DESC:FIELD OF INVENTION:
The present invention relates to pharmaceutical composition comprising combination of Progesterone and Dydrogesterone as luteal support regimen.
BACKGROUND:
Luteal phase is the period between ovulation and either establishment of pregnancy or onset of menstrual cycle 2 weeks later. Following ovulation, the luteal phase of a natural cycle is characterized by the formation of corpus luteum, which secretes steroid hormones estrogen and mainly progesterone. Embryonic implantation occurs during the implantation window where perfect synchronization of embryonic and endometrial signals is essential. Thus luteal phase support is a crucial for the process of implantation and early embryonic development, any abnormalities during luteal phase causes infertility, miscarriage, failure of embryo implantation during IVF and unsuccessful assisted reproduction. Low level secretion of progesterone by corpus luteum during luteal phase is known to be major cause of luteal phase deficiency. Progesterone is essential for secretory transformation of the endometrium that permits implantation as well as maintenance of early pregnancy and is essential for successful pregnancy [Daya S. Luteal support: Progestogens for pregnancy protection. Maturitas, 2009].
The luteal support regimen involved use of micronized progesterone vaginally or dydrogesterone orally or combinations of both. However, administrating drugs through two different routes is a complex and patient non-compliance approach. Additionally, vaginal delivery of progesterone has certain limitation like inter-variation in serum progesterone levels, insufficient absorption of the drug which may limit the bioavailability of the drug and vaginal route is not well acceptable among women in certain regions. Thus there is a need in art to develop a novel drug delivery system which avoid above mentioned drawbacks.
The present invention provides the oral delivery of Progesterone and Dydrogesterone in combination form which avoid the limitation of existing regimen of giving the two drugs through two different routes and provide safe, tolerable delivery system for luteal phase support in women undergoing in vitro fertilization (IVF). Delivery of drugs in combination formulations have unique advantages such as complementary mechanism of action, synergistic effects, better tolerability, elongated product life-cycle management, and cost savings. Use of the combination is a rational approach for achieving optimal therapeutic benefits while minimizing multiple route of administration burden. A key step in the design of a combination formulation is selection of effective and well- tolerated treatments. Moreover, it is essential that the components have complementary mechanisms of action and compatible pharmacokinetic profiles.

BRIEF SUMMARY OF THE INVENTION
The present invention provides a drug delivery system for the combinations of Progesterone and Dydrogesterone for effective management of luteal phase deficiency. The current regimen for luteal support include administered of progesterone vaginally and oral Dydrogesterone however dual route of administration is generally not preferable for patients and raises issues of non-compliance. The vaginal preparation of Progesterone has certain limitation such as inter-serum variation, low acceptability and low vaginal absorption. The present invention provides a novel, simple, safe and improved dosage form which is superior then the current regimen.
In another aspect, the present invention provides an oral drug delivery system comprising pharmaceutically effective amount of Dydrogesterone and Progesterone in a single dosage form and provide a method for preparation of oral drug delivery more preferably tablet.
The present invention provides a pharmaceutical composition comprising combinations of Dydrogesterone and Progesterone for luteal support in women undergoing in-vivo fertilization procedure with Frozen Embryo Transfers or other fertility treatment.
In an another embodiment the present invention provides sustained release formulation of Dydrogesterone and Progesterone which provide pre-determined release of the active agents with minimal side effects, reduces dose frequency and health care cost and avoid fluctuation in steady-state drug levels.
DETAILED DESCRIPTION OF THE INVENTION
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid or combi-kit etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.

The term “In vitro fertilization” or IVF is fertility treatment process which involves fertilization of eggs and sperms in vitro, the fertilized eggs are then transferred to a uterus.
The present invention relates to pharmaceutical composition comprising combination of Dydrogesterone and Progesterone.
In an embodiment the pharmaceutical composition comprising Dydrogesterone and Progesterone as oral dosage form most preferably solid unit dosage form.
In an another embodiment the solid oral pharmaceutical composition comprising:
a. therapeutically effective amount of Dydrogesterone or salts thereof;
b. therapeutically effective amount of Progesterone or salts thereof;
c. one or more pharmaceutically acceptable excipients
in an embodiment Dydrogesterone is present in an amount ranging from 2mg to 40 mg more preferably 10 to 20 mg.
in an another embodiment Progesterone is present in an amount ranging from 100 mg to 1000 mg more preferably 200 mg to 400 mg.
In an another embodiment the solid oral pharmaceutical composition can be present in form of tablets, capsules, powders, pellets, granules, microspheres, minitablets or any suitable solid unit forms known to person skilled in the art; mouth dissolving tablets; dispersible tablets; effervescent tablets; trilayer tablets; inlay tablets. In a preferred embodiment the preferred dosage form is tablet or capsule.
In an another embodiment the present invention provides a composition of Dydrogesterone and progesterone and one or more pharmaceutically acceptable excipients. Non-limiting examples of excipients that can be included in the oral dosage forms and compositions include fillers or diluents, binders, lubricants, glidants, antiadherents, flavoring agents, disintegrants, surfactants, and coloring agents.
In another embodiment the present invention provides a combi-kit comprising the combination of dydrogesterone and progesterone as separate tablets.
In an embodiment the combi-kit comprising
a. Dydrogesterone present in an amount ranging from 10mg to 20 mg and;
b. Progesterone present in an amount ranging from 200 mg to 400 mg
In an another embodiment the present invention provides a pharmaceutical composition comprising effective amount of Dydrogesterone and Progesterone in a single dosage unit form.
The pharmaceutical composition of present invention can be prepared by using various granulation techniques known to the person skilled in the art, such as, but not limited to direct compression, wet granulation, dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion, and solvent evaporation.
The components of the pharmaceutical composition defined hereinbefore can be brought together into a suitable composition for oral administration according to standard practice and procedures well known in the art of pharmaceutical science using conventional formulation and manufacturing techniques.
The tablet composition of the present invention can be coated with a coating. Various coating types known in the art can be utilized in the present invention. Examples of coating types include without limitation, film coatings, enteric or pH dependent coatings, delayed release coatings, and the likes thereof.
In an another embodiment the present invention provides a sustained release formulation of Progesterone and Dydrogesterone which results in reduction of dose frequency and maintained a predetermined rate by maintaining a constant drug level for a specific period of time with minimum side effects.
In an alternative embodiment the present invention provides an oral sustained release formulation further comprises release controlling agent.
In an another embodiment there is provided a process of preparing the solid oral pharmaceutical composition of Progesterone and Dydrogesterone wherein Progesterone is optionally micronized.
In an another embodiment the present invention is a tablet dosage form comprising:
a. Sustained release Dydrogesterone in an amount ranging from 10 mg to 20 mg and;
b. Sustained release progesterone in an amount ranging from 200 mg to 400 mg
Non-limiting examples of acceptable fillers, sometimes referred to as diluents, include mannitol, lactitol, dextrose, sucrose, maltose, starch, microcrystalline cellulose, lactose, isomalt, and combinations thereof.
Examples of binders that can be used in the oral dosage forms and compositions include, but are not limited to copovidone, hydroxypropylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, sugars, starches, and combinations thereof.
Glidants or lubricants that can be used in the oral dosage forms and compositions of the present invention include, but are not limited to colloidal silicon dioxides, talc, magnesium stearate, dibasic calcium phosphate, sodium stearyl fumarate, calcium stearate, stearic acid, polyethylene glycols, silicon dioxide, and combinations thereof.
Examples of surfactants that can be included in the oral dosage forms and compositions include without limitation, sodium lauryl sulfate, polysorbates, sodium taurochloate, and combinations thereof.
In an another embodiment the present invention provides an oral formulation of Dydrogesterone and Progesterone for luteal-phase support in women undergoing IVF.
In another embodiment the present invention provides a combi-kit comprising the combination of dydrogesterone and progesterone as separate tablets.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not 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.
Example-1 Combi kit for Progesterone and Dydrogesterone Tablet
Progesterone tablet
S.NO Ingredient Amount
1 Progesterone (Micronized) 10-20 mg
2 Pharmaceutically acceptable excipient As required

Dydrogesterone tablets
S.NO Ingredient Amount
1 Dydrogesterone 100-500 mg
2 Pharmaceutically acceptable excipient As required

Example 2: Tablet formulation
S.NO Ingredient Amount
1 Sustained release Dydrogesterone 100-500 mg
2 Progesterone (Micronized) 10-20 mg
3 Pharmaceutically acceptable excipient As required

,CLAIMS:1. A pharmaceutical composition comprising effective amount of Dydrogesterone and Progesterone including their pharmaceutically acceptable salts thereof.
2. A pharmaceutical composition as claimed in claim 1 is a solid oral composition which can be present in form of tablets, capsules, powders, pellets, granules, microspheres, minitablets, mouth dissolving tablets; dispersible tablets; effervescent tablets; trilayer tablets; inlay tablets.
3. A pharmaceutical composition as claimed in claim 1 is a combi-kit comprising combination of dydrogesterone and progesterone as separate tablets.
4. A combi-kit as claimed in claim 3 comprises:
i. Sustained release Dydrogesterone present in an amount ranging from 2 mg to 40 mg more preferably 10 to 20 mg and;
ii. Sustained release Progesterone present in an amount ranging from 100 mg to 1000 mg more preferably 200 mg to 400 mg.
5. A pharmaceutical composition as claimed in claim 1 comprises Dydrogesterone and Progesterone in a single unit dosage form.
6. A pharmaceutical composition as claimed in claim 5 is a tablet dosage form comprising:
i. Dydrogesterone present in an amount ranging from 2 mg to 40 mg and;
ii. Progesterone present in an amount ranging from 100 mg to 1000 mg and;
7. A tablet formulation comprising:
i. Sustained release Dydrogesterone present in an amount ranging from 10 to 20 mg and;
ii. Sustained release progesterone present in an amount ranging from 200 mg to 400 mg