DESC:A PHARMACEUTICAL COMBINATION FOR UTERINE DISORDERS AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical combination comprises of dydrogesterone or its ester (s), anthelmintic agent, wherein the said pharmaceutical combination is used for the treatment of uterine disorders preferably uterine fibroids, adenomyosis, endometriosis, heavy menstrual bleeding, or pain associated with uterine fibroids, endometriosis, or adenomyosis and other related disorders. Moreover, the present invention also relates to the pharmaceutical composition and process of preparing such composition thereof.

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. Dydrogesterone is a synthetic progestin that has found its niche in the field of gynecology and women’s health. Structurally akin to the natural hormone progesterone, dydrogesterone is renowned for its role in managing various gynecological conditions. It is frequently prescribed to address issues like irregular menstrual periods and endometriosis, as well as for its utility in hormone replacement therapy, especially in postmenopausal women.

Meanwhile, levamisole, although primarily known as an anthelmintic medication used to combat parasitic worm infections in both humans and animals, had been employed in the past as an adjuvant therapy for specific types of cancer. However, its oncological application has waned significantly due to safety concerns. In contrast, letrozole is a well-established aromatase inhibitor employed in postmenopausal women diagnosed with hormone receptor- positive breast cancer. It functions by suppressing the production of estrogen, a hormone that can fuel the growth of certain breast cancers. It’s important to note that while these drugs have individual medical applications, there is no widely recognized combination therapy involving dydrogesterone, levamisole and letrozole.

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.

Anthelmintic are drugs that are used to treat infections with parasitic worms. This includes both flat worms, e.g., flukes and tapeworms and round worms, i.e., nematodes. They are of huge importance for human tropical medicine and for veterinary medicine and other pharma medicines.

Levamisole is a synthetic imidazothiazole derivative which is used widely in the treatment of worm infestations in both humans and animals. As it is an anthelmintic, it works by targeting the nematode nicotinergic acetylcholine receptor. As an immunomodulator, it appears that Levamisole is an immunostimulant which has been shown to increase NK cells and activated T-cells in patients receiving this adjuvantly along with 5FU for Stage III colon cancer. Levamisole was also found to be effective in regression of the volume of endometriotic implants. Levamisole exerts its anti-inflammatory action because of its regulatory action on inflammatory cytokine TNF-a and the pro-inflammatory cytokine IL-6.

The mechanism of action of Levamisole as an anticancer drug in combination with fluorouracil is unknown. The effects of levamisole on the immune system is complex. The drug appears to restore depressed immune function rather than to stimulate response to above-normal levels. Levamisole can stimulate development of antibodies to different antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis and chemotaxis, and increase neutrophil mobility, adherence, and chemotaxis.

Niclosamide is an anthelmintic medication originally developed for the treatment of parasitic worm infections, particularly tapeworm. However, it has garnered increasing attention in recent years due to its potential applications beyond parasitic infections. Niclosamide has been investigated for its potential antiviral, anticancer, and anti-inflammatory properties. In the context of antiviral research, it has shown promise against several infections, including some RNA viruses such as SARS-CoV2, the virus responsible for COVID-19. Additionally, Niclosamide has been explored for its potential in cancer therapy, as it may inhibit the growth of cancer cells and exhibit anti-tumor properties. Its diverse pharmacological properties have made it a subject of interest for further research in various medical fields.

Niclosamide is a derivative of salicylamide and is an effective anthelmintic drug. Its action consists of inhibition of mitochondrial oxidative phosphorylation in both mammals as well as in parasites. It simultaneously inhibits glucose and oxygen uptake by the parasite. In therapeutic doses, it has practically no pharmacological effect on the host organism. Niclosamide is effective against intestinal cestodes, such as Diphyllobothrium la-tum, Taenia saginata, Taenia solium, Dipilidium caninum, Hymenolepis diminuta and Hymenolepis diminuta, but it is ineffective against nematodes.

Niclosamide is a chlorinated salicyl anilide possessing anthelmintic and potential antineoplastic activity. It is currently used against most tapeworm infections such as intestinal nematodes, filarial nematodes, flukes, and tapeworms. Niclosamide has been approved for nearly 50 years for the treatment of such infections in humans. Niclosamide has been identified as a potential anticancer agent by various high-throughput screening campaigns.

Although various combinations are known from prior known references, there still remains a need for pharmaceutical combination using dydrogesterone or its ester(s) along with anthelmintic agents to treat or prevent the uterine disorders.

The combination of dydrogesterone, and anthelmintic agents has advantageous properties which makes these combinations 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 etc.

OBJECTIVES OF THE INVENTION
An objective of the present invention to provide a pharmaceutical combination comprising therapeutically effective amount of dydrogesterone and Anthelmintic agent.

Another objective of the present invention to provide a pharmaceutical composition comprising therapeutically effective amount of dydrogesterone, anthelmintic agent and one or more pharmaceutically acceptable excipients.

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

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

Another objective of the present invention is to provide a pharmaceutical combination comprising dydrogesterone or its ester(s), an anthelmintic agent and/or an aromatase inhibitor.

Another objective of the present invention is to provide a pharmaceutical composition comprising dydrogesterone or its ester(s), an anthelmintic agent and/or an aromatase inhibitor along with one or more pharmaceutically acceptable excipient.

Another objective of the present invention to provide a pharmaceutical combination comprising therapeutically effective amount of dydrogesterone, anthelmintic agent, and aromatase inhibitor, wherein the said combination is administered either simultaneously or separately or sequentially.

Another objective of the present invention to provide a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone, levamisole and letrozole.

Another objective of the present invention to provide a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone, niclosamide and letrozole.

Another objective of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, levamisole and letrozole along with one or more pharmaceutically acceptable excipient.

Another objective of the present invention to provide a pharmaceutical composition comprising therapeutically effective amount of dydrogesterone, niclosamide and letrozole along with one or more pharmaceutically acceptable excipient.

Another objective of the present invention to provide a pharmaceutical combination comprising dydrogesterone, letrozole and levamisole/ niclosamide wherein the said combination shows a synergistic effect and significantly reduces the time required to treat and prevent the disorders related to uterus as compared to treatment with dydrogesterone, letrozole and levamisole/ Niclosamide alone.

Another objective of the present invention to provide a pharmaceutical composition/combination comprising of dydrogesterone, niclosamide and letrozole, wherein the said composition/combination is used for the treatment of uterine disorders such as lower back pain, abdominal pain, and haemostasis in the threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, adenomyosis, uterine fibroids.

Another objective of the present invention to provide a pharmaceutical composition/combination comprising of dydrogesterone, levamisole and letrozole, wherein the said composition/combination is used for the treatment of uterine disorders such as lower back pain, abdominal pain, and haemostasis in the threatened abortion, female infertility, pain during menstruation, premenstrual syndrome (PMS), endometriosis, heavy menstrual bleeding, adenomyosis, uterine fibroids

Another objective of the present invention to provide a process for the preparation pharmaceutical composition/combination for the treatment or prevention of uterine disorders.

Additional objectives and embodiments of the invention will be set forth in part of the description, or may be learned by practice of the invention.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a pharmaceutical combination comprising dydrogesterone or its ester(s), anthelmintic agent and aromatase inhibitor.

In an aspect the present invention relates to a pharmaceutical combination comprising:
(a) therapeutically effective amount of dydrogesterone or its esters;
(b) therapeutically effective amount of anthelmintic agent;
(c) therapeutically effective amount of aromatase inhibitor.

In an aspect the present invention relates to a pharmaceutical combination of dydrogesterone or its ester(s), anthelmintic agent, and aromatase inhibitor, wherein the anthelmintic agent is selected from the group comprising of levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine and pyrantel.

In an aspect the present invention relates to a pharmaceutical combination of dydrogesterone or its ester(s), anthelmintic agent, and aromatase inhibitor, wherein the anthelmintic agent preferably be levamisole.

In an aspect the present invention relates to a pharmaceutical combination of dydrogesterone or its ester(s), anthelmintic agent, and aromatase inhibitor, wherein the anthelmintic agent preferably be Niclosamide.

In an aspect the present invention relates to a pharmaceutical combination of dydrogesterone or its ester(s), anthelmintic agent, and aromatase inhibitor, wherein the aromatase inhibitor is selected from the group comprising of letrozole, anastrozole, exemestane.

In an aspect the present invention relates to a pharmaceutical combination of dydrogesterone or its ester(s), anthelmintic agent, and aromatase inhibitor, wherein the aromatase inhibitor preferably be letrozole.

In an aspect the present invention relates to a pharmaceutical composition comprising;
(a) therapeutically effective amount of dydrogesterone or its esters;
(b) therapeutically effective amount of anthelmintic agent; and
(c) one or more pharmaceutically acceptable excipients.

In an aspect the present invention relates to a pharmaceutical composition comprising;
(a) therapeutically effective amount of dydrogesterone or its esters;
(b) therapeutically effective amount of anthelmintic agent;
(c) therapeutically effective amount of aromatase inhibitor; and
(d) one or more pharmaceutically acceptable excipients.

In an aspect the present invention relates to a pharmaceutical composition comprising dydrogesterone or its esters and anthelmintic agent along with one or more pharmaceutically acceptable excipients, wherein the anthelmintic agent is selected from the group of levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine and pyrantel.

In an aspect the present invention relates to a pharmaceutical composition comprising dydrogesterone or its esters and anthelmintic agent along with one or more pharmaceutically acceptable excipients, wherein the anthelmintic agent is preferably be Levamisole.

In an aspect the present invention relates to a pharmaceutical composition comprising dydrogesterone or its esters and anthelmintic agent along with one or more pharmaceutically acceptable excipients, wherein the anthelmintic agent is preferably be Niclosamide.

In an aspect the present invention relates to a pharmaceutical composition comprising of dydrogesterone or its esters, levamisole and letrozole along with one or more pharmaceutically acceptable excipients.

In an aspect the present invention relates to a pharmaceutical composition comprising dydrogesterone or its esters, Niclosamide and letrozole along with one or more pharmaceutically acceptable excipients.

In an aspect of the present invention dydrogesterone or anthelmintic agent or aromatase inhibitor is present/used with the particle size in the range of D90 less than 200 microns (µ), preferably in the range of D90 less than 100 microns(µ).

In an aspect of the present invention, it relates to pharmaceutical composition comprising dydrogesterone, wherein the particle size of the dydrogesterone is D90 less than 50µ.

In an aspect of the present invention, it relates to pharmaceutical combination of dydrogesterone or its ester(s) anthelmintic agents, and aromatase inhibitor, wherein the particle size of the dydrogesterone is D90 less than 50µ.

In one aspect, the present invention provides a combination of dydrogesterone or its ester(s), anthelmintic agent and aromatase inhibitor in the preparation of medicines for the prevention and/or treatment of uterine 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 anthelmintic Drug;
c) therapeutically effective amount of aromatase inhibitor; and
d) one or more pharmaceutically acceptable excipients.

In an aspect of the present invention, the said dydrogesterone is in the range of 1mg -50mg, the said aromatase inhibitor preferably be letrozole is 1mg -12.5mg and the said anthelmintic agent is levamisole is in the range of 1mg - 500mg.

In an aspect of the present invention the said dydrogesterone is in the range of 1mg-50mg, the said aromatase inhibitor preferably be letrozole is 1mg - 12.5 mg and the said anthelmintic drug is Niclosamide is in the range of 1mg-500 mg.

In one aspect, the present invention provides a pharmaceutical combination comprising of dydrogesterone or its ester(s) anthelmintic agent, and aromatase inhibitor, wherein the said dydrogesterone is preferably be 10mg, levamisole is preferably in the range of 25mg-100mg and letrozole is preferably be 2.5mg – 5.0mg.

In one aspect, the present invention provides a pharmaceutical combination comprising of dydrogesterone or its ester(s) anthelmintic agent, and aromatase inhibitor, wherein the said dydrogesterone is preferably be 10mg, Niclosamide is preferably in the range of 1mg-500mg and letrozole is preferably be 2.5 mg-5.0 mg.

In one more aspect, the present invention provides a pharmaceutical combination comprising:
(a) therapeutically effective amount of Dydrogesterone or its ester(s);
(b) therapeutically effective amount of anthelmintic agent and aromatase inhibitor or metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters, solvate thereof,
wherein the said combination comprising dydrogesterone or its ester(s) is administered in an amount of about 1mg -50mg and the said anthelmintic drug(s) is administered in an amount of 1mg- 500mg.

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 aromatase inhibitor and one or more pharmaceutically acceptable excipients;
c) composition comprising therapeutically effective amount of anthelmintic agent and one or more pharmaceutically acceptable excipients;
wherein the said compositions are administered either simultaneously, concurrently, alternately and/or sequentially.

According to another aspect, the present invention provides a pharmaceutical combination comprising therapeutically effective amount of dydrogesterone or its ester(s) and therapeutically effective amount of anthelmintic agent, wherein the dydrogesterone and anthelmintic agents are administered either simultaneously, or concurrently or alternately or sequentially.

According to one more aspect, the present invention relates to a pharmaceutical composition comprising dydrogesterone and levamisole, wherein dydrogesterone is in the range of 1mg-50mg, and levamisole is in the range of 25mg-100 mg.

According to another aspect, the present invention provides a pharmaceutical composition comprising of dydrogesterone, and niclosamide wherein dydrogesterone is in the preferable range of 1mg-50mg, and Niclosamide is in the preferable range of 1mg- 500mg.

According to another aspect, the present invention provides a pharmaceutical composition/combination, wherein the composition/combination 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.

According to another aspect, the present invention provides a pharmaceutical composition along with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group comprising of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

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/FIGURES
Figure 1 illustrates the change in endometriosis lesions volume after 28-days of treatment. #Significant difference as compared to naïve 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 naïve 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 naïve 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 combination 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 combination and the process for preparation thereof as much as the objective(s) of the present invention is enumerated, it will be obvious to a person skilled in the art that, the enumerated objective(s) is not exhaustive of the present invention in its entirety, and is 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 is not intended to be limiting, but rather is 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.

Accordingly, the present invention relates to a pharmaceutical combination comprising dydrogesterone or its ester(s), anthelmintic agent and aromatase inhibitor along with one or more pharmaceutical excipients.

The term “dydrogesterone” includes its ester, metabolites, isomers, polymorphs, pharmaceutically acceptable salts, esters solvate thereof.

The term “anthelmintic agent” includes levamisole, niclosamide, albendazole, lvermectin, mebendazole, nitazoxamide, pyrvinium, flubendazole, piperazine and pyrantel.

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

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 inorganic acids and inorganic salts may further include alkali metal and alkaline earth metal salts.

Accordingly, in an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone and levamisole.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone and niclosamide.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone, levamisole and letrozole.

In an embodiment, the present invention provides a pharmaceutical combination comprising a therapeutically effective amount of dydrogesterone, niclosamide and letrozole.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, levamisole and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, levamisole and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, Niclosamide, letrozole and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of dydrogesterone, levamisole and letrozole along with one or more pharmaceutically acceptable excipients.

The term “excipient” or “pharmaceutical 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 may include one or more pharmaceutically acceptable excipients are selected from the group comprising of 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, zinc stearate, magnesium stearate, sodium stearyl fumarate, aluminium or calcium silicate, 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), carboxymethyl starch-Na (pirimojel and explotab), sodium starch glycolate, 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, polysorbate, cremophore, soluplus, lecithin and sodium lauryl sulfate and/or combinations thereof.

The pharmaceutical combination of the present invention may be 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, 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.

Suitable plasticizers are 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.

According to an embodiment of the present invention, the above-mentioned pharmaceutical combination 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, 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 anthelmintic drug;
(c) therapeutically effective amount of aromatase inhibitor; and
(d) one or more pharmaceutically acceptable excipients.

Wherein the said dydrogesterone is preferably in the range of 10mg – 50mg, the said anthelmintic agent is selected from the group of levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine and pyrantel, present in the range of 1mg -500mg and the aromatase inhibitor is selected from the group of letrozole, anastrozole, exemestane present in the range of 1mg -12.5mg.

In another embodiment of the present invention it relates to a pharmaceutical combination comprising of dydrogesterone, anthelmintic agent and aromatase inhibitor, wherein dydrogesterone present is preferably be 10mg, the preferable anthelmintic agent is levamisole in the range of 25mg-100mg and the preferable aromatase inhibitor is letrozole is 2.5mg -5.0mg.

In another embodiment of the present invention it relates to a pharmaceutical combination comprising of dydrogesterone, anthelmintic agent and aromatase inhibitor, wherein dydrogesterone present is preferably be 10 mg, the preferable anthelmintic agent is niclosamide in the range of 1mg-500mg and the preferable aromatase inhibitor is letrozole is 2.5mg-5.0mg.

In another embodiment of the present invention it relates to a pharmaceutical combination comprising of dydrogesterone, anthelmintic agent and aromatase inhibitor along with one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are selected from the group of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer and/or combinations thereof.

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 Anthelmintic agent; and
(c) one or more pharmaceutical acceptable excipients.

In another embodiment of the present invention it provides a pharmaceutical composition comprising dydrogesterone and anthelmintic agent, wherein the anthelmintic agent is selected from the group of levamisole, niclosamide, albendazole, lvermectin, mebendazole, nitazoxamide, pyrvinium, flubendazole, piperazine and pyrantel, in the range of 1mg -500 mg.

In another embodiment of the present invention it provides a pharmaceutical composition comprising of dydrogesterone and the anthelmintic agent, wherein the preferable anthelmintic agent is levamisole present in the range of 1mg-500mg.

In another embodiment of the present invention it provides a pharmaceutical composition comprising dydrogesterone and the anthelmintic agent, wherein the preferable anthelmintic agent is Niclosamide present in the range of 1mg-500mg.

In another embodiment of the present invention it provides a pharmaceutical composition comprising dydrogesterone and the anthelmintic agent along with one or more pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients selected from the group of diluent/filler, binder, surfactant, glidant, disintegrant, lubricant, film forming polymer, extended release polymer, coloring agent/colorant, opacifier, plasticizer 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, pharmaceutical excipient or carrier binders; disintegrating agents; absorption accelators; wetting agents; lubricants and mixtures thereof.

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.

Another embodiment of the present invention it provides a pharmaceutical composition, wherein the composition is in the form of a bilayer tablet.

Another embodiment of the present invention it provides a pharmaceutical composition, wherein the composition is in the form of a tri-layer tablet.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of Tablets in Tablets.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of capsules filled with granules.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of capsules filled with pellets.

Another embodiment of the present invention it provides composition, wherein the pharmaceutical composition is in the form of tablet coatings.

Another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of dydrogesterone,
(b) therapeutically effective amount of aromatase inhibitors;
(c) therapeutically effective amount of anthelmintic agent;
Wherein the composition is in the form of hard gelatin capsule, wherein the hard gelatin capsule comprising (i) tablet, granules, pellet or powder of aromatase inhibitors or anthelmintic agent, (ii) soft gelatin capsule of dydrogesterone or vice-versa.

In another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of dydrogesterone,
(b) therapeutically effective amount of aromatase inhibitors;
(c) therapeutically effective amount of anthelmintic agent;
wherein the said composition is prepared by dry granulation, wet granulation, direct compression, solid dispersion or compaction method.

In another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) therapeutically effective amount of dydrogesterone,
(b) therapeutically effective amount of aromatase inhibitors;
(c) therapeutically effective amount of anthelmintic agent;
wherein the dydrogesterone, aromatase inhibitors and anthelmintic agent are in the form of crystalline or amorphous polymorphic form.

In another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) about 1%w/w to about 75%w/w of dydrogesterone,
(b) about 1%w/w to about 50% w/w of letrozole,
(c) about 1%w/w/ to about 75%w/w of Levamisole,
(d) about 10%w/w to about 80%w/w of diluent,
(e) binder is in the range of 0.01%w/w to about 20%w/w,
(f) about 0.01%w/w to about 10%w/w of glidant,
(g) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) about 1%w/w to about 75%w/w of dydrogesterone,
(b) about 1%w/w to about 50% w/w of letrozole,
(c) about 1%w/w/ to about 75%w/w of niclosamide/ levamisole,
(d) about 10%w/w to about 80%w/w of diluent,
(e) binder is in the range of 0.01%w/w to about 20%w/w,
(f) about 0.01%w/w to about 10%w/w of glidant,
(g) about 0.01%w/w to about 20%w/w of disintegrant,
(h) about 0.01%w/w to about 10%w/w of lubricant,
(i) one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention provides a pharmaceutical composition comprising:
(a) about 10mg of dydrogesterone,
(b) about 2.5 of letrozole,
(c) about 25mg of niclosamide/ levamisole,
(d) about 75.5mg of Lactose,
(e) hypromellose is about 10mg,
(f) about 10.5mg of colloidal silicon dioxide,
(g) about 4mg of maize starch,
(h) about 2.5mg of magnesium stearate,
(i) one or more pharmaceutically acceptable excipients.

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 aromatase inhibitors and one or more pharmaceutically acceptable excipients;
(c) composition comprising therapeutically effective amount of anthelmintic agent and one or more pharmaceutically acceptable excipients’
wherein the composition of dydrogesterone, aromatase inhibitor and anthelmintic agent are administered either simultaneously, concurrently, alternately and/or sequentially.

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

Another embodiment of the present invention provides pharmaceutical kit, wherein the pharmaceutical kit is made up of primary packaging material selected from aluminium blister, clear PVC blister or PVdC blister, opaque PVC/PVdC blister or amber PVC/PVdC blister and cavities of the blister are sealed with aluminium foil and this aluminium 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 single cavity for other class of medicament.

Another embodiment of the present invention provides pharmaceutical kit comprising three parts, wherein three 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 second class of medicament and third part containing other class of medicament.

The combinations and the composition as per the present invention can 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:
Ingredients Quantity (%w/w)
Dydrogesterone 1-75%
Letrozole 1-50%
Levamisole 1-75%
Diluent 10-80%
Binder 0-20%
Disintegrant 0-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20% weight gain

Examples 2:
Ingredients Amount (mg)
Dydrogesterone 10.00
Letrozole 2.5
Levamisole 25
Lactose Monohydrate 75.50
Hypermellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10%

Process of Preparation:
Dydrogesterone, Letrozole, Levamisole and one or more pharmaceutically acceptable excipients are mixed together. The mixture is converted into suitable dosages form.

Example 3:
Ingredients Quantity (%w/w)
Dydrogesterone 1-75%
Levamisole 1-75%
Diluent 10-80%
Binder 0-20%
Disintegrant 0-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20%

Example 4:
Ingredients Amount (mg)
Dydrogesterone 10.00
Levamisole 50
Lactose Monohydrate 75.50
Hypermellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10%

Process of Preparation:
Dydrogesterone and Levamisole along with one or more pharmaceutically acceptable excipients are mixed together. The mixture is converted into suitable dosages form.

Example 5:
Ingredients Quantity (%w/w)
Dydrogesterone 1-75%
Niclosamide 1-90%
Diluent 10-80%
Binder 0-20%
Disintegrant 0-20%
Glidant 0.01-10%
Lubricant 0.01-10%
Optional Film Coating 1-20%

Example 6:
Ingredients Amount (mg)
Dydrogesterone 10.00
Niclosamide 100
Lactose Monohydrate 75.50
Hypermellose 10.00
Colloidal Silicon Dioxide 10.50
Maize Starch 4.00
Magnesium stearate 2.50
Film Coating 1-10%

Process of Preparation:
Dydrogesterone and Niclosamide along with one or more pharmaceutically acceptable excipients are mixed together. The mixture is converted into suitable dosages form.

Example 7 - Effect of Dydrogesterone, Letrozole and Levamisole combination on Endometriosis Model induced in Female BALB/c Mice.
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 are closed by 6-0 silk surgical sutures. The endometrial implants are grafted and allowed to grow for 14 days to develop endometriotic lesions. 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 (10 mg/kg) + levamisole (25 mg/kg) (G3), dydrogesterone (10 mg/kg) + levamisole (50 mg/kg) (G4), dydrogesterone (10 mg/kg) + levamisole (25 mg/kg) + letrozole (2.5 mg/kg) (G5), dydrogesterone (10 mg/kg) + levamisole (50 mg/kg) + letrozole (2.5mg/kg) (G6), dydrogesterone alone (10 mg/kg) (G7), letrozole alone (2.5 mg/kg) (G8), levamisole (25 mg/kg) alone (G9), levamisole (50 mg/kg) alone (G10) and leuprolide (1mg/kg) (G11). Groups G2-G11 is orally administered with respective treatments once daily for 28 days. A single dose of leuprolide (1mg/kg) is administered subcutaneously to G11 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-G11 throughout the dosing period. At the end of the study, volume of endometriosis lesions is measured, and endometriotic tissues from all animals were evaluated for histopathology and VEGF levels (biomarker for angiogenesis).
Results:
In the present invention study, endometriotic lesions are implanted in all mice (except naïve control) and endometriosis is successfully developed without any mortality. Endometriotic lesion volume is significantly increased in the disease control group. After 4 weeks of treatment, all study groups showed reduction in endometriotic lesions compared to the vehicle/disease control group. Treatment with dual combinations of dydrogesterone (10 mg/kg) and levamisole (25mg/kg or 50 mg/kg) significantly reduced endometriosis tissue volume, however, the decrease is similar to dydrogesterone alone (10 mg/kg). Similarly, treatment with dydrogesterone and levamisole combinations significantly decreased total histopathology score but marked decrease is not found compared to mice treated with dydrogesterone alone (10 mg/kg). Triple combination of dydrogesterone (10 mg/kg) + levamisole (25 mg/kg) + letrozole (2.5 mg/kg) showed more significant regression in endometriosis lesions and total histopathology score in comparison to dydrogesterone + levamisole combinations, and dydrogesterone, levamisole and letrozole monotherapies (as represented in Fig. 1 and Fig. 2). Positive control leuprolide (1 mg/kg, sc, single dose) did not exhibit significant reduction in endometriotic lesions compared to the vehicle group. Furthermore, a significant reduction in VEGF levels is observed in mice treated with dual and triple combinations, however, no significant reduction is found in dydrogesterone (10 mg/kg) and levamisole (25mg/kg and 50mg/kg) monotherapies as well as leuprolide treated group (as represented in Fig. 3).

In conclusion, the present study has demonstrated that the combination of levamisole (25 mg/kg), dydrogesterone (10 mg/kg), and letrozole (2.5 mg/kg) is associated with more significant regression of endometriotic implants and may be further evaluated in clinical setting.

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, aromatase inhibitor or salts thereof and anthelmintic agent 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 Anthelmintic agent or aromatase inhibitor 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 Anthelmintic agent is selected from the group comprising of levamisole, Niclosamide, Albendazole, lvermectin, Mebendazole, Nitazoxamide, Pyrvinium, flubendazole, piperazine and pyrantel.

6. The pharmaceutical composition as claimed in claim 1, wherein the dydrogesterone is present in the range of about 1mg to 50mg, aromatase inhibitor is present in the range of about 1 mg to 12.5mg, and Anthelmintic agent is in the range of 1mg to 500mg.

7. 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.

8. The pharmaceutical composition as claimed in claim 6, wherein binder is present about 1% w/w to about 50% w/w of the composition and 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;
(c) composition comprising therapeutically effective amount of Anthelmintic agent 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 three parts divided with a perforation or a punch or other suitable means to place three medicaments separately.

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

Dr. Anil Kumar

Chief Scientific Officer