DESC:PARENTERAL PHARMACEUTICAL COMPOSITIONS OF DYDROGESTERONE

FIELD OF THE INVENTION
The present invention relates to a parenteral pharmaceutical composition comprising a therapeutically effective amount of Dydrogesterone or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients.

The present invention further provides a parenteral pharmaceutical composition comprising a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt and a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt, for monthly, fortnightly, once weekly, twice weekly, or thrice weekly administration for the treatment of progesterone deficiency disorders.

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.

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.

Solid oral compositions of Dydrogesterone are known in art. However, because of the slow gastrointestinal absorption and high hepatic metabolism of Dydrogesterone, achieving the desired plasma levels is often difficult with oral administration. Attempts have been made to provide optimal, stable parenteral pharmaceutical compositions of Dydrogesterone, however, because of the lipophilicity and low aqueous solubility of Dydrogesterone, there is currently no commercially available composition of Dydrogesterone for parenteral administration. After extensive experimentation and lots of efforts, the inventors have developed a parenteral pharmaceutical composition of Dydrogesterone. The parenteral pharmaceutical composition of the present invention combines the advantages of both rapid onset and long-acting dosage forms thereby providing immediate action and at the same time avoiding repeated administration. Reducing the number of dosing frequency (clinic visits) is particularly important for parenterals and one way to improve the ease of use of drugs is by reducing the number of dosing frequency through prolonged and continuous release and absorption of medicament. The present invention provides a more patient compliant parenteral pharmaceutical composition which is optimal, stable, with less to no irritation or pain at the site of injection and is suitable for monthly, fortnightly, once weekly, twice weekly, or thrice weekly administration.

OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a parenteral pharmaceutical composition of Dydrogesterone which is optimal, stable, with less to no irritation or pain at the site of injection

Another objective of the present invention is to provide a parenteral pharmaceutical composition which is suited for monthly, fortnightly, once weekly, or thrice weekly administration.

Another objective of the present invention is to provide a parenteral pharmaceutical composition comprising – a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt; a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt; and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a parenteral pharmaceutical composition comprising:
- a therapeutically effective amount of Dydrogesterone or its pharmaceutically acceptable salt; and
- one or more pharmaceutically acceptable excipients.
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According to one aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- about 1mg to about 50mg of Dydrogesterone or its pharmaceutically acceptable salt; and
- one or more pharmaceutically acceptable excipients.

According to another aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt;
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt; and
- one or more pharmaceutically acceptable excipients.

According to one more aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt,
wherein the ratio of Dydrogesterone or its pharmaceutically acceptable salt in the fast-acting component and the long-acting component is 10:1 to 1:20.

According to one more aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt,
wherein the parenteral pharmaceutical composition is having a pH in a range of about 2 to 10.

According to one more aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients selected form the group comprising solubilizing agent(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), or combinations thereof; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.

According to another aspect, the long acting component of the parenteral pharmaceutical composition of the present invention comprises dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of about 0.1 µm to about 50 µm.

According to another aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution of Dydrogesterone or its pharmaceutically acceptable salt, solubilizing agent(s) in an amount of about 0.01% w/v to about 80 % w/v, one or more co-solvent(s), and optionally, one or more pharmaceutically acceptable excipients; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.

According to one more aspect, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt, Hydroxypropyl-ß-cyclodextrin as a solubilizing agent, a co-solvent selected from polyethylene glycol, propylene glycol, ethanol, glycerin, N-methyl pyrrolidone, or a combination thereof, and optionally, one or more pharmaceutically acceptable excipients; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.
wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising:
i. buffering agent(s) in an amount of about 0.01% w/v to about 20 % w/v,
ii. preservative(s) in an amount of about 0.001% w/v to about 20% w/v,
iii. tonicity agent(s) in an amount of about 0.01% w/v to about 10% w/v,
iv. chelating agent(s) in an amount of about 0.001% w/v to about 10% w/v,
v. antioxidant(s) in an amount of about 0.001% w/v to about 10% w/v, of the pharmaceutical composition.

According to one aspect, the present invention provides sterile Dydrogesterone having D90 particle size of about 0.1 µm to about 100 µm, wherein the Sterile Dydrogesterone is obtained by Gamma Irradiation sterilization, Dry heat sterilization, Moist heat sterilization, Ethylene oxide sterilization, Electron beam sterilization, sterile filtration, or a combination thereof.

According to one aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) Collecting water in a suitable vessel;
(b) Adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt simultaneously or one after the other to step (a) followed by stirring;
(c) Optionally, adding one or more other pharmaceutically acceptable excipients to step (b) to obtain a final composition having a part of Dydrogesterone or its pharmaceutically acceptable salt in solution or solubilized form and a part of Dydrogesterone or its pharmaceutically acceptable salt in suspended form;
(d) Making up the volume of the composition of step (c) to 100% batch size with water; and
(e) Filling the composition of step (d) in vial(s).

According to one aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) Collecting water in a suitable vessel;
(b) Adding cosolvent(s), solubilizing agent(s), and a part of Dydrogesterone or its pharmaceutically acceptable salt simultaneously or one after the other to step (a) to obtain a clear solution;
(c) Optionally, adding one or more other pharmaceutically acceptable excipients to the solution of step (b);
(d) Filtering the solution of step (c);
(e) Adding remaining part of Dydrogesterone or its pharmaceutically acceptable salt to the solution of step (d) that remains in suspended form to obtain a final composition;
(f) Optionally, adjusting the pH of the composition of step (e);
(g) Making up the volume of the composition of step (e) or (f) to 100% batch size with water; and
(f) Filling the composition of step (g) in vial(s).

According to another aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) Collecting water in a suitable vessel;
(b) Adding Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients in a portion of water of step (a) to obtain a suspension;
(c) Optionally, adjusting the pH of the suspension of step (b);
(d) Adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in a portion of water of step (a) to obtain a clear solution;
(e) Optionally, adjusting the pH of the solution of step (d);
(f) Filtering the solution of step (e);
(g) Mixing the suspension of step (b) or step (c) and the solution of step (f) to obtain a final composition;
(h) Optionally, adjusting the pH of the composition;
(g) Filling the composition of step (h) in vial(s).

According to another aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
1. Sterilizing Dydrogesterone or its pharmaceutically acceptable salt:
Subjecting Dydrogesterone or its pharmaceutically acceptable salt to Gamma Irradiation sterilization, Dry heat sterilization, Moist heat sterilization, Ethylene oxide sterilization, Electron beam sterilization, sterile filtration or a combination thereof to obtain sterile Dydrogesterone or its pharmaceutically acceptable salt,
2. Preparing a solubilized phase:
(a) Collecting water in a suitable vessel;
(b) Adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in water of step (a) followed by stirring;
(c) Optionally, adding one or more other pharmaceutically acceptable excipients to the solution of step (b);
(d) Optionally, adjusting the pH of the solution of step (c);
(e) Making up the volume of the solution of step (d) with water to obtain a solubilized phase;
(f) Filtering the solubilized phase,
3. Preparing a slurry phase:
(a) Collecting water in a suitable vessel;
(b) Adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in water of step (a) followed by stirring;
(c) Optionally, adding one or more other pharmaceutically acceptable excipients to step (b) to obtain a slurry;
(d) Milling the slurry to achieve a desired particle size,
4. Mixing the solubilized phase and the slurry phase under stirring,
5. Optionally, making up the volume of the solution of step (4) with water to obtain a final composition,
6. Filling the composition of step (5) in vial(s), and optionally, terminally sterilizing the composition filled vial(s).

According to one more aspect, the present invention provides a parenteral pharmaceutical composition comprising therapeutically effective amount of Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients; wherein the composition is administered for treatment of progesterone deficiency, threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, and/or pre-eclampsia.

According to one more aspect, the present invention provides a dosing schedule comprising administering a parenteral composition comprising about 1mg to about 50mg of Dydrogesterone or its pharmaceutically acceptable salt for the treatment of progesterone deficiency disorders, wherein the parenteral composition comprises:
- a fast-acting component that provides a loading dose of Dydrogesterone or its pharmaceutically acceptable salt on the first day of administration; and
- a long-acting component that provides subsequent maintenance dose of Dydrogesterone or its pharmaceutically acceptable salt over a period of 2-7 days.

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

DESCRIPTION OF THE INVENTION
The present invention provides a parenteral pharmaceutical composition comprising a therapeutically effective amount of Dydrogesterone or its pharmaceutically acceptable salt, 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.

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 composition of the invention can be biphasic, triphasic, or multiphasic based on the number of components with varying onset of action and/or varying duration of action. The term “onset of action” refers to the duration of time it takes for a drug’s effects to come to prominence upon administration. The term “duration of action” refers to the length of time of a drug for which the drug remains effective.

In particular, the present invention provides a parenteral pharmaceutical composition comprising a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt and a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt.

The term “fast-acting component” refers to a component with a rapid onset of action to provide a rapid relief of symptoms on administration or provides a loading dose of Dydrogesterone or its pharmaceutically acceptable salt on the first day of administration. The fast-acting component in other words is a component that provides a rapid onset of action, within 10 minutes or less, 15 minutes or less, 30 minutes or less, 1 hour or less, 24 hours or less.

The term “long-acting component” refers to a component with a longer duration of action or provides maintainence dose of Dydrogesterone or its pharmaceutically acceptable salt over a period of 2 to 30 days, preferably 5-15 days, more preferably for 2-7 days. The long-acting component in other words provides a long-term alleviation effect over 24 hours or longer, 48 hours or longer, 72 hours or longer, 96 hours or longer, 120 hours or longer and so on. The combination of fast-acting component and long-acting component provides a composition that is suitable for monthly, fortnightly, once weekly, twice weekly, or thrice weekly administration.

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 its pharmaceutically acceptable salt which is sufficient to elicit an appreciable biological response for required duration when administered to the patient.

The term “composition” or “pharmaceutical composition” or “parenteral pharmaceutical composition” or “dosage form” or “pharmaceutical composition” or “composition” as used herein synonymously include the pharmaceutical compositions in a form suitable for parenteral administration such as but not limited to sterile aqueous, hydro-alcoholic, or non-aqueous suspension, aqueous, hydro-alcoholic, or non-aqueous solution, or emulsion, suspension, liposomes, microparticles, or the like or any other suitable dosage form meant for parenteral administration. The parenteral pharmaceutical composition includes ready-to-use injectable and injection concentrates to be used post dilution. Further, parenteral pharmaceutical composition includes pharmaceutical composition for intramuscular, intravenous, sub-cutaneous, and intrathecal administration. In one embodiment, the pharmaceutical composition may be in the form of a unit dose composition or multi-dose composition.

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. “Pharmaceutically acceptable salt” or “salt” as used herein also includes prodrugs or esters of Dydrogesterone.

The term “excipient” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component. As pharmaceutical excipients have various functions and contribute to the pharmaceutical composition in many different ways, e.g., solubilisation, dilution, thickening, stabilization, prolonged release, and preservation. The properties that are commonly considered when formulating an active drug substance include bioavailability, ease of manufacture, ease of administration, onset and duration of action, 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.

Suitable “pharmaceutically acceptable excipients” include, without limitation, solubilizing agent(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), slow release polymer(s), or combinations thereof.

Suitable solubilizing agents include, without limitation, surfactants, lipids, organic 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/v to about 70% w/v of the pharmaceutical composition.

Suitable surfactants include, without limitation, poloxamers, polysorbates, alkylaryl polyethers, polyoxyethyleneglycol alkyl ethers, tyloxapol, 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 limitaion 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, a non-ionic surfactant may be employed in an amount ranging from about 0.01% w/v to about 50% w/v of the pharmaceutical composition.

Suitable lipids include, without limitation, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, palm seed oil, and combinations thereof.

Suitable organic liquids/semi-solids include, without limitation, beeswax, d-a-tocopherol, oleic acid, vegetable oils, ethyl oleate, propylene glycol, and polyethylene glycol, isopropyl myristate, glycerine, medium-chain mono- and di- glycerides, and combinations thereof. When present, organic liquids/semi-solids may be employed in an amount ranging from about 0.01% w/v to about 50% w/v of the pharmaceutical composition.

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/v to about 50% w/v of the pharmaceutical composition.

Suitable phospholipids include, without limitation, hydrogenated soy phosphatidyl choline, distearoyl phosphatidyl glycerol, l-a-dimyristoylphosphatidylcholine, l-a-dimyristoyl phosphatidyl glycerol, and combinations thereof. When present, phospholipid(s) may be employed in an amount ranging from about 0.01% w/v to about 50% w/v of the pharmaceutical composition.

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% v/v to about 70% v/v of the pharmaceutical composition or equivalent weight conversion based on the density of the solvent.

Suitable buffering agent(s) include, without limitation, to 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/v to about 25% w/v of the pharmaceutical composition.

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 15% w/v of the composition.

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 0.001% w/v to about 25.0% w/v of the pharmaceutical composition.

According to one embodiment of the present invention the pharmaceutical composition is free of preservative.

Suitable chelating agent(s) includes, without limitation, ethylenediaminetetraacetic acid and metal salts thereof, such as disodium edetate, trisodium edetate, tetrasodium edetate or mixtures thereof. When present, the chelating agent(s) may be added in an amount of about 0.001% w/v to about 15.0% w/v of the pharmaceutical composition.

Suitable antioxidant(s) include, but are not limited to, 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, Vitamin E and its derivatives e.g. Vitamin E TPGS and/or combinations thereof.

Suitable slow release polymer(s) include, but are not limited to, poly (ethylene glycol)/poly (propylene glycol) block copolymers (poloxamers), poly (ethylene glycol)/ poly (butylenes glycol) block copolymers, poloxamer-g-poly (acrylic acid). Diblock copolymers of poly (ethylene oxide) (PEG) and poly (lactic acid) (PLA), and triblock copolymers of PEG-PLGA- PEG. Some natural polymers including gelatin, agarose, amylase, amylopectin, cellulose derivatives, carrageenans, and gellan, exhibit thermoreversible gelation behavior. Some cellulose derivatives of natural polymers, such as hydroxypropyl methylcellulose, methyl cellulose and hydroxypropyl cellulose.

The pH adjusting agent is typically a mineral acid or metal hydroxide base preferably selected from the group of potassium hydroxide, sodium hydroxide, hydrochloric acid, or mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH adjusting agents are added to adjust the composition to the target pharmaceutically acceptable pH range. Hence, it may not be necessary to use both acid and base - depending on the composition, 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 2 to 11, preferably 2 to 10, more preferably 4 to 8.

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, glycerine, propylene glycol, corn oil, peanut oil, cotton seed oil, or combinations thereof. Solvent is present in an amount of more than 10% v/v, preferably more than 50% v/v of the pharmaceutical composition.

According to one embodiment, the present invention provides a parenteral pharmaceutical composition comprising about 1mg to about 100mg of Dydrogesterone, preferably 1mg to 50 mg of Dydrogesterone, and one or more pharmaceutically acceptable excipients.

According to one embodiment, the present invention provides a parenteral pharmaceutical composition comprising a fast-acting component comprising Dydrogesterone and a long-acting component comprising Dydrogesterone.
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According to one embodiment of the invention, the ratio of Dydrogesterone or its pharmaceutically acceptable salt in the fast-acting component and the long-acting component of the parenteral pharmaceutical composition of the present invention is 10:1 to 1:20.

According to one embodiment of the present invention, the fast-acting component of the parenteral pharmaceutical composition of the present invention comprises about 1mg to about 50mg Dydrogesterone, preferably 1mg to 20 mg of Dydrogesterone, more preferably 1mg, 2mg, 3mg, 5mg, or 10mg of Dydrogesterone.

According to another embodiment of the present invention, the long-acting component of the parenteral pharmaceutical composition of the present invention comprises about 1mg to about 100mg Dydrogesterone or its pharmaceutically acceptable salt, preferably 1mg to 50 mg of Dydrogesterone or its pharmaceutically acceptable salt.

According to one embodiment of the present invention, the fast-acting component of the parenteral pharmaceutical composition of the present invention comprises solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt and the long-acting component of the parenteral pharmaceutical composition of the present invention comprises suspended form or slow release form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt. The solution or solubilized form act as fast-acting component and provides for rapid and immediate absorption of Dydrogesterone or its pharmaceutically acceptable salt upon administration. Suspended form or slow release form or slow release particles act as long-acting component and provides for slower dissolution/release and prolonged absorption of Dydrogesterone or its pharmaceutically acceptable salt upon administration.

According to another embodiment, the suspended form, slow release form or slow release particles include crystals or particles of Dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of 0.1µm to 100µm or 0.1µm to 50µm, or 0.1µm to 20µm having low solubility, and are dissolved and absorbed slowly or the particles such as matrices or reservoirs comprising Dydrogesterone or its pharmaceutically acceptable salt and one or more slow release polymers.

According to one embodiment, the long acting component of the parenteral pharmaceutical composition of the present invention comprises dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of about 0.1 µm to about 100 µm or 0.1µm to 50µm, 0.1µm to 20µm, or 0.1µm to 20µm.

According to one more embodiment, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients selected form the group comprising solubilizing agent(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), or combinations thereof; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt, solubilizing agent(s) in an amount of about 0.01% w/v to about 80 % w/v, and optionally, one or more pharmaceutically acceptable excipients; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.

According to another embodiment, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt, solubilizing agent(s) in an amount of about 0.01% w/v to about 80 % w/v, one or more co-solvent(s), and optionally, one or more pharmaceutically acceptable excipients; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.

According to one more embodiment, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising a solution or solubilized form of Dydrogesterone or its pharmaceutically acceptable salt, Hydroxypropyl-ß-cyclodextrin as a solubilizing agent, a co-solvent selected for polyethylene glycol, propylene glycol, ethanol, glycerin, N-methyl pyrrolidone, or a combination thereof, and optionally, one or more pharmaceutically acceptable excipients; and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt in suspended form or slow release particles of Dydrogesterone or its pharmaceutically acceptable salt and optionally, one or more pharmaceutically acceptable excipients.
wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising:
i. buffering agent(s) in an amount of about 0.01% w/v to about 20 % w/v,
ii. preservative(s) in an amount of about 0.001% w/v to about 20% w/v,
iii. tonicity agent(s) in an amount of about 0.01% w/v to about 10% w/v,
iv. chelating agent(s) in an amount of about 0.001% w/v to about 10% w/v,
v. antioxidant(s) in an amount of about 0.001% w/v to about 10% w/v, of the pharmaceutical composition.

According to another embodiment, the fast-acting component of the parenteral pharmaceutical composition of the present invention comprises Dydrogesterone or its pharmaceutically acceptable salt and Hydroxypropyl-ß-cyclodextrin, and optionally, one or more pharmaceutically acceptable excipients, and water for injection; wherein Dydrogesterone or its pharmaceutically acceptable salt and Hydroxypropyl-ß-cyclodextrin are present in a molar ratio of about 1:1 to about 1:20.

According to another embodiment, the fast-acting component of the parenteral pharmaceutical composition of the present invention comprises about 1 mg to about 50 mg of Dydrogesterone or its pharmaceutically acceptable salts, Hydroxypropyl-ß-cyclodextrin in an amount of about 1% w/v to about 50 % w/v of the fast-acting component, a cosolvent selected from polyethylene glycol, propylene glycol, ethanol, glycerin, N-methyl pyrrolidone, or a combination thereof in an amount of about 1% v/v to about 50% v/v of the fast-acting component, optionally, one or more pharmaceutically acceptable excipients, and water for injection.

According to another embodiment, the parenteral pharmaceutical composition of the present invention comprises Dydrogesterone or its pharmaceutically acceptable salt in solution or solubilized form and in suspended form or slow release form in a ratio of 10:1 to 1:20. In one embodiment 1% to 90% by weight of the total dydrogesterone or its pharmaceutically acceptable salt is in solution or solubilized form. In another, embodiment 1% to 90% by weight of the total dydrogesterone or its pharmaceutically acceptable salt is in suspended form or slow release form.

According to one embodiment of the present invention, the present invention provides a parenteral pharmaceutical composition comprising:
- a fast-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of less than 0.1µm and
- a long-acting component comprising Dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of more than 0.1µm.
- one or more pharmaceutically acceptable excipients.

According to one embodiment, Dydrogesterone or its pharmaceutically acceptable salt having a smaller particle size of D90 of less than 0.1µm in fast-acting component and Dydrogesterone or its pharmaceutically acceptable salts having a larger particle size of D90 of more than about 0.1µm in long-acting component are present in the ratio of 10:1 to 1:20. The inclusion of Dydrogesterone or its pharmaceutically acceptable salt having a smaller particle size of D90 of less than 0.1µm in fast-acting component promotes rapid dissolution and absorption, and the inclusion of Dydrogesterone its pharmaceutically acceptable salts having a larger particle size of D90 of more than about 0.1µm in long-acting component promotes slower dissolution and absorption.

According to one embodiment of the present invention, the parenteral pharmaceutical composition of the present invention is an emulsion comprising an oily phase and an aqueous phase. In particular, an oil-in-water emulsion. In one embodiment, the oily phase comprises solubilized form of Dydrogesterone and the aqueous phase comprises Dydrogesterone in slow release form or suspended form. In another embodiment, the oil phase comprises Dydrogesterone in slow release form or suspended form and the aqueous phase comprises solubilized form of Dydrogesterone.

According to one aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) collecting water in a suitable vessel;
(b) adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt simultaneously or one after the other to step (a) followed by stirring;
(c) optionally, adding one or more other pharmaceutically acceptable excipients to step (b) to obtain a final composition having a part of Dydrogesterone or its pharmaceutically acceptable salt in solution or solubilized form and a part of Dydrogesterone or its pharmaceutically acceptable salt in suspended form;
(d) making up the volume of the composition of step (c) to 100% batch size with water; and
(e) filling the composition of step (d) in vial(s).

According to one aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) collecting water in a suitable vessel;
(b) adding cosolvent(s), solubilizing agent(s), and a part of Dydrogesterone or its pharmaceutically acceptable salt simultaneously or one after the other to step (a) to obtain a clear solution;
(c) optionally, adding one or more other pharmaceutically acceptable excipients to the solution of step (b);
(d) filtering the solution of step (c);
(e) adding remaining part of Dydrogesterone or its pharmaceutically acceptable salt to the solution of step (d) that remains in suspended form to obtain a final composition;
(f) optionally, adjusting the pH of the composition of step (e);
(g) making up the volume of the composition of step (e) or (f) to 100% batch size with water; and
(f) filling the composition of step (g) in vial(s).

According to another aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
(a) collecting water in a suitable vessel;
(b) adding Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients in a portion of water of step (a) to obtain a suspension;
(c) optionally, adjusting the pH of the suspension of step (b);
(d) adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in a portion of water of step (a) to obtain a clear solution;
(e) optionally, adjusting the pH of the solution of step (d);
(f) filtering the solution of step (e);
(g) mixing the suspension of step (b) or step (c) and the solution of step (f) to obtain a final composition;
(h) optionally, adjusting the pH of the composition;
(g) filling the composition of step (h) in vial(s).

According to another aspect, the present invention provides a process for preparation of a parenteral pharmaceutical composition comprising Dydrogesterone or its pharmaceutically acceptable salt, wherein said process comprises:
1. sterilizing Dydrogesterone or its pharmaceutically acceptable salt:
Subjecting Dydrogesterone or its pharmaceutically acceptable salt to Gamma Irradiation sterilization, Dry heat sterilization, Moist heat sterilization, Ethylene oxide sterilization, Electron beam sterilization, sterile filtration or a combination thereof to obtain sterile Dydrogesterone or its pharmaceutically acceptable salt,
2. Preparing a solubilized phase:
(a) collecting water in a suitable vessel;
(b) adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in water of step (a) followed by stirring;
(c) optionally, adding one or more other pharmaceutically acceptable excipients to the solution of step (b);
(d) optionally, adjusting the pH of the solution of step (c);
(e) making up the volume of the solution of step (d) with water to obtain a solubilized phase;
(f) filtering the solubilized phase,
3. Preparing a slurry phase:
(a) collecting water in a suitable vessel;
(b) adding cosolvent(s), solubilizing agent(s), and Dydrogesterone or its pharmaceutically acceptable salt, simultaneously or one after the other in water of step (a) followed by stirring;
(c) optionally, adding one or more other pharmaceutically acceptable excipients to step (b) to obtain a slurry;
(d) milling the slurry to achieve a desired particle size,
4. mixing the solubilized phase and the slurry phase under stirring,
5. optionally, making up the volume of the solution of step (4) with water to obtain a final composition,
6. filling the composition of step (5) in vial(s), and optionally, terminally sterilizing the composition filled vial(s).

According to one aspect, the present invention provides a process for the preparation of a parenteral pharmaceutical formulation comprising:
(a) an oily phase comprising Dydrogesterone or its pharmaceutically acceptable salt and one or more lipid(s);
(b) an aqueous phase comprising Dydrogesterone or its pharmaceutically acceptable salt and on or more pharmaceutically acceptable excipients;
(c) mixing the oily phase and aqueous phase and emulsifying in the presence of a surfactant;
(d) optionally, adding pH adjusting agent(s) to adjust the pH and homogenizing under high-pressure;
(e) filling the composition of step (d) in vial(s), and optionally, terminally sterilizing the composition filled vial(s).

In one embodiment, terms suspension, suspended form, slow release form, and slurry are used interchangeably. In another embodiment, slurry refers to a concentrated suspension.

According to one embodiment, the present invention provides a parenteral pharmaceutical composition comprising therapeutically effective amount of Dydrogesterone or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients; wherein the composition is administered for 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, heavy menstrual bleeding.

According to other embodiment, the present invention provides a dosing schedule comprising administering a parenteral composition comprising about 1mg to about 100mg, preferably 1mg to 50mg of Dydrogesterone or its pharmaceutically acceptable salt for the treatment of progesterone deficiency disorders, wherein the parenteral composition comprises:
- a fast-acting component that provides a loading dose of Dydrogesterone or its pharmaceutically acceptable salt on the first day of administration; and
- a long-acting component that provides subsequent maintenance dose of Dydrogesterone or its pharmaceutically acceptable salt over a period of 2-7 days.

According to one embodiment, the composition of the present invention is suitable for monthly, fortnightly, once weekly, twice weekly, or thrice weekly administration.

The present invention further relates to a process for preparation of parenteral pharmaceutical composition of Dydrogesterone or its pharmaceutically acceptable salt, wherein the process comprises inert gas purging such as Nitrogen purging to reduce the oxygen concentration or flushing with oxygen-free gas, substitution with oxygen-free gas, or bubbling with oxygen-free gas such as Nitrogen.

The present invention further relates to a package or storage container for packaging or storing the parenteral pharmaceutical composition, wherein the package or container is made up of material that blocks oxygen or is impervious to oxygen or comprises an oxygen scavenger.

In one embodiment, the composition of the present invention can be prepared aseptically and terminally sterilized.

The pharmaceutical compositions as per the present invention can be bulk sterilized and/or terminally sterilized using any methods, such as filtration, moist heat, dry heat, gas sterilization or irradiation (gamma and electron beam). The container in which composition is filled can be sterilized using oven, autoclaving, gamma irradiation or ethylene oxide or pre-acetic acid or any other conventional method of sterilization.

According to one embodiment, the Dydrogesterone or its pharmaceutically acceptable salt used in the invention is sterilized Dydrogesterone or its pharmaceutically acceptable salt.

One embodiment of the present invention provides sterile dydrogesterone or its pharmaceutically acceptable salt having D90 particle size of 0.1µm to 100 µm or 0.1µm to 50 µm or 0.1µm to 20 µm or 0.1µm to 10 µm.

Sterile Dydrogesterone or its pharmaceutically acceptable salt according to the present invention can be obtained by Gamma Irradiation sterilization, Dry heat sterilization, Moist heat sterilization, Ethylene oxide sterilization, Electron beam sterilization, sterile filtration, or a combination thereof.
In another embodiment of the present invention, there is provided a parenteral pharmaceutical composition comprising a fast-acting component and a long-acting component, wherein the long-acting component is prepared by the milling process or precipitation process.

In another embodiment of the present invention, there is provided a parenteral pharmaceutical composition comprising a fast-acting component and a long-acting component, wherein the long-acting component is prepared by the milling process, wherein the particle size of dydrogesterone is D10 about 0.1µm to 2µm.

In another embodiment of the present invention, there is provided a parenteral pharmaceutical composition comprising a fast-acting component and a long-acting component, wherein the long-acting component is prepared by the milling process, wherein the particle size of dydrogesterone is D50 is about 0.5µm to about 10µm.

In another embodiment of the present invention, there is provided a parenteral pharmaceutical composition comprising a fast-acting component and a long-acting component, wherein the long-acting component is prepared by the milling process, wherein the particle size of dydrogesterone is D90 is about 1µm to about 20µm.

In another embodiment of the present invention, there is provided a parenteral pharmaceutical composition comprising a fast-acting component and a long-acting component, wherein the long-acting component is prepared by the precipitation process, wherein the particle size of dydrogesterone is D90 is about 0.1µm to about 15µm.

In another embodiment of the present invention, there is provided a stable parenteral pharmaceutical composition of Dydrogesterone or its pharmaceutically acceptable salt wherein the assay of the Dydrogesterone is 9.38 mg/ml.

According to one embodiment, the Dydrogesterone or its pharmaceutically acceptable salt in the slurry phase or suspended form or slow release form is milled using bead mill, piston gap homogenizer, colloidal mill, ball mill, or any other method to achieve the desired particle size.

In another embodiment of the present invention, there is provided a stable parenteral pharmaceutical composition of Dydrogesterone or its pharmaceutically acceptable salt, wherein said composition is stable at 40 °C ± 2 °C and 75% ± 5% Relative Humidity (RH) for at least one month, at least three months, at least six months.

In another embodiment of the present invention, there is provided a stable parenteral pharmaceutical composition of Dydrogesterone or its pharmaceutically acceptable salt, wherein said composition is stable at 25 °C ± 2 °C and 60% ± 5% RH for a period of at least three months, at least six months, at least twelve months.

In another embodiment of the present invention, there is provided a stable parenteral pharmaceutical composition of Dydrogesterone or its pharmaceutically acceptable salt, wherein the composition is having impurities below Regulatory Agency’s acceptable daily intake limit. The total impurity(is) of about 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less at 40 °C ± 5 °C and 75% ± 5% RH for a period of at least six months or at 25 °C ± 2 °C and 60% ± 5% RH for a period of at least twelve months.

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.
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.
S. No. Ingredient % w/v of the total composition
Fast-Acting Component
1 Dydrogesterone 0.1-10%
2 Solubilizing agent(s) 0.01-80%
3 Cosolvent(s) 0.01-80%
Long-Acting component
4 Dydrogesterone (D90 =0.1 µm) 0.1-10%
Optionally, one or more pharmaceutically acceptable excipients:
5 Buffering agent(s) 0.01-20%
6 Preservative(s) 0.001-20%
7 Tonicity agent(s) 0.01-10%
8 Antioxidant(s) 0.001-10%
9 Chelating agent(s) 0.001-10%
Volume makeup and pH adjustment
10 pH adjusting agent(s) q.s.
11 Solvent(s) q.s.

Example 1-5: Pharmaceutical composition of Dydrogesterone
S. No Name of Ingredient Quantity
1 2 3 4 5
Fast-Acting Component
1 Dydrogesterone 5mg 5mg 5mg 5mg 5mg
2 Hydroxypropyl-ß-cyclodextrin - - - 225mg 225mg
3 PEG 400 0.20ml - -- - -
4 Ethanol 0.50ml 0.60ml 0.50ml 0.50ml 0.30ml
5 N-methyl pyrrolidone 0.19ml 0.19ml 0.19ml - -
6 Sodium chloride 9mg 9mg 9mg 9mg -
Long-Acting Component
7 Dydrogesterone (D90 - 0.1µm to 50µm) 5mg 5mg 5mg 5mg 5mg
9 Water for injection q.s. to 1ml
Buffer and pH Adjusting agent to adjust pH ?7, if required.

Process:
1. collecting water for injection in a vessel;
2. adding ethanol to water for injection of step 1 with stirring;
3. adding excipient(s) 2, 3, 5, and/or 6 and kept stirring till clear solution is formed;
4. adding dydrogesterone to step 3 and kept stirring continuously till a clear solution is obtained;
5. optionally, adjusting the pH and filtered the solution;
6. adding Dydrogesterone (D90 =0.1 µm) and stirred to obtain a composition;
7. optionally, adjusted the pH;
8. making up the volume with water for injection to 100% batch size;
9. filling the composition in glass vial(s).

Example 6-11: Pharmaceutical composition of Dydrogesterone
S. No Name of Ingredient Quantity
6 7 8 9 10 11
Fast-Acting component
1 Dydrogesterone 5mg 5mg 5mg 5mg 5mg 5mg
2 Hydroxypropyl-ß-cyclodextrin 450mg 450mg 360mg 270mg 135mg 225mg
3 Ethanol - - 0.3ml 0.3ml 0.4ml 0.2ml
4 N-methyl pyrrolidone - - - - 0.15ml 0.15ml
5 Water for injection q.s. to 1ml
Long-Acting component
6 Dydrogesterone (D90 - 0.1µm to 50µm) 5mg 5mg 5mg 5mg 5mg 5mg
7 Sodium chloride - 9mg - 9mg - 9mg
5 Water for injection q.s. to 1ml
Buffer and pH Adjusting agent to adjust pH ?7, if required.
Process:
1. collecting water for injection in a vessel;
2. adding ethanol to water for injection of step 1 with stirring;
3. adding excipient(s) 2 and/or 4 and kept stirring till clear solution is formed;
4. adding dydrogesterone to step 3 and kept stirring continuously till a clear solution is obtained;
5. optionally, adjusting the pH;
6. making up the volume with water for injection;
7. filtering the solution;
8. collecting water for injection in a vessel;
9. adding Sodium chloride to water for injection of step 8 with stirring;
10. filtering the solution;
11. adding dydrogesterone (D90 =0.1 µm) to step 10 and stirred to obtain a suspension;
12. optionally, adjusting the pH;
13. mixing the solution of step 7 and the suspension of step 12 to obtain a final composition;
14. filling in glass vial(s);
15. autoclaving at 121 °C for 15 - 30 minutes at 15 psi.

Example 12-16: Pharmaceutical composition of Dydrogesterone
S No. Ingredient Quantity
12 13 14 15 16
1. Dydrogesterone (sterile) 10 mg 10 mg 10 mg 10 mg 10 mg
2. Hydroxypropyl Betacyclodextrin 225 mg 135 mg 225 mg 225 mg 225 mg
3. Ethanol 300 µL 300 µL - -
4. N-methyl pyrrolidone - - - 190 µL 190 µL
5. Benzyl alcohol - - 30 mg 12 mg -
6. Sodium Chloride - - 9 mg 9 mg -
7. Polysorbate 80 5 mg 5 mg 5 mg 5 mg 5 mg
8. Water for Injection q.s. to 1 mL

Process:
1) Preparation of Sterile Dydrogesterone:
Sterile Dydrogesterone is produced by Gamma Irradiation sterilization, Dry heat sterilization, Moist heat sterilization, Ethylene oxide sterilization, Electron beam sterilization, sterile filtration or a combination of any.
2) Preparation of solubilized phase:
a. collecting the required quantity of water for injection in a SS316L vessel with lid;
b. adding excipients 2, 3, 4, 5, 6, and/or 7 and Dydrogesterone simultaneously or one after the other to step (a) followed by stirring to obtain a solubilized phase;
c. making up the volume of the composition of step (b) to 100% batch size with water; and
d. sterile filtering the solubilized phase.
3) Preparation of slurry phase
a. collecting the required quantity of water for injection in a SS316L vessel;
b. adding excipients 2, 3, 4, 5, 6, and/or 7 and Dydrogesterone simultaneously or one after the other to step (a) followed by stirring to obtain a slurry;
c. milled the slurry under aseptic conditions using bead mill, piston gap homogenizer, colloid mill, or any other method to achieve appropriate particle size.
4) Mixing of the solubilized drug phase and the slurry phase to produce final suspension
a. The slurry phase of step 3(c) is adding to the solubilized phase of step 2(d) under stirring to produce the final suspension bulk;
5) filling in the final vial (s) and optionally, terminally sterilized.

Example 17-18: Pharmaceutical composition of Dydrogesterone
S. No
Name of Ingredient
Quantity
12 13
Fast-Acting Component
1 Dydrogesterone 5 mg 5 mg
2 Ethanol 0.25ml 0.25ml
3 Benzyl Alcohol 0.12ml 0.12ml
4 Propylene glycol 0.25ml 0.18ml
Long-Acting Component
5 Dydrogesterone (D90 - 0.1µm to 20µm) 5mg 5mg
6 Water for injection (WFI) q.s. to 1ml q.s. to 1ml

Process:
1. collecting water for injection in a vessel;
2. adding ethanol, propylene glycol, benzyl alcohol to water for injection of step 1 with stirring;
3. adding dydrogesterone and kept stirring till clear solution is formed;
4. optionally, adjusting the pH and filtered the solution;
5. adding Dydrogesterone (D90 =0.1 µm) and stirred;
6. optionally, adjusting the pH;
7. making up the volume with water for injection to 100% batch size;
8. filling the composition in glass vial(s);
9. optionally, autoclaving at 121° C for 15 - 30 min at 15 psi.

Example 19: Pharmaceutical suspension of Dydrogesterone
S. No. Ingredient % w/v of the total composition
1 Dydrogesterone D90 = 0.1 µm 0.1-10%
2 Dydrogesterone D90 =0.1 µm 0.1-10%
One or more pharmaceutically acceptable excipients:
3 Solubilizing agent(s) 0.01-70%
4 Cosolvent(s) 0.01-70%
5 Buffering agent(s) 0.01-25%
6 Preservative(s) 0.001-25%
7 Tonicity agent(s) 0.01-15%
8 Antioxidant(s) 0.001-15%
9 Chelating agent(s) 0.001-15%
Volume makeup and pH adjustment
10 pH adjusting agent(s) q. s.
11 Solvent(s) q. s.

Example 20-31 – Parenteral Pharmaceutical composition of Dydrogesterone
Excipient/Example 20 21 22 23 24 25 26 27 28 29 30 31
Dydrogesterone 10 mg
Hydroxypropyl Betacyclodextrin 225 mg 180 mg 135 mg 90 mg 67.5 mg 45 mg 90 mg 78.75 mg 67.5 mg 56.25 mg 50.625 mg 45 mg
Polysorbate 80 4 mg
Sodium phosphate Monobasic dihydrate 3.8 mg
Sodium phosphate dibasic dihydrate 8.9 mg
Disodium edetate 0.1 mg
Water for injection (WFI) q.s. to 1 mL
pH 7.15
Assay of Dydrogesterone (mg/mL) 9.38
Soluble fraction of Dydrogesterone (mg/mL) - 8.68 8.42 8.63 5.83 4.37 2.84 6.1 5.25 4.45 3.66 3.19

Process:
A. Dydrogesterone solution phase (70% of batch size) -
i. solubilizing the EDTA disodium dihydrate, dibasic sodium phosphate dihydrate and monobasic sodium phosphate dihydrate into water for injection (WFI) under stirring;
ii. adding Hydroxypropyl betacyclodextrin to above solution as obtained in step A(i) and allow it to solubilize under stirring followed by adding Dydrogesterone to above step under stirring condition and solution stirred until Dydrogesterone completely solubilized;
iii. making up the volume of Dydrogesterone solution to batch size.
B. Dydrogesterone slurry phase (10% of batch size)
i. solubilizing the Polysorbate 80 into water for injection (WFI) under stirring condition and further adding Dydrogesterone to above step under stirring and allowing to stir until properly wetted;
ii. making up the volume of Dydrogesterone slurry phase to batch size.
C. Dydrogesterone suspension preparation
i. mixing the Dydrogesterone solution phase and Dydrogesterone slurry phase under stirring condition and further making up the volume of Dydrogesterone Suspension to batch size.

Example 32 - 43: Parenteral Pharmaceutical composition of Dydrogesterone
Excipient/Example 32 33 34 35 36 37 38 39 40 41 42 43
Dydrogesterone 10 mg 30 mg
Hydroxypropyl Betacyclodextrin 45 mg 67.5 mg 90 mg
Ethanol 150 uL 120 uL 100 uL 150 uL 120 uL 100 uL 150 uL 120 uL 100 uL 150 uL 150 uL 150 uL
Polysorbate 80 4 mg 7.5 mg 6.0 mg
Sodium phosphate Monobasic dihydrate 3.8 mg
Sodium phosphate dibasic dihydrate 8.9 mg
Disodium edetate 0.1 mg
Polyvinyl alcohol 5.9 mg
Water for injection q.s. to 1 mL
pH - - - 7.48 7.41 7.39 7.4 7.36 7.25 - 7.39 -
Viscosity (cps) - - - 2.37 1.95 1.71 2.1 2.95 2.57 - - -
Soluble fraction of Dydrogesterone (mg/mL) 1.89 1.98 2.06 2.8 2.91 2.6 2.8 3.95 4.12 4.37 - -
Particle size (um) D10 - - - - - - - - - - 10.6 4.92
D50 - - - - - - - - - - 21.0 10.5
D90 - - - - - - - - - - 36.6 20.7

Process:
A. Dydrogesterone slurry phase (20% of batch size)
i. weighing Polysorbate 80 into a suitable container and solubilize in Water for injection under stirring then filtering the Polysorbate 80 solution using 0.2 um sterile grade membrane filter;
ii. adding Dydrogesterone to above step under stirring and allow to stir until properly wetted and further making up the volume of Dydrogesterone slurry phase to batch size;
iii. Sterilizing the Dydrogesterone slurry using moist sterilizer at 121°C for 30 min and cool to the room temperature under stirring followed by Homogenizing the DYDROGESTERONE slurry using silverson homogenizer to disaggregate the particles formed during sterilization process.
B. Aqueous buffer phase (25% of batch size)
i. collecting water for injection into a suitable container and stirring and then adding and dissolving the EDTA disodium dihydrate, dibasic sodium phosphate dihydrate and monobasic sodium phosphate dihydrate into water for injection (WFI) under stirring;
ii. making up the volume of Aqueous buffer phase to batch size and filtering the Aqueous buffer phase through 0.2 um sterile grade membrane filter.
C. Hydroxypropyl betacyclodextrin solution (40% of batch size)
i. collecting water for injection in a suitable container and stir, followed by addition and dissolving the Ethanol and hydroxypropyl betacyclodextrin to above WFI under stirring;
ii. making up the volume of Hydroxypropyl betacyclodextrin solution to batch size and then Filtering the Hydroxypropyl betacyclodextrin solution through 0.2 um sterile grade membrane filter.
D. Dydrogesterone suspension preparation
i. mixing the Dydrogesterone slurry phase into Hydroxypropyl betacyclodextrin solution and stir for 60 min then adding aqueous buffer phase to above suspension under stirring and stir for 30 min;
ii. making up the volume of Dydrogesterone Suspension to batch size.

Example 44 - 47: Parenteral Pharmaceutical composition of Dydrogesterone
Excipient/Example 44 45 46 47
Dydrogesterone 30 mg 30 mg 30 mg 30 mg
Ethanol 150 uL 150 uL 125 uL 125 uL
Polysorbate 80 6.0 mg 6.0 mg 6.0 mg 6.0 mg
Sodium phosphate Monobasic dihydrate 3.8 mg 3.8 mg 0.38 mg 3.8 mg
Sodium phosphate dibasic dihydrate 8.9 mg 8.9 mg 0.89 mg 8.9 mg
Sodium chloride - - 5.1 mg -
Disodium edetate 0.1 mg 0.1 mg 0.1 mg 0.1 mg
Polyvinyl alcohol 5.9 mg 5.9 mg 5.9 mg 5.9 mg
Water for injection q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL
Particle size (um) D10 0.571 0.505 0.921 1.1
D50 1.64 1.52 2.94 6.14
D90 3.63 2.9 8.93 15.2

Process:
A. Dydrogesterone slurry phase (20% of batch size)
i. Weighing Polysorbate 80 in a suitable container and solubilize in Water for injection under stirring then filtering the Polysorbate 80 solution using 0.2 um sterile grade membrane filter;
ii. adding Dydrogesterone to above step under stirring and allowing to stir until properly wetted, followed by making up the volume of Dydrogesterone slurry phase to batch size;
iii. Sterilizing the Dydrogesterone slurry using moist sterilizer at 121°C for 30 min and cooling to the room temperature under stirring and then milling the Dydrogesterone slurry using we media mill to reduce the particle size at desired range then collecting the milled Dydrogesterone slurry in suitable container and stir.
B. Aqueous buffer phase (25% of batch size)
i. collecting water for injection and stir, followed by adding and dissolve the EDTA disodium dihydrate, dibasic sodium phosphate dihydrate, monobasic sodium phosphate dihydrate and polyvinyl alcohol into water for injection (WFI) under stirring;
ii. making up the volume of Aqueous buffer phase to batch size then filtering the Aqueous buffer phase through 0.2 um sterile grade membrane filter.
C. Dydrogesterone suspension preparation
i. mixing the Dydrogesterone slurry phase into aqueous phase and stir followed by adding ethanol to above suspension under stirring then making up the volume of Dydrogesterone Suspension to batch size.

Example 48 – 50: Parenteral Pharmaceutical composition of Dydrogesterone
Excipients/Example 48 49 50
Dydrogesterone 3.0 g 3.0 g 3.0 g
N-Methyl pyrrolidone - - 37.6 g
Benzyl alcohol 10.0 g 7.1 g -
Poloxamer 407 (Kolliphor P 407) 0.5 g 0.5 g -
Poloxamer 188 (Kolliphor P 188) - - 0.4 g
Kolliphor HS 15 0.25 g 0.25 g 0.25 g
Polyvinyl alcohol 1.0 g 1.0 g 1.0 g
Water for injection q.s. to 100 mL q.s. to 100 mL q.s. to 100 mL
Particle size (um) 0.440 - 1.165 um 0.440 - 1.165 um 1.0 - 10 um
¬¬¬¬¬
Process:
A. Dydrogesterone solution phase
i. collecting N-Methyl pyrrolidone/Benzyl alcohol solvent in a suitable container followed by adding and dissolving Dydrogesterone to above solvent under stirring;
B. Aqueous phase preparation
i. Collecting water for injection in a suitable container and stir followed by adding and dissolving poloxamer 407/Poloxamer 188, Kolliphor HS 15 and Polyvinyl alcohol simultaneously under stirring;
ii. adding and dissolving Dydrogesterone to above solvent under stirring and further making up the volume of aqueous phase to batch size.
C. Dydrogesterone suspension preparation
i. adding Dydrogesterone solution phase into aqueous phase as obtained in the above step (B) using appropriate sized syringe in dropwise manner under stirring;
ii. keeping product under stirring until saturation attained in aqueous phase with precipitation of Dydrogesterone to give white suspension and then making up the volume of aqueous phase to batch size.
,CLAIMS:We Claim:

1. A parenteral pharmaceutical composition comprising a fast-acting component comprising dydrogesterone or its pharmaceutically acceptable salts thereof; a long-acting component comprising dydrogesterone or its pharmaceutically acceptable salts thereof; one or more pharmaceutically acceptable excipients.

2. The parenteral pharmaceutical composition as claimed in claim 1, wherein the ratio of dydrogesterone or its pharmaceutically acceptable salts in the fast-acting component and the long-acting component is 10:1 to 1:20.

3. The parenteral pharmaceutical composition as claimed in claim 1, wherein the parenteral pharmaceutical composition is having a pH in a range of about 2 to 10.

4. The parenteral pharmaceutical composition as claimed in claim 1, wherein the long-acting component comprises dydrogesterone having D90 particle size of about 0.1 µm to about 50 µm.

5. The parenteral pharmaceutical composition as claimed in claim 1, wherein the fast-acting component further comprises one or more solubilizing agent.

6. The parenteral pharmaceutical composition as claimed in claim 5, wherein the solubilizing agent(s) is present in an amount of about 0.01% w/v to about 80 % w/v.

7. The parenteral pharmaceutical composition as claimed in claim 5, wherein the solubilizing agent(s) is Hydroxypropyl-ß-cyclodextrin.

8. The parenteral pharmaceutical composition as claimed in claim 1, wherein the fast-acting component further comprises cosolvent, wherein the cosolvent is selected from the group comprising polyethylene glycol, propylene glycol, ethanol, glycerin, N-methyl pyrrolidone, or a combination thereof.

9. The parenteral pharmaceutical composition as claimed in claim 8, wherein the cosolvent is present in an amount of about 1% v/v to about 50% v/v of the fast-acting component.

10. The parenteral pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient is selected from the group comprising solubilizing agents(s), cosolvent(s), preservative(s), tonicity agent(s), pH adjusting agent(s), buffering agent(s), antioxidant(s), chelating agent(s), stabilizer(s), solvent(s), bulking agent(s), slow release polymer(s), or combinations thereof.

Dated this the 28th day of August 2024.
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer