DESC:A COMPOSITION FOR UTERINE DISODERS AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to the pharmaceutical composition comprising dydrogesterone or ester (s) thereof in combination with aromatase inhibitor or salts thereof and one or more pharmaceutically acceptable excipients for the treatment or prevention of uterine disorders preferably uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, and other related disorders. Moreover, the present invention also relates to the process of preparing such composition.

BACKGROUND OF THE INVENTION

Condition that affects the uterus or any other part of the reproductive system causes uterine disorder. Some common uterine disorders are pain in the uterine region, abnormal or heavy vaginal bleeding, irregular menstrual cycle, abnormal vaginal discharge, pain in the pelvis, lower abdomen, pain during intercourse, uterine fibroids, endometriosis, or adenomyosis and other related disorders. Endometriosis is a very painful disorder in which tissue similar to the tissue that normally lines the inside of the uterus of the female body, the endometrium grows outside the uterus. Endometriosis most commonly involves the ovaries, fallopian tubes and the tissue lining pelvis. Rarely, endometrial-like tissue may be found beyond the area where pelvic organs are located in the body.

With endometriosis, the endometrial-like tissue acts as endometrial tissue would — it thickens, breaks down and bleeds with each menstrual cycle. But because this tissue has no way to exit the body, it becomes trapped. When endometriosis involves the ovaries, cysts called endometriomas may form. Surrounding tissue can become irritated, eventually developing scar tissue and adhesions, bands of fibrous tissue that can cause pelvic tissues and organs to stick to each other. Endometriosis can cause pain, sometimes severe, especially during menstrual periods. Fertility problems also may develop.

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, 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.
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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.

Letrozole is also an important component that is used in the treatment of uterine diseases, it is a member of triazoles and a nitrile. It has a role as an antineoplastic agent and (aromatase) inhibitor. Letrozole is an oral non-steroidal type-II aromatase inhibitor. Letrozole is a medication that has been widely used in women with breast cancer. As it belongs to a class of Aromatase inhibitor. Aromatase is an enzyme that is responsible for the production of estrogen in the female body.

Additionally, Letrozole is further used by women those have experienced menopause as a first treatment of breast cancer that has spread within the breast or to other areas of the body or in women whose breast cancer has worsened while they were taking tamoxifen. Letrozole is in a class of medications called nonsteroidal aromatase inhibitors. It works by decreasing the amount of estrogen produced by the body. This can slow or stop the growth of some types of breast cancer cells that need estrogen to grow.

The combination of dydrogesterone, along with aromatase inhibitor has advanced & advantageous properties which makes these combinations particularly suitable for treating & preventing uterine disorders including 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.

OBJECTIVES OF THE INVENTION

The principal objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, aromatase inhibitor or salts thereof and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone or its ester(s), aromatase inhibitor and one or more pharmaceutically acceptable excipients, wherein the said composition is used in the treatment of uterine disorder.

Another objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone or its ester(s) and aromatase inhibitor or its metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters, solvate thereof along with one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone, aromatase inhibitor and one or more pharmaceutically acceptable excipients, wherein the aromatase inhibitor is selected from the group comprising letrozole, anastrozole or exemestane.

Another objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone, aromatase inhibitor and one or more pharmaceutical excipients selected from a group of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

Further objective of the present invention is to provide pharmaceutical composition comprising:
a) therapeutically effective amount of Dydrogesterone or its ester(s);
b) therapeutically effective amount of aromatase inhibitor; and
c) one or more pharmaceutically acceptable excipients,
wherein the pharmaceutical composition is used for the prevention and/or treatment of uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis.

SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, aromatase inhibitor or salts thereof and one or more pharmaceutically acceptable excipients.

The present invention relates to a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, aromatase inhibitor or salts thereof and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical composition is used for the treatment of uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis and other related disorders.

The term “aromatase inhibitor includes letrozole, anastrozole, exemestane.

According to the present invention Dydrogesterone or aromatase inhibitor are present/used in with the particle size in the range of D90 less than 200 microns (µ), preferably in the range of D90 less than 100 microns.

In one of the aspects of the present invention, it relates to pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, aromatase inhibitor(s) or salts thereof and one or more pharmaceutically acceptable excipients, wherein the particle size of the dydrogesterone is D90 less than 50µ.

In another aspect of present invention provides a pharmaceutical combination comprising dydrogesterone or its ester(s) thereof and aromatase inhibitor(s) or salts thereof.

In another aspect of present invention provides a pharmaceutical combination comprising dydrogesterone or its ester(s) thereof and aromatase inhibitor(s) or salts thereof, wherein the aromatase inhibitor is selected from the group comprising letrozole, anastrozole or exemestane.

In another aspect of present invention provides a pharmaceutical combination comprising dydrogesterone or its ester(s) thereof and letrozole or salts thereof.

In another aspect of present invention provides a pharmaceutical combination comprising dydrogesterone or its ester(s) thereof and letrozole or salts thereof, wherein the said combination is used in the treatment of uterine disorders.

In another aspect of the present invention provides a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, letrozole or salts thereof and one or more pharmaceutical excipients.

In another aspect of the present invention provides a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, letrozole or salts thereof and one or more pharmaceutical excipients, wherein the pharmaceutical composition is used in the treatment of uterine disorders.

In another aspect of the present invention provides a pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, letrozole or salts thereof and one or more pharmaceutical excipients, wherein the particle size of the dydrogesterone is D90 less than 50µ.

In one of the aspects of the present invention it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of aromatase inhibitor; and
(c) one or more pharmaceutically acceptable excipients,
wherein the said composition is used for the treatment of uterine disorders.

In one more aspect, the present invention, provides the use of combination of dydrogesterone or its ester(s), aromatase inhibitor and one or more pharmaceutical excipients in the preparation of medicines for the prevention and/or treatment of uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis and other related disorders.

In one more aspect, the present invention provides a pharmaceutical composition comprising:
a) therapeutically effective amount of dydrogesterone or its ester(s);
b) therapeutically effective amount of aromatase inhibitor and
c) one or more pharmaceutically acceptable excipients
wherein the said Dydrogesterone or its ester(s) is administered in an amount of about 1 to 50 mg and the said aromatase inhibitor is administered in 1mg to 12.5 mg.

In one more aspect, the present invention provides a pharmaceutical composition comprising:
a) therapeutically effective amount of Dydrogesterone or its ester(s);
b) therapeutically effective amount of letrozole or salts thereof and
c) one or more pharmaceutically acceptable excipients,
wherein the said dydrogesterone or its ester(s) is administered in an amount of about 1 to 50 mg and the letrozole is administered in 1mg to 12.5 mg.

In one more aspect, the present invention provides a kit comprising:
a) composition comprising therapeutically effective amount of dydrogesterone and one or more pharmaceutically acceptable excipients;
b) composition comprising therapeutically effective amount of letrozole and one or more pharmaceutically acceptable excipients.

In one more aspect, the present invention provides a pharmaceutical composition comprising therapeutically effective amount of dydrogesterone or its ester(s) thereof; therapeutically effective amount of aromatase inhibitor or salts thereof and one or more additional excipients, wherein the said dydrogesterone or its ester(s) is administered in an amount of about 1 to 50 mg and the said aromatase inhibitor is administered in 1mg to 12.5 mg.

According to another aspect, the present invention provides a pharmaceutical composition comprising therapeutically effective amount of dydrogesterone or its ester(s), a therapeutically effective amount of aromatase inhibitor and one or more pharmaceutically acceptable excipients, wherein the dydrogesterone and aromatase inhibitor are administered either simultaneously, concurrently, alternately and/or sequentially.

According to one more aspect, the present invention relates to a pharmaceutical composition comprising of dydrogesterone and letrozole, wherein Dydrogesterone is present in the amount of about 1 to 50 mg, and letrozole is present in the amount of about 1mg to 12.5mg.

According to one more aspect, the present invention relates to pharmaceutical composition comprising of dydrogesterone and letrozole, wherein dydrogesterone is present in the amount of about 10 mg, and letrozole is present in the amount of about 2.5 mg.

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.

BRIEF DESCRIPTION OF DRAWINGS/FIGURE

Figure 1 illustrates the change in endometriosis lesions volume after 28-days of treatment. #Significant difference as compared to naive control; *Significant difference as compared to Vehicle (Disease) Control. One-way ANOVA followed by Dunnett’s Multiple Comparison Test. #/* P < 0.05, ##/**P < 0.01 ###/***P < 0.001, ####/****P < 0.0001.

Figure 2 illustrates the total histopathology score after 28-days of treatment. #Significant difference as compared to naive control; *Significant difference as compared to Vehicle (Disease) Control. One-way ANOVA followed by Dunnett’s Multiple Comparison Test. #/* P < 0.05, ##/**P < 0.01 & ###/***P < 0.001, ####/****P < 0.0001.

Figure 3 illustrates the change in VGEF levels in endometriosis tissue after 28-days of treatment. #Significant difference as compared to naive control; *Significant difference as compared to Vehicle (Disease) Control. One-way ANOVA followed by Dunnett’s Multiple Comparison and Unpaired t-Test. #/* P < 0.05, ##/**P < 0.01, ###/***/P < 0.001, ####/****/P < 0.0001.

DETAIL DESCRIPTION OF THE INVENTION

The present invention as embodied by “A pharmaceutical composition for uterine disorders and process for preparation thereof” succinctly fulfils the above-mentioned need[s] in the art. The present invention has objective[s] arising as a result of the above-mentioned need[s], said objective[s] having been enumerated hereinabove.

The following description is directed to a pharmaceutical composition for endometriosis and the process for preparation thereof as much as the objective(s) of the present invention are enumerated, it will be obvious to a person skilled in the art that, the enumerated objective(s) are not exhaustive of the present invention in its entirety, and are enclosed solely for the purpose of illustration. Further, the present invention encloses within its scope and purview, any structural alternative(s) and/or any functional equivalent(s) even though, such structural alternative(s) and/or any functional equivalent(s) are not mentioned explicitly herein or elsewhere, in the present disclosure. The present invention therefore encompasses also, any improvisation[s]/modification[s] applied to the structural alternative[s]/functional alternative[s] within its scope and purview. The present invention may be embodied in other specific form[s] without departing from the essential attributes thereof.

Furthermore, the terms and phrases used herein are not intended to be limiting, but rather are to provide an understandable description. Throughout this specification, the use of the word "comprise" and variations such as "comprises" and "comprising" may imply the inclusion of an element or elements not specifically recited.

Term “dydrogesterone” includes dydrogesterone or its esters, isomers, polymorphs, solvates and pharmaceutically acceptable salts.

Term “aromatase inhibitor” includes aromatase inhibitor or its esters, isomers, polymorphs, solvates and pharmaceutically acceptable salts.

Accordingly, the present invention relates to a pharmaceutical composition comprising dydrogesterone and aromatase inhibitor, wherein the said pharmaceutical composition is used for treatment of uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis and other related disorders,

The term ‘extended release’ as used herein refers to release of drug over an extended period of time i.e. from about 2 hours to about 24 hours. The extended release includes but is not limited to sustained release, controlled release, delayed release, or modified release form or combination thereof. The term “therapeutically effective amount” or “effective amount” used interchangeably, is defined to mean the amount or quantity of the active drug, which is sufficient to elicit an appreciable biological response when administered to the patient. It will be appreciated that the precise therapeutic dose will depend on the age and condition of the patient, nature of the condition to be treated and will be at the ultimate discretion of the attendant physician.

The term “composition” or “solid oral composition” or “dosage form” or “pharmaceutical composition” as used herein synonymously include tablet such as mono-layered tablets, bilayer tablets, trilayered tablet, multilayer tablet, caplets, minitablets, micro tablets, capsules, tablet in tablet, tablets in a capsule, micro tablets in a capsule, minitablets in a capsule, granules in a capsule, pellets, pellets in a capsule, powder, granules, extrudes, pellets, beads or spheroids, suspension or any other suitable dosage form meant for oral, parenteral, topical, transdermal, mucosal, nasal, buccal, or sublingual administration to a patient, preferably oral.

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 organic acids and inorganic acid salts.

The term “excipient” or “pharmaceutical excipients” or “pharmaceutically acceptable excipients” means a pharmacologically inactive component such as a diluent, disintegrant, carrier, 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 include diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

Suitable fillers/ diluents include, without limitation, starch, corn starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, cellulose derivatives, such as silicified microcrystalline cellulose, microcrystalline cellulose, mannitol, sorbitol, xylitol, trehalose, colloidal silica, sucrose or other sugars or sugar derivatives, calcium hydrogen phosphate, dicalcium phosphate, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and/or combinations thereof.

Suitable binders include, without limitation, microcrystalline cellulose, polyvinylpyrrolidone (PVP), such as e.g., PVP K 30 or PVP90F, polyethylene glycols (PEG), e.g., PEG 4000, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, both preferably of medium to high viscosity, e.g. viscosity grades 3 or 6 cps, pregelatinized starch, copovidone, gelatin, sugars and/or combinations thereof.

Suitable lubricants include, without limitation, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, aluminium or calcium silicate, fumaric acid, stearic acid, PEG, talc and/or combinations thereof.

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, alginic acid, sodium alginate and guar gum, most preferably crosslinked PVP (crospovidone), crosslinked CMC (Ac-Di-Sol), starch, modified starch, corn starch, maize starch, pregelatinized starch, sodium starch glycolate, carboxymethyl starch-Na (pirimojel and explotab), sodium starch glycolate, magnesium aluminium silicate, low-substituted hydroxypropyl cellulose, polacrillin and/or combinations thereof.

Suitable glidants include, without limitation, zinc stearate, colloidal silicon dioxide (e.g., Aerosil 200), magnesium trisilicate, powdered cellulose, starch, talc and/or combinations thereof.

The surfactants include but are not limited to anionic, cationic, non-ionic or amphoteric surfactants or those known to the person skilled in the art. Suitable surface active are poloxamer, polysorbates, cremophore, soluplus, lecithin and sodium lauryl sulfate and/or combinations thereof.

The pharmaceutical composition of the present invention may further be film coated. Film coating may be an immediate release or an extended release coating. The extended release coating comprises at least one or more extended release polymer and one or more pharmaceutically acceptable excipients.

Suitable film forming agents include, for example, polyvinylpyrrolidone, natural gums, starches, and cellulosic polymers. Examples of cellulosic polymers include, but are not limited to, polyvinyl alcohol, hydroxypropyl methyl cellulose ("HPMC"), carboxymethyl cellulose ("CMC") or salts thereof, hydroxypropyl cellulose ("HPC"), methylcellulose ("MC"), hydroxyethyl cellulose ("HEC"), ethylcellulose, acrylates, Eudragits, phalates and the like. Further, commercially available coating materials are available marketed under the brand name Opadry®. The polymers such as polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate can be used as a film forming agent.

Coloring agents include any FDA approved color for pharmaceutical use.

Additional excipients include Plasticizers, Preferable plasticizers is selected from the group comprising of triethylcitrate, dibutyl sebacate, acetylated triacetin, tributylcitrate, glycerlotributyrate, monoglyceride, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate and/or combinations thereof.

Suitable opacifiers is selected from the group comprising of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide and/or combinations thereof.

Solid form preparations for oral administration may include capsules, tablets, pills, powders, granules and suppositories. For solid-form preparations, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filter an extender.

In case of capsules, tablets, or pills, the dosage form may also comprise buffering agents. The solid preparation of tablets, capsules, pills, granules can be prepared with coatings and shells, such as enteric coating and other coatings well known in the pharmaceutical formulating art.

Liquid-form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs. For liquid-form preparations, the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers.

Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.

According to a specific embodiment of the present invention, the above-mentioned pharmaceutical combination/composition may be any dosage form suitable for oral administration. When administered orally, the pharmaceutical dosage form of the present invention using the pharmaceutical combination/composition as the active ingredient includes, but is not limited to, tablets, sublingual tablets, effervescent tablets, coated tablets, sugar-coated tablets, dispersible tablets, enteric-coated tablets, granules, hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, sustained-release capsules, controlled-release capsules, oral liquids, preferably tablets or capsules.

Accordingly, in an embodiment, the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of Aromatase inhibitor; and
(c) one or more pharmaceutically acceptable excipients selected from binders, disintegrates, lubricants, plasticizers, opacifiers and/or diluents.

In another embodiment of the present invention it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of Aromatase inhibitor; and
(c) about 1% w/w to about 50% w/w of binders;
(d) about 1% w/w to about 95% w/w of diluents;
(e) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of Aromatase inhibitor; and
(c) about 1% w/w to about 50% w/w of binders;
(d) about 1% w/w to about 95% w/w of diluents;
(e) about 0.1% w/w to about 10% w/w of lubricants;
(f) about 0.1% w/w to about 10% w/w of disintegrants;
(g) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention it provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of Aromatase inhibitor; and
(c) about 1% w/w to about 50% w/w of binders;
(d) about 1% w/w to about 95% w/w of diluents;
(e) about 0.1% w/w to about 10% w/w of disintegrants selected from the group comprising starch, modified starch, corn starch, maize starch, pregelatinized starch or sodium starch glycolate.
(f) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention it provides a pharmaceutical composition comprising a combination of dydrogesterone and Aromatase inhibitors preferably, Letrozole, wherein the said composition is used for the treatment or prevention of uterine disorders.

In another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone, letrozole and one or more pharmaceutically acceptable excipients, wherein the dydrogesterone is present in the range of 1mg to 50mg.

In another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the said composition is prepared by dry granulation, wet granulation, direct compression or compaction method.

In another embodiment of the present invention provides a pharmaceutical composition comprising letrozole, wherein the said composition is prepared by dry granulation, wet granulation, direct compression or compaction method.

In another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the dydrogesterone is in the form of crystalline or amorphous polymorphic form.

In another embodiment of the present invention provides a pharmaceutical composition comprising letrozole, wherein the letrozole is in the form of crystalline or amorphous polymorphic form.

In another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone, wherein the composition is in the form of solid dispersion composition.

In another embodiment of the present invention provides a pharmaceutical composition comprising letrozole, wherein the composition is in the form of solid dispersion composition.

In another embodiment of the present invention the said dydrogesterone is in the range of 1mg to 50mg.

In another embodiment of the present invention the said aromatase inhibitor is selected from the group of letrozole, Anastrozole, and exemestane.

In another embodiment of the present invention, the said Aromatase inhibitor is preferably Letrozole in the range of 1mg to 12.5mg.

In another embodiment of the present invention, the said dydrogesterone is in amount of about 10mg and letrozole is in the amount of 2.5mg.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is in the form of a bilayer tablet, wherein dydrogesterone is present in one layer and letrozole is present in another layer, to facilitate optimized drug release and therapeutic effect.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is in the form of Tablets in Tablets, wherein the dydrogesterone is present in the tablet core and Letrozole is in the tablet shell or vice-versa.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is encapsulated in to soft gel Capsules filled with liquid active ingredients for improved bioavailability and ease of administration.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is in the form of capsules with pellets or granules or powders.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising dydrogesterone in the form of soft gelatin capsule and letrozole is in the form of pellet, mini-tablet, granule or powders.

Another embodiment of the present invention provides a pharmaceutical composition comprising dydrogesterone and letrozole, wherein the pharmaceutical composition is in the form of hard gelatin capsule, wherein the capsule comprising letrozole in the form of soft gelatin capsule and dydrogesterone is in the form of pellet, mini-tablet, granule or powders.

Another embodiment of the present invention provides a kit comprising:
(a) composition comprising therapeutically effective amount of dydrogesterone and one or more pharmaceutically acceptable excipients;
(b) composition comprising therapeutically effective amount of letrozole and one or more pharmaceutically acceptable excipients;
wherein the composition of dydrogesterone and composition of letrozole are administered either simultaneously, concurrently, alternately and/or sequentially.

Another embodiment of the present invention provides pharmaceutical kit comprising two parts divided with a perforation or a punch or other suitable means to place two medicaments separately, wherein medicaments are selected from dydrogesterone and aromatase inhibitors respectively.

Another embodiment of the present invention provides pharmaceutical kit, wherein the pharmaceutical kit is made up of primary packaging material selected from aluminum blister, clear PVC blister or PVdC blister, opaque PVC/PVdC blister or amber PVC/PVdC blister and cavities of the blister are sealed with aluminum foil and this aluminum foil is printed with necessary information related to doses of medication.

Another embodiment of the present invention provides pharmaceutical kit comprising two parts, wherein two parts are divided with perforation or punch or other suitable means; wherein one part containing single cavity for one class of medicament and second part containing one or more than one cavities for other class of medicament.

The combination of the present invention may be given in single dose or as divided dose administered at appropriate intervals i.e. two, three, four or more sub-doses per patient per day, with or without food.

Various modifications of these embodiments will readily apparent to those skilled in the art in view of present disclosure, and generic method defined herein may be applied to other embodiments.

EXAMPLES
The examples used herein for such illustration are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the following examples should not be construed as limiting the scope of the embodiments herein.

Example 1: Composition of Dydrogesterone and Letrozole

Ingredients Quantity % w/w
Dydrogesterone 1-50
Letrozole 1-15
Lactose Monohydrate 1-95
Microcrystalline Cellulose 1-50
Sodium starch Glycolate type-A 0.1-20
Povidone (K-30) 0.01-10
Maize Starch 0.1-10
Colloidal Silicon Dioxide 0.1-20
Magnesium stearate 0.1-10
Film Coating 0.1-10

Process of preparation: Dydrogesterone and Letrozole along with one or more pharmaceutically acceptable excipients are mixed together and converted into final dosages form.

Example 2: Composition of Dydrogesterone and Letrozole

Ingredients Quantity % w/w
Dydrogesterone 1-50
Letrozole 1-15
Lactose Monohydrate 1-95
Hypromellose 1-50
Colloidal Silicon Dioxide 0.1-20
Maize Starch 0.1-10
Magnesium stearate 0.1-10
Film Coating 0.1-10

Process of preparation: Dydrogesterone and Letrozole along with one or more pharmaceutically acceptable excipients are mixed together and converted into final dosages form.

Example 3: Composition of Dydrogesterone and Letrozole

Ingredients Amount (mg)
Dydrogesterone 10.00
Letrozole 2.5
Lactose Monohydrate 45.50
Hypromellose 10.00
Colloidal Silicon Dioxide 5.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10%

Process of preparation: Dydrogesterone and Letrozole along with one or more pharmaceutically acceptable excipients are mixed together and converted into final dosages form.

Example 4: Composition of Dydrogesterone and Letrozole

Ingredients Amount (mg)
Dydrogesterone 10.00
Letrozole 2.5
Lactose Monohydrate 45.50
Hypromellose 10.00
Colloidal Silicon Dioxide 5.50
Pregelatinized Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10%

Process of preparation: Dydrogesterone and Letrozole along with one or more pharmaceutically acceptable excipients are mixed together and converted into final dosages form.

Pharmaceutical composition of the present invention is subjected to in-vivo testing to determine the synergistic effect of dydrogesterone and letrozole.

Example 4: Effect of dydrogesterone and letrozole combination in Endometriosis Model induced in Female BALB/c Mice.

Method - Female BALB/c mice (7-8-week age) with estrous cycle is used in the study. An endometriosis mouse model is developed by laparotomy followed by oophorectomy. After the oophorectomy the uterine horn from mice is removed and cut longitudinally into small 2 mm pieces. Horn piece is anchored onto the abdominal wall of same mice by using sterile 6-0 surgical suture. The abdominal wall and skin is closed by 6-0 silk surgical sutures. The endometrial implants are grafted and allowed to grow for 14 days to develop endometriotic lesion. Estradiol (10 mg/kg in sesame oil) is administered subcutaneously twice a week throughout the experiment. On 15th day, animals are randomized into different groups based on body weight and treated for 28 days.

The study groups comprised, naïve control (G1), vehicle/disease control (G2), Dydrogesterone (10mg/kg) + Letrozole (2.5 mg/kg) (G3), Dydrogesterone alone (10mg/kg) (G4), Letrozole alone (2.5mg/kg) (G5), and leuprolide (1 mg/kg) (G6). Groups G2-G5 are orally administered with respective treatments once daily for 28 days. A single dose of leuprolide (1mg/kg) is administered subcutaneously to G6 with dosing volume 5 ml/kg. Naïve control and vehicle control received 10 ml/kg of vehicle [0.5% v/v Tween-80 and 99.5% Methylcellulose (0.5% w/v in RO water)]. The dosing volume of each formulation is kept constant at 10 mL/kg to all the mice in G1-G5 throughout the dosing period. At the end of the study, volume of endometriosis lesions is measured and endometriotic tissues from all animals are evaluation for histopathology and VEGF levels (biomarker for angiogenesis).

Results: In study, endometriotic lesions are implanted in all mice (except naïve control) and endometriosis was successfully developed without any mortality. Endometriotic lesion volume was significantly increased in the disease control group. Treatment with the combination of dydrogesterone (10 mg/kg) + letrozole (2.5 mg/kg) resulted in a significant reduction in endometriotic lesion volume. The reduction in endometriotic lesion volume is found more significant in combination compared to dydrogesterone (10 mg/kg) alone or Letrozole (2.5 mg/kg) alone as represented in the Figure. 1. Positive control leuprolide (1 mg/kg, sc, single dose) did not exhibit significant reduction in endometriotic lesion volume compared to the vehicle group.

Also, dydrogesterone (10 mg/kg) + letrozole (2.5 mg/kg) combination treatment decreased total histopathology score more significantly compared to dydrogesterone (10 mg/kg) alone and Letrozole (2.5 mg/kg) alone as represented in the Figure. 2. Further, a significant reduction in VEGF levels is observed in dual combination of dydrogesterone (10 mg/kg) and letrozole (2.5 mg/kg), however, no significant reduction is found in dydrogesterone (10 mg/kg) and letrozole (2.5 mg/kg) monotherapy as well as leuprolide treated group as represented in Figure. 3. Overall, dual combination of dydrogesterone and letrozole showed more prominent effects against endometriosis compared to dydrogesterone and letrozole monotherapies. Hence, this combination therapy has the potential to alleviate endometriosis in the clinical settings.

It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements without deviating from the spirit and the scope of the invention may be made by a person skilled in the art.
,CLAIMS:We Claim:

1. A Pharmaceutical composition comprising dydrogesterone or its ester(s) thereof, and aromatase inhibitor or salts thereof along with one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein the particle size of dydrogesterone is about D90 less than 200 microns.

3. The pharmaceutical composition as claimed in claim 1, wherein the particle size of letrozole is about D90 less than 200 microns.

4. The pharmaceutical composition as claimed in claim 1, wherein the aromatase inhibitor is selected from the group of letrozole, anastrozole and exemestane.

5. The pharmaceutical composition as claimed in claim 1, wherein the dydrogesterone is present in the range of about 1 to 50mg and aromatase inhibitor is present in the range of about 1 mg to 12.5mg.

6. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from the group comprising binders, disintegrates, lubricants, plasticizers, opacifiers and/or diluents.

7. The pharmaceutical composition as claimed in claim 6, wherein binders is present about 1% w/w to about 50% w/w of the composition.

8. The pharmaceutical composition as claimed in claim 6, wherein diluent is present about 1% w/w to about 95% w/w of the composition.

9. A kit comprising:
(a) composition comprising therapeutically effective amount of dydrogesterone and one or more pharmaceutically acceptable excipients;
(b) composition comprising therapeutically effective amount of letrozole and one or more pharmaceutically acceptable excipients;
wherein the composition of dydrogesterone and composition of letrozole are administered either simultaneously, concurrently, alternately and/or sequentially.

10. The kit as claimed in claim 9, wherein kit comprises two parts divided with a perforation or a punch or other suitable means to place two medicaments separately.

Dated this the 13th day of September 2024.
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer