WO2017072629A1

WO2017072629A1 - Pharmaceutical combination of nk3 receptor antagonist and biguanides

Info

Publication number: WO2017072629A1
Application number: PCT/IB2016/056271
Authority: WO
Inventors: Mukul Jain; Kaushik BANERJEE; Amit JOHARAPURKAR; Arti PANDYA; Samadhan KSHIRSAGAR
Original assignee: Cadila Healthcare Limited
Priority date: 2015-10-29
Filing date: 2016-10-19
Publication date: 2017-05-04
Also published as: AR106477A1; TW201729808A

Abstract

The present invention describes a synergistic composition comprising of NK3 receptor antagonist or a pharmaceutically effective salts thereof and biguanides or a pharmaceutically effective salts thereof for the treatment of PCOS and related diseases. The present invention is directed to a synergistic combination comprising combinations of a NK3 receptor antagonist or pharmaceutically effective salts thereof and biguanides or pharmaceutically effective salts thereof in a single unit pharmaceutical composition. The invention is further related to methods of preparing such pharmaceutical composition in separate in either a kit form containing both the active agents and methods of treating a subject with the same.

Description

PHARMACEUTICAL COMBINATION OF NK3 RECEPTOR ANTAGONIST AND BIGUANIDES

FIELD OF THE INVENTION

The present invention describes a synergistic composition comprising of NK3 receptor antagonist or a pharmaceutically effective salts thereof and biguanides or a pharmaceutically effective salts thereof for the treatment of PCOS (Polycystic ovarian syndrome) and related diseases. In one embodiment, the present invention is directed to a synergistic combination comprising combinations of a NK3 receptor antagonist or pharmaceutically effective salts thereof and biguanides or pharmaceutically effective salts thereof in a single unit pharmaceutical composition. The invention is further related to methods of preparing such pharmaceutical composition in separate in either a kit form containing both the active agents and methods of treating a subject with the same.

BACKGROUND OF THE INVENTION

Polycystic ovarian syndrome (PCOS) is a disease occurring in females, and is characterized by hyperandrogenism. PCOS represents a spectrum of phenotypes associated with follicle growth arrest, chronic anovulation, minimal granulosa cell proliferation, hyperthecosis, hyperandrogenemia, central adiposity and insulin resistance. In PCOS, plasma luteinizing hormone (LH) is high and FSH is low, increasing the LH/FSH ratio, typically due to increased LH or GnRH (Gonadotropin releasing hormone) pulse (Semin Reprod Med. 2002 Nov;20(4):317-26). In PCOS, disturbances occur in ovarian steroid synthesis, hyperinsulinemia being one of the condition which increases ovarian androgen production and stimulate LH and increases LH/GnRH secretion. A neuroendocrine defect of GnRH secretion leads to persistent hypersecretion of LH in non-obese PCOS patients (Endocrinol Metab Clin North Am. 1999 Jun; 28(2):295-324.). Many females with PCOS suffer from menstrual cycle abnormalities, hirsutism and infertility (Hum Reprod Update. 2015 Sep; 21(5):575-92).

There are no successfully approved treatments for PCOS (Syst Rev. 2015 Sep 23; 4(1): 125). Optimal first line treatment of PCOS in adolescents remains controversial. Lifestyle changes (dietary and exercise modification) followed by either oral contraceptive pills (OCP) to control symptoms of hyperandrogenism is normally recommended, which has not more than 50% clinical success. However, there is significant variability in clinical practice, depending on whether the physician and patient's primary goal of treatment is to treat the symptoms of hyperandrogenism or the features of metabolic syndrome. Additionally, in clinical practice anti-androgenic medications such as spironolactone, flutamide or pioglitazone are used as add-on therapy for PCOS when oral contraceptive pill (OCP) or metformin fail to produce the clinically desired outcomes, yet their use in adolescent population is not recommended. Antiandrogens like spironolactone are second choice having risk of electrolyte imbalance. GnRH analogue is the next line of therapy to reduce androgen with lack of potency needing additional hormonal therapy to counteract the chemical menopause that they induce. Metformin may be administered to reduce androgen level, improve menstrual regularity and fertility as well as insulin resistance. Clomiphene with or without metformin improves conception rates with risk of ovarian hyperstimulation and multiple pregnancies (J Clin Endocrinol Metab. 2013 Dec; 98(12):4565-92).

Since current treatment strategies for PCOS have limited efficacy and marked side effects, and further there are no consistent guidelines for their uses, a therapeutic option which can cure the underlying pathophysiology related to hypothalamic pituitary gonadal (HPG) axis, correct the LH pulsatility, and treat the symptoms of metabolic disturbances without significant side effects is needed.

NK3 receptor antagonist have been disclosed in WO 95/32948, WO 97/19927, WO 97/19928, WO 97/19926, WO 97/21680, WO2000031037, WO2006137789, WO2009019163, WO2010086259, WO2010094667, WO0031037, WO0238548, WO 006137789

WO 95/32948 discloses compounds of the following general formula:

Talnetant (SB 223412) is a NK3 receptor antagonist, 3-hydroxy-2-phenyl-N-(l- phenylpropyl)quinoline-4-carboxamide of formula (I) and is disclosed in W095/32948, the disclosures of which are incorporated herein in their entirety.

Formula (I)

The term biguanide refers to a group of oral type 2 diabetes drugs that work by preventing the production of glucose in the liver, improving the body's sensitivity towards insulin and reducing the amount of sugar absorbed by the intestines.

The major biguanides, metformin and Phenformin were introduced way back in the 1950s as oral glucose-lowering agents to treat non-insulin-dependent diabetes mellitus. Now, the only available biguanide medication is Metformin, which is commonly used as a first- line treatment for type 2 diabetes (i.e. the first option for type 2 diabetics who are unable to control their blood sugars through diet and exercise alone). Metformin has traditionally been used as an oral drug to help control diabetes.

Despite recent advances, there is a continuing need for new and improved methods of treating and preventing PCOS and related disorders. Due to the limited efficacy of currently available therapies there is also a need for a combination PCOS treatment with enhanced efficacy, and fewer undesirable side effects, such as infertility, electrolyte disturbances, premature menopause, ovarian hyperstimulation, multiple pregnancies, and metabolic disturbances. The instant invention addresses this problem by providing a combination therapy comprising of an NK3 receptor antagonist or its pharmaceutically effective salts thereof and a biguanide or pharmaceutically effective salts thereof useful in the treatment and prevention of PCOS and related disorders.

It has now been found that a combination of a NK3 receptor antagonist or pharmaceutically effective salts thereof and a biguanides or pharmaceutically effective salts thereof is useful to treat and prevent PCOS and related disorders. In particular it has been surprisingly found that a combination of a NK3 receptor antagonist agent or a pharmaceutically effective salts thereof and a biguanides or pharmaceutically effective salts thereof exhibit unexpected and advantageous results. It has also been surprisingly found that the combination of the present invention is advantageous and surprisingly synergistic results in the treatment of PCOS over treatment with either a NK3 receptor antagonist or a biguanide agent alone.

EMBODIMENTS OF THE PRESENT INVENTION

In a first aspect, the present invention relates to pharmaceutical combinations comprising an NK3 receptor antagonist or pharmaceutically effective salts thereof and a biguanide or a pharmaceutically effective salt thereof, optionally in the presence of a pharmaceutically acceptable carrier and suitable pharmaceutical compositions containing them. The invention also relates to combining separate pharmaceutical compositions of the two drugs in kit form. In a second aspect, the present invention provides a synergistic composition comprising low dose of a compound which is an NK3 receptor antagonist or pharmaceutically effective salts thereof with a biguanide or pharmaceutically effective salts thereof for the treatment of PCOS and related diseases.

In a third aspect, the present invention provides a synergistic composition comprising a low dose of compound of NK3 receptor antagonist or pharmaceutically effective salts thereof with a biguanide or a pharmaceutically effective salt thereof for the treatment of humans. In an embodiment, the NK3 receptor antagonist may be selected from Talnetant (SB223412), AZD-4901, AZD-2624 and the biguanide is metformin.

In another embodiment is provided a pharmaceutical composition containing effective amount of synergistic composition as disclosed herein suitable for treatment of PCOS and related diseases.

In yet another embodiment is provided a process for the preparation of pharmaceutical composition comprising an NK3 receptor antagonist or pharmaceutically effective salts thereof with a biguanide or a pharmaceutically effective salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to pharmaceutical combinations comprising NK3 receptor antagonist or pharmaceutically effective salts thereof and biguanides or pharmaceutically effective salts thereof, optionally in the presence of pharmaceutically acceptable carriers and pharmaceutical compositions comprising them.

The NK3 receptor antagonist of the present invention may be selected from Talnetant (SB223412), AZD-4901, AZD-2624 and the biguanide is Metformin.

The pharmaceutically acceptable carrier may be selected from sugars such as lactose, sucrose, mannitol and sorbitol; starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose ; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate ; calcium sulfate ; polyvinylpyrrolidone; polyvinyl alcohol ; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil ; non-ionic, cationic and anionic surfactants; ethylene glycol polymers; β-cyclodextrin; fatty alcohols; and hydrolyzed cereal solids, as well as other non-toxic compatible fillers, binders, disintegrates, buffers, preservatives, antioxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.

The invention also relates to combining separate pharmaceutical compositions in kit form. That is a kit combining two separate units: NK3 receptor antagonist or pharmaceutically effective salts thereof and biguanides or a pharmaceutically effective salt thereof. The kit form is particularly advantageous when the separate components must be administered in different dosage forms or are administered at different dosage intervals.

These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeo therms with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compounds.

Pharmaceutical preparations for enteral or parenteral administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules.

The pharmaceutical compositions are prepared in a manner which is known per se, for example using conventional mixing, granulation, and coating, solubilizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.

The dosage of the active compound can depend on a variety of factors, such as mode of administration, homoeothermic species, age and/or individual condition. Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutically effective dosages, especially those which are commercially available.

In an aspect, the present invention provides a synergistic composition comprising Talnetant and Metformin at a dosage ranging from 1 mg to 1000 mg for each. In a preferred embodiment, is provided such pharmacological combination containing Talnetant ranging from 1 mg to 50 mg. and a Metformin ranging from 10 mg to 500 mg.

Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg combined dose is to be estimated e. g. for a patient of approximately 75 kg in weight.

In a third aspect, the present invention is provided a synergistic composition comprising a low dose of a NK3 receptor antagonist or pharmaceutically effective salts thereof with a biguanides or a pharmaceutically effective salt thereof for the treatment of PCOS and related diseases

Many symptoms of PCOS are related not only to increased LH pulse, but also due to insulin resistance and hyperinsulinemia. Insulin synergistically acts with LH to enhance androgen production in theca cell in PCOS, which leads to hyperthecosis and follicular cyst formation. Insulin also inhibits hepatic sex hormone binding globulin (SHBG) production in women with PCOS, increasing the proportion of biologically available androgens and thereby contributing to hyperandrogenism. Insulin also potentiates ACTH-mediated adrenal androgen production. A functional link between insulin and the activity of the hypothalamic -pituitary ovary (HPO) axis is well documented (Am. J. Transl. Res., 5(1): 15- 20 (2013). The symptoms like amenorrhea, oligomenorrhea and anovulation can arise out of these disturbances in HPG axis and hyperinsulinemia. Hence, a combination of NK3 antagonist SB223412 (Talnetant) or its acceptable salts and metformin or its acceptable salts will be useful for the treatment of amenorrhea, oligomenorrhea and anovulation. In an embodiment use of the combination of the present invention is to correct PCOS by modulating hypothalamic pituitary gonadal (HPG) axis, and by regulating the LH or GnRH pulse levels.

In another embodiment use of the combination of the present invention is to treat infertility and multiple cyst formation. This combination will have an advantage over combination of clomiphene and metformin which improves conception rates, but with the associated risks of ovarian hyperstimulation and multiple pregnancies.

In another embodiment use of the combination of the present invention to reduce testosterone levels in the adolescent and adult women suffering from PCOS.

In another embodiment use of the combination of the present invention to treat precocious puberty, endometriosis, heavy menstrual bleeding, uterine fibroids, pre-eclampsia, androgenic acne, benign prostatic hyperplasia and/or androgenic alopecia associated with PCOS.

The quantity of the NK3 receptor antagonist or its acceptable salts to be administered will vary for the patient being treated and will vary from about 0.1 mg to 1000 mg per day. The quantity of metformin or its acceptable salts will vary from about 100 mg to 1000 mg per day depending on the patient profile.

NK3 antagonist or its acceptable salts and metformin or its acceptable salts may be given in combination, sequential or individual component of treatment.

The compounds of formula (I) can be prepared by the general processes and examples disclosed in WO 9532948. The metformin used in the invention may be available commercially or may be prepared conveniently by known prior art processes.

Biological studies:

Experiment- 1 - In vivo effect of the NK3 antagonist Talnetant and Metformin on feeding response in overnight fasted C57 mice

Animals deprived of food for 20 h were administered orally with Talnetant (5, 10 and 20 mg/kg) and metformin (50, 100 and 300 mg/kg) or vehicle. Food intake was measured for 4h and body weight was recorded at 0 and 4 h. Talnetant reduced food intake by 1.9, 8.6 and 9.5 %, reduced gain in body weight by 8.5, 16.0 and 20.8% at 5, 10 and 20 mg/kg respectively as shown in figure- lA.Metformin reduced food intake 11.0, 16.4 and 18.7 %, reduced body weight gain 17, 37 and 41 % at 50, 100, and 300 mg/kg respectively. Metformin 50 and 100 mg/kg showed significant reduction in food intake and gain in body weight respectively when compared with vehicle control. Data represents mean ± SEM, n=6 per group, were analyzed by one way ANOVA followed by Dunnet-t test (n=6).

Table 1A: In vivo effect of the NK3 antagonist Talnetant at 5, 10 and 20 mg/kg on food intake and change in body weight to overnight fasted C57 mice.

NS= Non significant

Table 1 B: In vivo effect of the metformin at 50, 100 and 300 mg/kg on food intake and change in body weight to overnight fasted mice.

Note-* indicate p<0.05 against vehicle control

NS= Non significant Experiment-2 - In vivo effect of the NK3 antagonist Talnetant and Metformin on glucose tolerance response to overnight fasted C57 mice.

Animals deprived of food for 20 h were administered orally with Talnetant (5, 10 and 20 mg/kg) and metformin (50, 100 and 300 mg/kg) or vehicle. Glucose load (5g/kg) was given 15 minute after treatment orally. Glucose was measured with one touch ultra-glucometer at -15, 0, 15, 30, 60 and 120 min after glucose load. Result indicates Talnetant reduced AUC glucose 1.4, 3.3 and 10.8 % at 5, 10 and 15mg/kg respectively shown in figure-2, Metformin reduced AUCglucose 120min*mg/dL 4.7, 15.2 and 32.1% at 50, 100 and 300 mg/kg respectively shown in figure-2 when compared with vehicle control. Only the metformin 100 and 300 mg/kg significantly reduced AUC glucose 120min*mg/dL when compared to vehicle group. Data represents Mean ± SEM, n=6 per group, were analyzed by one way ANOVA followed by Dunnett-t test.

Table-2A: In vivo effect of the NK3 antagonist Talnetant on glucose tolerance response to an overnight fast in mice.

NS= Non significant

Table-2B: In vivo effect of the metformin on glucose tolerance response to an overnight fast in mice.

Note-* indicate p<0.05 against vehicle control

NS= Non significant

Experiment-3 - In vivo effect of the NK3 antagonist Talnetant, Metformin dosed individually and their combination on feeding response to overnight fasted C57 mice

Animals deprived of food for 20 h were administered orally with Talnetant (10 mg kg), Metformin (100 mg/kg), combination or vehicle. Food intake for 4h and body weight was recorded at 0 and 4 h. Result indicated Talnetant reduced food intake 1.9 % and body weight gain 12.6 % when compared with vehicle, Metformin significantly reduced food intake 19.3 % and body weight change 43.2 % when compared with vehicle and combination group significantly reduced food intake 24 % and body weight change 37.9 % when compared to vehicle group. Combination treatment showed synergistic effect on reduction in food intake . Data represents Mean±Sem, n=6 per group, were analyzed by one way ANOVA followed by Dunnett-t test.

Table 3: In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on feeding response to overnight fasted C57 mice.

Note-* indicate p<0.05 against vehicle control

NS= Non significant

Experiment-4 - In vivo effect of the NK3 antagonist Talnetant, Metformin alone and in combination on glucose tolerance response to an overnight fasted C57 mice. Animals deprived of food for 20 h were administered orally with Talnetant (10 mg kg), Metformin (100 mg/kg), Combination or vehicle. Glucose load (5g/kg) was given 15 minute after treatment orally. Glucose was measured with one touch ultra-glucometer at - 15, 0, 15, 30, 60 and 120 min after glucose load. Result showed reduction in AUC glucose (120min*mg/dL) 3.1 %, 20.5 % and 31.4 % with Talnetant, metformin and combination respectively when compared with vehicle control group. Combination treatment showed synergistic effect on reduction in AUC glucose (120 min*mg/dL) than Talnetant and metformin alone. Data represents Mean±Sem, n=6 per group, were analyzed by one way ANOVA followed by Dunnett-t test.

Table 4: In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on glucose tolerance response to overnight fasted C57 mice.

Note-* indicate p<0.05 against vehicle control

NS= Non significant Experiment-5A - In vivo effect of the NK3 antagonist Talnetant, Metformin and their combination on body weight in DHT-induced PCOS Sprague Dawley rats

Animals were treated with DHT (Dihydrotestosterone) at 20 mg/kg intraperitoneally (IP) for 8 weeks and one normal control group not treated with DHT. All DHT treated animals were grouped on basis of body weight and administered orally with Talnetant (10 mg/kg), Metformin (100 mg/kg), combination or vehicle for 30 days .Body weight was recorded alternate day throughout the study. Result in figure-5A showed reduction in body weight 3.3, 2.1, 9.9 and 19.7 % with Talnetant (10 mg/kg), Metformin (100 mg/kg), combination and normal control group respectively when compared to vehicle group. Combination treatment showed synergistic effect on reduction in body weight. Body weight in normal control significantly lower than DHT Control. Data represents Mean ± SEM, n=6 per group, were analyzed by one way ANOVA followed by Dunnet-t test.

Table 5A: In vivo effect of the NK3 antagonist Talnetant, Metformin and their combination on body weight in DHT- induced PCOS Sprague Dawley rats.

Note-* indicate p<0.05 against vehicle control

NS= Non significant

Experiment-5B - In vivo effect of the NK3 antagonist Talnetant, Metformin and their combination on insulin tolerance test response to 6h- fasted Sprague Dawley rats

Eight weeks after 20 mg/kg DHT (Dihydrotestosterone) treatment animals were grouped on basis of body weight and administered orally with Talnetant (10 mg/kg), Metformin (100 mg/kg), combination or vehicle for 30 days. After 30 days of DHT all animals were deprived of food for 6 h were administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), Combination or vehicle. Insulin (0.5 IU/kg) was given intraperitoneally 15 minute after drug treatment. Glucose was measured with one touch ultra-glucometer at -15, 0, 15, 30, 60 and 120 min after Insulin. Result showed in figure -5B, reduction in AUCglucose 15.6%, 20.6%, 23.6% and 29.1 % with Talnetant, metformin, Combination and normal control respectively. Combination group significantly normalized insulin sensitivity when compared to vehicle group and better than Talnetant and metformin alone. Data represents Mean ± SEM, n=6 per group, were analyzed by one way ANOVA followed by Dunnet-t test. Table 5B: In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on Insulin tolerance test response to 6h-fasted Sprague Dawley rats.

Note-* indicate p<0.05 against vehicle control

NS= Non significant

Experiment-5C - In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on glucose tolerance test response to overnight fasted Sprague Dawley rats.

Eight weeks after 20 mg/kg DHT (Dihydrotestosterone) treatment animals were grouped on basis of body weight and administered orally with Talnetant (10 mg kg), Metformin (100 mg/kg), combination or vehicle for 30 days. After 30 days overnight fasted were administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), Combination or vehicle. Glucose load 5g/kg was given orally 15 minute after drug treatment. Glucose was measured with one touch ultra-glucometer at -15, 0, 15, 30, 60 and 120 min after glucose load. Result showed in figure-5C, reduction in AUC glucose 1.1%, 12.7%, 19.9% and 20.8 % with Talnetant, Metformin, Combination and Normal control respectively when compared with vehicle control. Combination treatment showed synergistically improved glucose tolerance. Data represents Mean±Sem, n=6 per group, were analyzed by one way ANOVA followed by Dunnett-t test.

Table 5C: In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on glucose tolerance test response to overnight fasted Sprague Dawley rats.

Vehicle Control 12226.6 ± 1650.3

Talnetant (10 mg/kg,PO) 12089.0 ± 783.4 -1.1 ± 6.4 NS

Metformin (100 mg/kg,PO) 10669.0 ± 1154.5 -12.7 ± 9.4 NS

Talnetant (10 mg/kg,PO)

9782.0 ± 804.1 -19.9 ± 6.6 NS

+Metformin (100 mg/kg,PO)

Normal control 9681.5 ± 842.1 -20.8 ± 6.9 NS

Experiment-5D - In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on ovary weight in Sprague Dawley rats

Eight weeks after 20 mg/kg DHT (Dihydrotestosterone) treatment animals were grouped on basis of body weight and orally administered with Talnetant (10 mg/kg), Metformin (100 mg/kg), combination or vehicle for 30 days. At the end of study all animals were sacrificed by cervical dislocation and both ovaries were collected and weighed, stored in 10 % formalin for histopathology. Result showed in figure-5D, reduced ovary weight 15.7%, 28.3%, 40.2% and 33.2 % with treatment of Talnetant, metformin, combination treatment and normal control respectively when compared to vehicle group. Combination treatment synergistically normalized ovary weight. Data represents Mean±Sem, n=6 per group, were analyzed by one way ANOVA followed by Dunnett-t test.

Table-5D: In vivo effect of the NK3 antagonist Talnetant, Metformin and combination on ovary weight in Sprague Dawley rats.

Note-* indicate p<0.05 against vehicle control

NS= Non significant Insulin resistance and compensatory hyperinsulinemia are risk factors for type II diabetes mellitus, dyslipidemia, hypertension and atherosclerosis, a constellation of findings termed the metabolic syndrome (J Am Sci 2013;9(12):54-62). Both are also prominent features of the polycystic ovarian syndrome (PCOS), a disorder characterized by chronic anovulation and hyperandrogenism that affect women of reproductive age. In PCOS -affected women, hyperinsulinemia may contribute to the pathogenesis of polycystic ovarian syndrome by promoting abnormal androgen secretion and disrupting folliculogenesis and menstrual cyclicity (Azziz, 2003 and Feng et al., 2013). In PCOS, LH levels are increased and FSH levels are reduced leading to elevated LH/FSH ratio (Semin Reprod Med. 2002 Nov;20(4):317-26). Experimental model of DHT-induced PCOS is characterized by features that closely mimic the pathophysiological consequences of PCOS in patients, includes follicle growth arrest, chronic anovulation, minimal granulosa cell proliferation, hyperthecosis, hyperandrogenemia, central adiposity, glucose intolerance and insulin resistance (J Am Sci 2013;9(12):54-62,Endocrine Reviews, October 2015, 36(5):487-525). Our data demonstrates that, combination of talnetant and metformin synergistically reduced body weight and food intake after acute treatment, while synergistic effect of combination on body weight, ovary weight and glucose tolerance while additive effects on insulin sensitivity were observed after chronic treatment. Thus findings in these studies support that combination of metformin and NK3 antagonist may be used as an effective approach to restore PCOS and associated abnormalities.

Claims

We Claim:

1. Synergistic composition comprising (i) an NK3 receptor antagonist or pharmaceutically effective salts thereof (ii) a biguanide or a pharmaceutically effective salt thereof.

2. The synergistic composition as claimed in claim 1, wherein an NK3 receptor antagonist is selected from Talnetant (SB223412), AZD-4901 and AZD-2624.

3. The synergistic composition as claimed in claim 1, wherein the biguanide is Metformin.

4. The synergistic composition as claimed in claim 1 for the treatment of PCOS and their associated disorders selected from hypothalamic pituitary gonadal (HPG) axis, correct the LH pulsatility and treat precocious puberty, endometriosis, heavy menstrual bleeding, uterine fibroids, pre-eclampsia, androgenic acne, benign prostatic hyperplasia and/or androgenic alopecia.

5. A pharmaceutical composition comprising an NK3 receptor antagonist or pharmaceutically effective salts thereof (ii) a biguanide or a pharmaceutically effective salt thereof and pharmaceutically acceptable excipients.

6. The pharmaceutical acceptable excipients as claimed in claim 5 is selected from suitable binding agents, fillers, lubricants, glidants, disintegrants and wetting agents.

7. The pharmaceutical composition as claimed in claim 5 which can be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations.

8. The pharmaceutical composition as claimed in claim 5 to 7 comprising an NK3 receptor antagonist or pharmaceutically effective salts thereof (ii) a biguanide or a pharmaceutically effective salt thereof, for use in the treatment of PCOS and their associated disorders selected from hypothalamic pituitary gonadal (HPG) axis, correct the LH pulsatility and treat precocious puberty, endometriosis, heavy menstrual bleeding, uterine fibroids, pre-eclampsia, androgenic acne, benign prostatic hyperplasia and/or androgenic alopecia.

9. The pharmaceutical composition as claimed in claim 5 to 8, wherein the composition is in the form of a unit dose.

10. The pharmaceutical composition as claimed in claim 5, an NK3 receptor is selected from Talnetant and a biguanide is selected from metformin.

11. The pharmaceutical composition as claimed in claim 5, wherein Talnetant and metformin at a dosage ranging from 1 mg to 1000 mg.

12. A pharmacological combination of claim 3, wherein Talnetan is ranging from 1 mg to 50 mg and a metformin is ranging from 10 mg to 500 mg.

13. A kit comprising in separate containers in a single package pharmaceutical compositions comprising in one container a pharmaceutical composition comprising a Talnetant and in a second container a pharmaceutical composition comprising Metformin.