (egg) and phosphatidylcholine hydrogenated (soya), poloxamers, polysorbates, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, poloxamines, polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters or sorbitan fatty acid esters, derivatives of tocopherol such as tocopherol PEG succinate, long chain fatty acids such as oleic acid, stearic acid, palmitic acid, bile acids such as cholic acid and deoxycholic acid or surface active derivatives and polyoxyls. Poloxamers are nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Polysorbates are oily liquids derived from ethoxylated sorbitan esterified with fatty acids. Cyclodextrins are composed of 5 or more a-D-glucopyranoside units linked together at position 1 and 4. Polyoxyls are a mixture of mono- and diesters of stearate and polyoxyethylene diols. Preferred embodiments include but are not limited to poloxamer 188 (such as Pluronic® F-68) and poloxamer 407 (such as Pluronic® F127); polysorbate 20, polysorbate 60, polysorbate 80, tyloxapol, Brij® 35, Brij® 78, Brij® 98 and Brij® 700, Span® 20, Span® 40, Span® 60, Span® 80; and polyoxylspolyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil; Hydrogenated Castor oil (or PEG (40 Hydrogenated Castor Oil) (HCO-40) or combinations thereof. In preferred embodiment, the surfactant includes, without limitation non-ionic surfactants such as Kolliphore EL (Cremophor EL), Cremophor RH 40, Cremophor RH 60, d-a-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750, and combinations thereof. When present, emulsifier(s), co-emulsifier(s), and/or surfactant(s) may be employed in an amount ranging from about 0.005% w/w to about 25% w/w of the pharmaceutical formulation.

Suitable lipid(s) include, without limitation, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, sunflower oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, medium-chain triglycerides of coconut oil, palm seed oil, Hydrogenated palm oil glyceride, a medium chain triglyceride such as Miglyol™ 812 or 810 or triacetin, and combinations thereof. As used herein, the term “lipid” in the formulations is any pharmaceutically acceptable oil, preferably a triglyceride. The lipid may also be a propylene glycol diester or monoglyceride (such as acetylated monoglyceride). The lipid can also be a mixture of one or more of these lipids. The amount of lipid in the formulations of the present invention can vary depending on the total overall volume of the formulation and the concentration of the other components. The lipid(s) may be employed in an amount ranging from about 5%w/w to about 50% w/w.

Suitable hydrophobic liquids/semi-solids include, without limitation, waxes such as beeswax, carnauba wax, polawax, Candelilla wax etc., veegum, d-a-tocopherol, oleic acid, vegetable oils, ethyl oleate, propylene glycol, and polyethylene glycol, transcutol, isopropyl myristate, glycerine, medium-chain mono- and di- glycerides, diethylene glycol, glyceryl monostearate, Liquid petrolatum (mineral oil, liquid paraffin, paraffin oil), White petrolatum (petroleum jelly, Vaseline), Yellow petrolatum (petroleum jelly) Squalane (perhydrosqualene, spinacane); Silicones such as Liquid polydimethylsiloxanes (dimethicone, silastic, medical grade silicone oil); Alcohols such as Lauryl alcohols (1-dodecanol, dodecyl alcohols), Myristyl alcohols (tetradecanol, tetradecyl alcohols), Cetyl alcohols (hexadecanol, ethal, palmityl alcohols), Stearyl alcohols (stenol, cetosteryl alcohols), Oleyl alcohols (ocenol) Sterols; sterol esters: Lanolin (hydrous wool fat, lanum), Anhydrous lanolin (wool fat, anhydrous lanum, agnin), Semi synthetic lanolin’s; Carboxylic Acids such as Lauric acid, Myristic acid, palmitic acid, stearic acid, oleic acid Esters; polyesters: Cholesterol esters (stearate), Ethylene glycol monoesters, Propylene glycol monoesters, Glyceryl monoesters, Glyceryl monostearate, Sorbitol monoesters, Sorbitain monoesters, Sorbitol diesters, Sorbitan polyesters (spans, arlacels), Glyceryl tristearate, Lard, Almond oil, Corn oil, Caster oil, Cottonseed oil, Olive oil, Soyabean oil, Hydrogenated oils, Sulfated oils, Isopropyl myristate, Isopropyl palmitate. Ethers; polyethers: Polyethylene-polypropylene glycols (pluronics) and combinations thereof. When present, organic liquids/semi-solids may be employed in an amount ranging from about 0.01% w/w to about 25% w/w of the pharmaceutical formulation.

Suitable cyclic oligosaccharides/cyclodextrins include, without limitation, a-cyclodextrin, ß-cyclodextrin, hydroxypropyl-ß-cyclodextrin, and sulfobutylether-ß-cyclodextrin, cyclodextrins-2-HP25, ionically charged (e.g. anionic) ß-cyclodextrins with or without a butyrated salt (Captisol®), hydroxypropyl-gamma-cyclodextrin, gamma cyclodextrin, and combinations thereof. When present, a cyclodextrin may be employed in an amount ranging from about 0.01% w/w to about 25% w/w of the pharmaceutical formulation, preferably from about 0.01% w/w to 10% w/w of the pharmaceutical formulation.

Suitable phospholipids include, without limitation, hydrogenated soy phosphatidyl choline, distearoyl phosphatidyl glycerol, l-a-dimyristoylphosphatidylcholine, l-a-dimyristoyl phosphatidyl glycerol, and combinations thereof. of the present invention may further comprise synthetic phospholipids comprised following one or more: hydrogenated soybean lecithin, Dipalmitoylphosphatidylcholine (DOPC), 1,2-Dimyristoyl-sn-glycero-3-phosphorylethanolamine (DMPEA), 1,2-Dipalmitoyl-sn-glycero-3-phosphorylethanolamine (DPPE), two myristoyl Phosphatidylserine, 1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE), dilinoleoylphosphatidylcholine (DLPC), two myristoyl lecithin, Dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine, distearoylphosphatidylcholine, and their polyethylene glycol derivative. When present, phospholipid(s) may be employed in an amount ranging from about 0.01% w/w to about 10% w/w of the pharmaceutical formulation.

Suitable humectant(s) and viscosity modifier(s) include, without limitation, glycerol (glycerine), propylene glycol, polymeric polyols, such as, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 6000), butylene glycol, triethylene glycol, collagen, dextrans such as dextran 70, water soluble proteins such as gelatin, polyvinyl alcohols, polyvinylpyrrolidones, cellulose derivatives, carbomers, gums such as gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, and hyaluronic acid derivatives, dextrans, polyvinyl alcohol, polyacrylic acids, povidone such povidone K90, and polysaccharides such as hyaluronic acid and its salts and chondroitin sulfate and its salts, or combinations thereof. The viscosity modifiers may be present in an amount of about 0.05% w/w to about 10 % w/w.

Suitable buffering agent(s) include, without limitation, phosphate buffer, acetate buffer, citrate buffer, succinate buffer, borate buffers, tris HCl and amino acids such as glycine, aspartate, histidine, cysteine, tyrosine, phenylalanine, proline, arginine, threonine, serine, valine, isoleucine, lycine, and glutamine. The particular concentration of the buffer will differ, depending on the specific agent employed. When present, the buffering agent(s) is preferably used in an amount of about 0.01% w/w to about 20% w/w, preferably about 0.05% w/w to about 10% w/w of the pharmaceutical formulation.

Suitable tonicity agent(s) include, without limitation, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, non-ionic diols such as glycerol and propylene glycol, dextrose and/or mannitol, sorbitol. Amount of tonicity agent will vary, depending on the certain agent to be added. When present, the tonicity agent(s) is preferably used in an amount of about 0.01% w/v to about 10% w/v of the pharmaceutical composition.

The formulations of the present invention may include a preservative. In some embodiments, the preservative is an “antimicrobial agent” that inhibits the growth of microorganisms such as bacteria and fungi (molds and yeast). Suitable preservative includes, 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, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl-p-hydroxybenzoate, chlorobutanol, sorbic acid, 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% w/v to about 5.0% w/v of the pharmaceutical formulation.

Suitable chelating agents, includes, without limitation, ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate, sodium citrate, or mixtures thereof. When present, the chelating agent(s) may be added in an amount of about 0.001% w/w to about 5.0% w/w of the pharmaceutical formulation.

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

The pH adjusting agent is typically an organic or inorganic acid or an organic or inorganic base preferably selected from the group of potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, N-methylglucamine, L-lysine, hydrochloric acid, phosphoric acid, or mixtures thereof, preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH adjusting agents are added to adjust the formulation to the target pharmaceutically acceptable pH range. Hence, it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range. The compositions will typically have a pH in the range of 1 to 7, preferably 1 to 5. In one embodiment, the initial pH of the composition is adjusted to 3.0 ± 0.5.

Suitable solvent(s) includes, without limitation, an aqueous or a non-aqueous solvent such as purified water, water for injection, bacteriostatic water for injection, sterile water, isotonic saline water, buffered aqueous solution, ethanol, glycerin, propylene glycol, or combinations thereof. Solvent(s) is present in an amount of about 10% w/w to about 90% w/w of the pharmaceutical formulation.

Suitable co-solvent(s) include, without limitation, organic or inorganic solvents solvents selected from but not limited to monohydric or polyhydric alcohols including ethanol, isopropyl alcohol, polyethylene glycol (PEG), propylene glycol (PG), sorbitol, glycerine, acetone, benzyl alcohol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofurol, solketal, glycerol formal, or combinations thereof. When present, cosolvent(s) may be employed in an amount ranging from about 0.01% w/w to about 50% w/w of the pharmaceutical formulation or equivalent weight conversion based on the density of the co-solvent.

In another embodiment, one or more additional components such as suspending agents, e.g., veegum, talc, bentonite, clay etc. used in topical formulations may be included.

While selected embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

EXAMPLES
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.

Table 1: A representative gel, cream, or gel forming suspension of this invention comprises or consists essentially of, or consists of the following composition:
Ingredient % by weight of total composition
Dydrogesterone micronized 0.1-10%
Gelling agent 0.1-25%
Solubilizing agent(s) 0.01% - 80%
Cosolvent(s) 0-50%
Viscosity modifier(s) 0-20%
Buffering agent(s) 0-10%
Chelating agent(s) 0-5%
Preservative 0-5%
Antioxidant(s) 0-5%
pH adjusting agent q.s.
Water q.s. to make 100%

Example 1: Vaginal Gel composition comprising of Dydrogesterone
Ingredients Amount (%w/w)
Oil phase
Dydrogesterone 1.00
Glycerin 12.5
Liquid paraffin 4.50
Hydrogenated palm oil glyceride 1.00
Water Phase
Polycarbophil 2.00
Carbomer 1.00
Sorbic acid 0.08
Sodium Hydroxide 1.00
Purified water q.s. to make 100%

Process for Preparation:
1. Dispensing: Dispensed all the materials.
2. Sifting: Sifted Dydrogesterone through appropriate sieve & collected in double lined polybag.
3. Soaking of polymers (water phase): Soaked the Polycarbophil and Carbomer 934P into appropriate quantity of purified water for suitable time. Dissolved Sorbic acid into Purified water and mixed with soaked polymer. Stirred until homogenous phase obtained and kept the temperature 60 ºC.
4. Oil phase: Heated the liquid paraffin at 60 ºC-70 ºC and dispersed Dydrogesterone under stirring and added glycerine and Hydrogenated palm oil into it. Mixed properly and allowed to cool up to 60 ºC.
5. Mixing of water phase and oil phase: Mixed the water phase into oil phase and stirred until homogenous gel is obtained. Homogenised if required.
6. Packaging: Packed the drug loaded gel into approved packing.

Example 2: Vaginal Gel composition comprising of 1% Dydrogesterone
Ingredient %w/w
Dydrogesterone micronized 1.000
Polycarbophil 2.250
Carbomer 1.125
Sorbic acid 0.090
Glycerin 14.510
Liquid Paraffin 4.725
Hydrogenated palm oil glyceride 1.125
Purified water q.s to make 100%

Process for Preparation:
Dispensing and Sifting: Dispensed all the materials. Sifted Dydrogesterone through appropriate sieve and collected in double lined polybag.
Aqueous Phase: Co-sifted polymers through# 20 mesh sieve and collected in double lined polybag. Dissolved the sorbic acid by heating the purified water up to 80 -95°C. Added Dydrogesterone into it and mix thoroughly. Added sifted polymers and stirred to allow soaking of polymers to make it homogenous.
Oil phase: Heated the glycerine, liquid paraffin, and hydrogenated palm oil at 60-75ºC.
Mixing of Aqueous phase and oil phase: Mixed the aqueous phase into oil phase with maintaining the same temperature for both phase 60-75ºCand stirred until homogenous gel is obtained. Homogenised if required.
Packaging: Packed the drug loaded gel into approved packing.

Gel composition of Example 2 was formulated and subjected to the stability study. The results of the stability study are shown in the below table as follows:
Test Specification Initial 25°C/60%RH 40°C/75%RH
3M 6M 3M 6M
pH 2.0 - 6.0 2.76 2.81 2.8 2.8 2.81
Viscosity (cps) For information only 11223 10300 10716 10034 12297
Assay (By HPLC) 90.0% to 110.0% of Labelled amount 100.8 101 97.3 97.2 97.8
Related Substances (wt%. By HPLC)
Dydrogesterone Impurity A Not more than 0.5% 0.05 0.06 0.04 0.06 0.04
Dydrogesterone Impurity B Not more than 0.5% 0.02 0.02 0.01 0.02 0.01
Dydrogesterone Impurity C Not more than 0.5% 0.05 0.04 0.04 0.04 0.05
Any unspecified degradation products Not more than 0.2% 0.002 0.03 0.05 0.04 0.06
Total Degradation products Not more than 1.5% 0.12 0.15 0.14 0.15 0.15

Example 3: Vaginal Gel composition comprising of 1% Dydrogesterone
Ingredient %w/w
Dydrogesterone micronized 1.000
Polycarbophil 0.500
Carbomer 0.500
Sorbic acid 0.090
Sodium Hydroxide q.s
Glycerin 15.000
Purified water q.s to make 100%

Process for Preparation:
1. Dispensed all the materials.
2. Sifted Dydrogesterone through appropriate sieve and collected in double lined polybag.
3. Sifted separately carbopol and polycarbophil through #20 mesh sieve and collected in double lined polybag.
4. Dissolved the sorbic acid by heating Purified water to 80-95°C. Cooled at room temp.
5. Divided the step 4 solution into 2 parts.
6. In one part added sifted Dydrogesterone and mix thoroughly. Added carbopol into it and stir to make homogeneous.
7. In second part added polycarbophil and stirred till homogenous gel is obtained.
8. Checked pH of step 6 materials and adjusted to 5.
9. Mixed the step 7 and 8 materials and measured pH. Added glycerine and water to make up the volume by stirring.
10. Homogenised if required.
11. Packed the drug loaded gel into approved packing.

Example 4: Cream composition comprising of Dydrogesterone
Ingredients Amount (in mg)
Dydrogesterone 10
Propylene Glycol 50.00
Methyl paraben 1.50
Propyl Paraben 0.30
Titanium dioxide 10.00
Emulsifying wax 170.00
Sorbitan Stearate 20.00
Corn oil 100.00
Butylated Hydroxyanisole 0.029
Propyl Gallate 0.029
Glycerine 50.00
Sorbitol solution (70% non-crystallizing) 30.00
Veegum 10.50
Polysorbate 80 15.00
Purified water q.s

Example 5-7: Vaginal Gel composition of Dydrogesterone
Ingredient Example 5 Example 6 Example 7
Dydrogesterone 10 mg 10 mg 10 mg
Hydroxypropyl Betacyclodextrin 450 mg 450 mg 450 mg
Benzalkonium chloride 1 mg 1 mg 1 mg
Hydroxy Propyl Methyl Cellulose 10 mg 25 mg 35 mg
Carbomer 974P - - -
Sodium Hydroxide
Water for injection (WFI) q.s. to 1ml q.s. to 1 ml q.s. to 1 ml

Process for Preparation:
1. Collect 30% Nitrogen purged water for injection in glass beaker.
2. Add the required quantity of Hydroxypropyl ß-cyclodextrin under stirring.
3. Add the required quantity of Dydrogesterone under stirring until clear solution obtained.
4. Add required quantity of Benzalkonium chloride under stirring till clear solution obtained.
5. Start heating the solution to 70° to 80°C (Target: 75°C) and add the required quantity of Hydroxypropyl methyl cellulose under stirring.
6. Stop the heating when solutions get cleared and kept for cooling to room temperature.
7. Volume make up to 100% batch size and check pH of bulk solution.
8. The above process provides a Viscous translucent gel

Example 8-11: Vaginal Gel composition of Dydrogesterone
Ingredient Example 8 Example 9 Example 10 Example 11
Dydrogesterone 10 mg 10 mg 10 mg 10 mg
Hydroxypropyl Betacyclodextrin 450 mg 450 mg 405 mg 360 mg
Benzalkonium chloride 1 mg 1 mg 1 mg 1 mg
Carbomer 974P 8 mg 6 mg 6 mg 6 mg
Sodium Hydroxide q.s. to pH 4 q.s. to pH 5.5
Water for injection (WFI) q.s. to 1 ml

Example 12-14: Vaginal Gel composition of Dydrogesterone
Name of Ingredient Example 12 Example 13 Example 14
Dydrogesterone 10 mg 10 mg 10 mg
Hydroxypropyl Betacyclodextrin 315 mg 270 mg 225 mg
Benzalkonium chloride 1 mg 1 mg 1 mg
Carbomer 974P 6 mg 6 mg 6 mg
Sodium Hydroxide q.s. to pH 5.5 q.s. to pH 5.5 q.s. to pH 5.5
Water for injection (WFI) q.s. to 1 ml q.s. to 1 ml q.s. to 1 ml

Process for Preparation:
1. Collect 30% Nitrogen purged water for injection in glass beaker.
2. Add the required quantity of Hydroxypropyl ß-cyclodextrin under stirring.
3. Sonicate the product, if required, to obtained the clear viscous solution.
4. Add the required quantity of Dydrogesterone under stirring until clear solution obtained.
5. Add required quantity of Benzalkonium chloride under stirring till clear solution obtained.
6. Add required quantity of Carbomer 974P under stirring till clear viscous solution obtained.
7. Check the pH and adjust the pH using 1N Sodium hydroxide solution under stirring.
8. Volume make up to 100% batch size.
9. The above process provides a Viscous translucent gel.

Dated this the 12th day of January 2024. For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer
,CLAIMS:We Claim:

1. A topical pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone and one or more pharmaceutically acceptable excipients.

2. The topical pharmaceutical composition as claimed in claim 1, wherein the dydrogesterone is present in amount of about 1mg to about 50mg.

3. The topical pharmaceutical composition as claimed in claim 1, wherein the topical pharmaceutical composition is in the form of cream, foam, ointment, lotion, aqueous gel or emulgel.

4. The topical pharmaceutical composition as claimed in claim 3, wherein the topical pharmaceutical composition is a vaginal gel.

5. The topical pharmaceutical composition as claimed in claim 1, wherein the topical pharmaceutical composition further comprises gelling agent(s).

6. The topical pharmaceutical composition as claimed in claim 5, wherein the gelling agent(s) is present in amount of about 0.1% w/w to about 25% w/w.

7. The topical pharmaceutical composition as claimed in claim 5, wherein the gelling agent(s) is selected from the group comprising polycarbophil, carbomer, gellan gum, xanthan gum, guar gum, chitosan, alginic acid and its salts, xyloglucan, pectin, hyaluronic acid-agar, carrageenan, shellac, hyaluronic acid derivatives, cellulose derivatives and combinations thereof.

8. The topical pharmaceutical composition as claimed in claim 5, wherein the gelling agent(s) are selected from the group comprising polycarbophil, carbomer or combinations thereof.

9. A topical pharmaceutical composition comprising dydrogesterone, one or more gelling agent(s) and one or more pharmaceutically acceptable excipients, wherein the dydrogesterone and gelling agent(s) is present in ratio of 1:30 to 30:1.

10. A topical pharmaceutical composition comprising about 1 mg to about 100 mg of dydrogesterone, gelling agent(s) in an amount of about 0.1% w/w to about 25% w/w, and one or more pharmaceutically acceptable excipients selected form the group comprising:
- one or more solubilizing agent(s) in an amount of about 0.01% w/w to about 80 % w/w,
- one or more co-solvent(s) in an amount of about 0.01% w/w to about 50 % w/w,
- viscosity modifier(s) in an amount of about 0.01% w/w to about 20 % w/w;
- buffering agent(s) in an amount of about 0.01% w/w to about 20 % w/w;
- preservative(s) in an amount of about 0.001% w/w to about 20% w/w;
- chelating agent(s) in an amount of about 0.001% w/w to about 10% w/w;
- antioxidant(s) in an amount of about 0.001% w/w to about 10% w/w;
- pH adjusting agent(s); based on the total weight of the composition.

Dated this the 12th day of January 2024. For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer