DESC:

IMMEDIATE RELEASE PHARMACEUTICAL COMPOSITIONS OF DYDROGESTERONE AND A KIT THEREOF

FIELD OF THE INVENTION

The invention relates to an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, along with one or more pharmaceutically acceptable excipients.

Present invention further provides a kit comprising: a) one 40 mg tablet or capsule as loading dose, and b) fourteen (14) tablets or capsules of 10 mg each as subsequent maintainence doses.

BACKGROUND OF THE INVENTION

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

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

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

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

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

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

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

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

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

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

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

Currently, dydrogesterone is available in the form of 10 mg immediate release tablet. Patients need to take four (4) tablets of dydrogesterone to meet the requirement of 40 mg as first single loading dose. There are chances that patient may forget to take dose properly or inadvertently take less or more dose, which can lead to under or over dosing, and decreased patient compliance.

Dydrogesterone helps in relieving lower back pain, abdominal pain, and haemostasis in the threatened abortion. Further, the present invention is focussed towards preparation of stable formulation which is patient compliant and provides specific results towards treatment of threatened abortion and pre-eclampsia.

SUMMARY OF THE INVENTION

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

According to one aspect, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises from about 10 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof.

According to another aspect, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof.

According to another aspect, the immediate release pharmaceutical composition of the present invention is a tablet or a capsule dosage form.

According to another aspect, the present invention provides an immediate release pharmaceutical composition comprising about 10 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof; wherein the pharmaceutical composition comprises:
- 1 – 80 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 1 - 20% w/w of binder(s), and
- 0-5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

According to another aspect, the present invention provides an immediate release pharmaceutical composition comprising 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof; wherein the pharmaceutical composition comprises:
- 25 – 75 % w/w diluent(s),
- 20 - 50% w/w of disintegrant(s),
- 1 - 10% w/w of binder(s), and
- 0.5-5% w/w lubricant(s) or glidant(s), based on the total weight of the composition and optionally a film-coating.

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

According to one more aspect, the present invention provides a dosing schedule comprising administering:
a) one 40 mg tablet or capsule as a first loading dose on the first day of administration,
b) one 10 mg tablet or capsule as a second dose and third dose on the first day of administration, wherein said second dose and third dose is administered every eight hours, and
c) one 10 mg tablet or capsule every eight hours as a subsequent maintainence dose on the subsequent day(s).

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

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

According to another aspect, the present invention provides a kit comprising:
a) one 40 mg tablet or capsule,
b) fourteen (14) tablets or capsules of 10 mg each.

According to one more aspect, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients; wherein the composition is administered for treatment of threatened abortion 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts front view of the kit according to the present invention.
Figure 2 depicts back view of the kit according to the present invention.
Figure 3 depicts perspective view of the kit according to the present invention.
Figure 4 depicts kit with dosing schedule according to the present invention.

DESCRIPTION OF THE INVENTION

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

The term “composition” or “formulation” or “solid oral composition” or “dosage form” or “pharmaceutical composition” as used herein synonymously include tablet such as mono-layered tablets, bilayered tablets, trilayered tablet, multilayer tablet, minitablets, microtablets, capsules, tablet in tablet, tablets in a capsule, microtablets in a capsule, minitablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, extrudes, pellets, beads or spheroids, or any other suitable dosage form meant for oral administration to a patient. In one embodiment of the present invention, the immediate release pharmaceutical composition of the present invention is a tablet or a capsule dosage form.

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

As pharmaceutical excipients have various functions and contribute to the pharmaceutical formulation in many different ways, e.g., solubilisation, dilution, thickening, stabilization, preservation, coloring, and flavoring. 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 ‘immediate release” as used herein refers to immediate release of drug is where the majority (e.g., substantially all or all) of the pharmaceutically active ingredient is released within a relatively short time, for example within 2 hour, preferably within 1 hour and more preferably within 30 minutes, after oral ingestion.

According to one aspect, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises from about 10 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof.

In another embodiment, the composition preferably comprises about 40 mg of dydrogesterone or its pharmaceutically acceptable salt along with one or more excipients.

In a preferred embodiment, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients, wherein said composition comprises 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof.

In one another embodiment, the pharmaceutically acceptable excipients are selected from, but not limited to, glidants, lubricants, pH regulators, fillers, surfactants, binder, diluents and the like. Specifically, the composition of the present invention contains glidant(s), lubricant(s), binder(s), and diluent(s) along with at least one disintegrant(s) that are used for the preparation of immediate release composition of dydrogesterone or pharmaceutically acceptable salts thereof.

Suitable fillers/diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose anhydrous, lactose monohydrate, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, polyols, mannitol, sorbitol, xylitol, trehalose, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and combinations thereof. Diluent/filler may be present in an amount ranging from about 10% to about 80%, preferably from about 25% to about 75% by weight of the pharmaceutical composition. According to one embodiment, the filler or diluent used in present invention includes lactose monohydrate.

Suitable binders include, without limitation, microcrystalline cellulose, polyvinylpyrrolidone (PVP), e.g., PVP K 30 or PVP90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hypromellose, copovidone, pregelatinized starch and combinations thereof. When present, a binder may be employed in an amount ranging from about 0.1% to about 20%, preferably from about 0.5% to about 15% by weight of the pharmaceutical composition. In one embodiment, the binder is hydroxypropyl methylcellulose and is in an amount ranging from 1.0% to 5.0%, by weight of total weight of the pharmaceutical composition.

Suitable lubricants include, without limitation, zinc stearate, magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, colloidal silica, aluminum or calcium silicate, stearic acid, cutina, PEG 4000-8000, talc and combinations thereof. When present, a lubricant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5.0%, by weight of the pharmaceutical composition. In one embodiment, the lubricant is preferably magnesium stearate and is in an amount ranging from 0.05%-1.5% by weight of total weight of the pharmaceutical composition.

Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (colloidal anhydrous silica), magnesium trisilicate, powdered cellulose, starch, talc and combinations thereof. When present, a glidant may be employed in an amount ranging from about 0.01% to about 10%, preferably from about 0.1% to about 5%, by weight of the pharmaceutical composition. In one embodiment, the lubricant is preferably colloidal anhydrous silica and is in an amount ranging from 0.1%-0.6% by weight of total weight of the pharmaceutical composition.

Suitable disintegrants include, without limitation, carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g. crospovidone, polyplasdone XL or kollidon CL), croscarmellose sodium, sodium starch glycolate, polacrillin potassium, low substituted hydroxypropyl cellulose, alginic acid, sodium alginate, maize (corn) starch and guar gum, and/or combinations thereof, most preferably maize (corn) starch. In an embodiment, the compositions of present invention employ higher amount of disintegrant(s). A disintegrant is employed in an amount of 5.0% to 50%, such as of 15% to 50%, such as at least 25% to 40%, by weight of the pharmaceutical composition.

According to another aspect, the present invention provides an immediate release pharmaceutical composition comprising about 10 mg to about 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof; wherein the pharmaceutical composition comprises:
- 1 – 80 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 1 - 20% w/w of binder(s), and
- 0 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition.

According to another aspect, the present invention provides an immediate release pharmaceutical composition comprising 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof; wherein the pharmaceutical composition comprises:
- 25 – 75 % w/w diluent(s),
- 20 - 50% w/w of disintegrant(s),
- 1 - 10% w/w of binder(s), and
- 0.5 - 5% w/w lubricant(s) or glidant(s), based on the total weight of the composition and optionally a film-coating.

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

In a specific embodiment, the present invention provides an immediate release pharmaceutical composition comprising 40 mg of dydrogesterone or pharmaceutically acceptable salts thereof, wherein said composition further comprises:
- lactose monohydrate in an amount of 50%-60% by weight of total weight of the pharmaceutical composition;
- maize starch in an amount of 30%-40% by weight of total weight of the pharmaceutical composition;
- hydropropyl methylcellulose as binder in an amount of 1.0%-2.5% by weight of total weight of the pharmaceutical composition;
- magnesium stearate and/or colloidal anhydrous silica in an amount of 0.1%-2.5% by weight of total weight of the pharmaceutical composition; and
- optionally a film coating.

Another embodiment of the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D90 between 5 µm and 100 µm.

Another embodiment of the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D50 between 10 µm and 40 µm.

Another embodiment of the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D10 between 1.0 µm and 10 µm.

Another embodiment of the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, wherein the particle size of dydrogesterone or pharmaceutically acceptable salts thereof is D90 less than 50 µm, preferable less than 25 µm, more preferably less than 10 µm.

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

According to one more aspect, the present invention provides a dosing schedule comprising administering:
a) one 40 mg tablet or capsule as a first loading dose on the first day of administration,
b) one 10 mg tablet or capsule as a second dose and third dose on the first day of administration, wherein said second dose and third dose is administered every eight hours, and
c) one 10 mg tablet or capsule every eight hours as a subsequent maintainence doses on the subsequent day(s).

According to one more embodiment, the present invention provides an immediate release pharmaceutical composition comprising dydrogesterone or pharmaceutically acceptable salts thereof, one or more disintegrants, and optionally one or more pharmaceutically acceptable excipients; wherein the composition is administered for treatment of threatened abortion and/or pre-eclampsia.

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

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

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

According to another aspect, the present invention provides a kit comprising:
a) one 40 mg tablet or capsule, and
b) fourteen (14) tablets or capsules of 10 mg each.

A 40 mg tablet or capsule acts as a loading dose followed by 10 mg tablets every eight hour acts as maintainence dose.

The term “kit” herein refers to a package comprising a plurality of containers coded for administration on a certain day or time and a medication administration record sheet coded in the same manner. The pill containers may be in the form of a cup, an envelope or a receptacle in a plastic pill case or a blister pack, preferably a blister pack. The kit according to the present invention is represented in Figs. 1-4.

According to one embodiment, the present invention provides a blister pack comprising:
a) one 40 mg tablet or capsule, and
b) fourteen (14) tablets or capsules of 10 mg each.

According to one embodiment, the present invention provides a blister pack comprising:
a) one (1) immediate release tablet or capsule comprising about 40 mg dydrogesterone or a pharmaceutically acceptable salt thereof, and
b) fourteen (14) immediate release tablets or capsules each comprising about 10 mg dydrogesterone or a pharmaceutically acceptable salt thereof,
wherein the blister pack is made of PVC (Polyvinyl Chloride), PVDC (Polyvinylidene chloride, or polyvinylidene dichloride), Alu Alu, OPA-ALU-PVC (nylon-ALU-PVC) or CFF (Cold Formed Foil).

According to one embodiment, the present invention provides a blister pack comprising:
a) one 40 mg tablet or capsule, and
b) fourteen (14) tablets or capsules of 10 mg each,
wherein the blister pack is made of PVC (Polyvinyl Chloride), PVDC (Polyvinylidene chloride, or polyvinylidene dichloride), Alu Alu, OPA-ALU-PVC (nylon-ALU-PVC) or CFF (Cold Formed Foil).

According to one embodiment, the present invention provides a blister pack, wherein the blister pack is made of PVC (Polyvinyl Chloride), PVDC (Polyvinylidene chloride, or polyvinylidene dichloride), Alu Alu, OPA-ALU-PVC (nylon-ALU-PVC) or CFF (Cold Formed Foil).

The pharmaceutical composition of the present invention releases more than 75% of dydrogesterone or pharmaceutically acceptable salts thereof within 1 hour in 900 ml or appropriate volume of 0.1N HCl or 0.3% SLS in Water or simulated gastric fluid, paddle or basket apparatus.

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.

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

EXAMPLES

Immediate Release Pharmaceutical Compositions of Dydrogesterone

Example 1: Immediate Release Dydrogesterone 40mg Tablets

S. No. Ingredient Qty/Tablet (mg)
Granulation
1 Dydrogesterone 40.00
2 Hypromellose 11.20
3 Isopropyl alcohol q.s.
4 Methylene chloride q.s.
5 Lactose monohydrate 300.40
6 Maize (corn) starch 144.00
Pre-lubrication
7 Maize (corn) starch 56.00
8 Colloidal anhydrous silica 2.80
Lubrication
9 Magnesium stearate 5.60
Film Coating
10 Opadry white
(Hypromellose, Macrogol, titanium dioxide and talc) 16.80
11 Isopropyl alcohol q.s
12 Methylene chloride q.s

Process:
1. Sifting:
Sifted all the ingredients through appropriate sieves.
2. Drug dispersion:
Added dydrogesterone to methylene chloride in a stainless steel (SS) vessel under continuous stirring then added some quantity of isopropyl alcohol into it. In a separate vessel took isopropyl alcohol and added hypromellose under continues stirring. Added hypromellose dispersion into drug solution under continuous stirring till a clear dispersion is formed.
3. Granulation:
Sprayed the drug dispersion of step 2 to lactose monohydrate and maize (corn) starch granulate in a fluidized bed processor (FBP).
4. Drying:
Dried the granules till required LOD is achieved at required temperature.
5. Sifting and Milling of Granules:
Passed the granules through appropriate sieve and through multi mill.
6. Pre-lubrication & Lubrication:
Mixed the sifted granules with silicon dioxide and maize starch in a blender and then added magnesium stearate followed by mixing.
7. Compression:
Compressed the lubricated blend into tablets using suitable tools.
8. Coating:
Took isopropyl alcohol in a suitable SS Container; added Opadry white under continuous stirring. Added methylene chloride into it under continuous stirring till homogeneous coating dispersion is obtained. Filtered the dispersion through 100 mesh nylon cloth and coated the tablets with the dispersion in a suitable coating machine.
9. Packing:
Packed the tablets in suitable packs as per the requirement.

Particle size of Dydrogesterone (API):
The particle size distribution of Dydrogesterone used in formulation is mentioned in Table 1 below.

Table 1:
Test Results
Particle size (µm, by Malvern) Dv(10): 3.31
Dv(50): 22.1
Dv(90): 75.4

Dissolution Profile: The composition of Example 1 was subjected to dissolution studies. The results are tabulated in Table 2 below:

Table 2:
Dissolution conditions: Medium: 0.3% SLS in Water, Volume: 500 mL, RPM 100, Apparatus paddle
Product details
Single tablet of 40 mg
DTK1/214/011
Time (minutes) % Drug release
15 95
30 100
45 100
60 101

Stability Studies: The composition of Example 1 was subjected to stability studies. The results are tabulated in Table 3 below:

Table 3:
Product name Dydrogesterone Tablets 40 mg
Batch number DTK1/214/011
Tests Initial 3 Months
(40°C / 75%RH) 3 Months
(30°C / 75%RH)
Description Complies Complies Complies
Water determination (wt%, By KF) 7.11 7.34 7.39
Assay (Each Film coated tablet contains)
Dydrogesterone (mg)
% Label claim 39.71 mg
(99.3%) 39.16 mg
(97.9%) 39.96 mg
(99.9%)
Dissolution (%)
0.3% SLS, Volume: 500mL, RPM 100,
Apparatus paddle 101% 104% 104%
Related Substances (%)
Dydrogesterone Impurity A 0.06 0.06 0.06
Dydrogesterone Impurity B 0.03 0.03 0.03
Dydrogesterone Impurity C 0.07 0.07 0.07
Any other secondary impurity Not Detected Not Detected Not Detected
Sum of all other secondary impurity Not Detected Not Detected Not Detected

Example 2: Immediate Release Dydrogesterone 10 mg tablets

S. No. Ingredients Qty/Tablet
(mg)
Dry-Mix
1 Dydrogesterone 10.000
2 Lactose Monohydrate 101.100
Binder dispersion
3 Hypromellose 3 cps (2910) 2.800
4 Isopropyl Alcohol q.s.
5 Methylene Chloride (Dichloromethane) q.s.
Extragranular (Pre-lubrication)
6 Maize Starch (Corn starch) 14.000
7 Colloidal Anhydrous Silica 1.400
Extragranular (Lubrication)
8 Magnesium Stearate 0.700
Uncoated tablet weight 130.000
Film Coating
9 Opadry white YS-1-7040 (Hypromellose, Macrogol/Polyethylene glycol, Titanium dioxide, talc) 3.900
10 Isopropyl Alcohol q.s.
11 Methylene Chloride (Dichloromethane) q.s.
Coated tablet weight 133.900

Process:
1. Sifting:
Sifted all the ingredients through appropriate sieves.
2. Dry mixing:
Dry mixed the dry mixing ingredients in a Rapid Mixer Granulator (RMG).
3. Binder addition:
Added hypromellose to Isopropyl alcohol (IPA) and mixed the add methylene chloride (MDC) to it and stirred till a homogenous dispersion is obtained.
4. Granulation:
Granulated the dry mixed ingredients of step 2 in the RMG with binder of step 3.
5. Drying:
Dried the wet granules of step 4 in a Fluidized Bed Dryer (FBD) till required LOD is achieved.
6. Milling and sieving:
Passed the dried granules through appropriate mesh and milled the oversized granules using a multi-mill/Co-mill.
7. Pre-lubrication:
Blended the granules of step 6 with presifted pre-lubrication material in a suitable blender.
8. Lubrication:
Lubricated step 7 blend with pre-sifted Magnesium stearate in a blender.
9. Compression:
Compressed the blend of step 9 into tablets using suitable punches.
10. Film coating:
Added Opadry white to a mixture of IPA & MDC and mix to make a homogenous dispersion. Film coat the compressed tablets of step 9 using coating dispersion.
11. Packing:
Packed the tablets as per requirement.

Example 3: Immediate Release Dydrogesterone 10 mg tablets

S. No Ingredients Qty/Tablet
(mg)
Dry-Mix
1 Lactose Monohydrate 65.100
2 Maize Starch (Corn starch) 36.000
Drug dispersion
3 Dydrogesterone 10.000
4 Hypromellose 3 cps (2910) 2.800
5 Isopropyl Alcohol q.s.
6 Methylene Chloride (Dichloromethane) q.s.
Extragranular (Pre-lubrication)
7 Maize Starch (Corn starch) 14.000
8 Colloidal Anhydrous Silica 1.400
Extragranular (Lubrication)
9 Magnesium Stearate 0.700
Uncoated tablet weight 130.000
Film Coating
10 Opadry white YS-1-7040 (Hypromellose, Macrogol/Polyethylene glycol, Titanium dioxide, talc) 3.900
11 Isopropyl Alcohol q.s.
12 Methylene Chloride (Dichloromethane) q.s.
Coated tablet weight 133.900

Process:
1. Sifting:
Sifted all the ingredients through appropriate sieves.
2. Drug dispersion addition
Added dydrogesterone to methylene chloride (MDC) and mixed till completely soluble. Added hypromellose to Isopropyl alcohol (IPA) and mixed. Added Dydrogesterone, methylene chloride mix to Isopropyl alcohol and Hypromellose mixed and stirred till a homogenous dispersion is obtained.
3. Granulation:
Granulated the dried mix ingredients Lactose monohydrate and Maize starch in a Fluidized Bed Processor (FBP) to obtain granules.
4. Drying:
Dried the granules of step 4 in the FBP till required LOD is achieved.
5. Milling and sieving:
Passed the dried granules through appropriate mesh and milled the oversized granules using a multi-mill/Co-mill.
6. Pre-lubrication
Blended the granules of step 5 with presifted pre-lubrication material in a suitable blender.
7. Lubrication:
Lubricated step 6 blend with pre-sifted Magnesium stearate in a blender.
8. Compression:
Compressed the blend of step 7 into tablets using suitable punches.
9. Film coating:
Added Opadry white to a mixture of IPA & MDC and mixed to make a homogenous dispersion. Film coated the compressed tablets of step 8 using coating dispersion.
10. Packing:
Packed the tablets as per requirement.

,CLAIMS:We Claim:

Claim 1. An immediate release pharmaceutical composition comprising dydrogesterone or a pharmaceutically acceptable salt thereof in an amount of about 40mg and one or more pharmaceutically acceptable excipients.

Claim 2. The immediate release pharmaceutical composition as claimed in claim 1, comprising:
- about 40 mg of dydrogesterone or a pharmaceutically acceptable salt thereof;
- lactose in an amount of 25%-80% w/w;
- maize starch in an amount of 5%-50% w/w;
- hydroxypropyl methylcellulose as binder in an amount of 1.0%-2.5% w/w;
- magnesium stearate and/or colloidal anhydrous silica in an amount of 0.1%-2.5% w/w,
based on the total weight of the composition, and optionally a film coating.

Claim 3. A blister pack comprising:
a) one (1) immediate release tablet or capsule comprising about 40 mg dydrogesterone or a pharmaceutically acceptable salt thereof, and
b) fourteen (14) immediate release tablets or capsules each comprising about 10 mg dydrogesterone or a pharmaceutically acceptable salt thereof.

Claim 4. The immediate release tablet or capsule as claimed in claim 3, comprising:
- about 10 mg or about 40 mg of dydrogesterone or a pharmaceutically acceptable salt thereof,
- 1 - 80 % w/w diluent(s),
- 1 - 50% w/w of disintegrant(s),
- 1 - 20% w/w of binder(s), and
- 0-5% w/w lubricant(s) or glidant(s),
based on the total weight of the composition.

Claim 5. The immediate release tablet or capsule as claimed in claim 3, wherein the particle size of dydrogesterone or a pharmaceutically acceptable salt thereof is D90 between 10 µm and 100 µm, D50 between 5 µm and 50 µm, and D10 between 1.0 µm and 10 µm.

Claim 6. The immediate release tablet or capsule as claimed in claim 3, is prepared by direct compression, dry granulation, wet granulation, or drug dispersion process.

Claim 7. The immediate release tablet or capsule as claimed in claim 3, wherein the composition releases more than 75% of dydrogesterone or a pharmaceutically acceptable salt thereof within 1 hour in 500 mL of 0.3% SLS in Water at 100 RPM in paddle apparatus.

Claim 8. The immediate release tablet or capsule as claimed in claim 3, wherein the total amount of impurity after exposure of the tablet or capsule to 40°C/75% RH or 30°C/75%RH for a period of three (3) months is not more than 5% and any individual impurity is not more than 0.5%.

Claim 9. The immediate release tablet or capsule as claimed in claim 3, is prepared by a process comprising: a) preparing suspension or solution of dydrogesterone or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients in a solvent; b) adding the suspension or solution of step a) onto one or more pharmaceutical acceptable excipients to make granules; and (c) compressing the granules to form tablets or filling the granules in capsules.

Claim 10. The immediate release tablet or capsule as claimed in claim 3, is administered according to a dosing schedule comprising administering:
a) one immediate release tablet or capsule comprising 40 mg dydrogesterone or a pharmaceutically acceptable salt thereof as a first loading dose on the first day of administration,
b) one immediate release tablet or capsule comprising 10 mg dydrogesterone or a pharmaceutically acceptable salt thereof as a second dose and third dose on the first day of administration, wherein said second dose and third dose is administered every eight hours, and
c) one immediate release tablet or capsule comprising 10 mg dydrogesterone or a pharmaceutically acceptable salt thereof every eight hours as a subsequent maintainence dose on the subsequent day(s).