Stable pharmaceutical formulations of progestogens

Abstract

Disclosed herein are aqueous pharmaceutical formulations of progestogens, along with methods of making and using the same.

Description

[0001] STABLE PHARMACEUTICAL FORMULATIONS OF PROGESTOGENS

[0002] FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to stable pharmaceutical formulations of progesterone for the treatment of endometriosis. The disclosure also relates to methods for preparation of such formulations and uses thereof. The present disclosure relates to a medicament and methods for the treatment of endometriosis, including endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, endometriotic or adenomyotic nodules of the uterosacral ligaments and endometriotic nodules elsewhere such as scar endometriosis. The present disclosure also relates to the stable pharmaceutical formulations of progesterone for the treatment of fibroids by intralesional administration.

[0004] BACKGROUND

[0005] Endometriosis is non-malignant disorder in which functioning endometrial tissue is present outside the uterine cavity. It is sometimes referred to as endometriosis externa or adenomyosis externa. Endometriosis is usually confined to the peritoneal or serosal surfaces of abdominal organs and is primarily found in tissues around the pelvis, such as the ovaries, uterus, fallopian tubes, uterosacral ligaments, broad ligaments, round ligaments, cul-de-sac or ovarian fossa, appendix, small or large bowels, ureters, bladder, vagina, and / or rectovaginal septum. Endometriosis outside of the pelvic area is rare, but can occur in the upper abdomen, diaphragm, abdominal wall or abdominal scar tissue, surgical scars, gastrointestinal tract, lungs, liver, pericardium, and / or the brain.

[0006] Adenomyosis or adenomyoma also referred to as endometriosis interna, is the invasion of endometrial tissue into the muscular tissue (myometrium) of the uterus. If the lesion is generalized the lesion is called adenomyosis and when it is localized to a smaller area of the uterus it is called adenomyoma.

[0007] Endometriotic tissues contain estrogen and progestogen receptors that enable them to grow and differentiate in response to changes in hormonal levels during the menstrual cycle. It is a chronic and progressive disease that may give rise to a variety of severe and disabling symptoms such as painful menses, painful intercourse (dyspareunia), chronic pelvic pain, and / or infertility. Other common symptoms of endometriosis include painful, debilitating menstrual cramps that may get worse over time, pain in the intestine or lower abdomen, painful bowel movements, painful urination during menstrual periods, dyschezia, heavy menstrual periods, premenstrual spotting, or bleeding between periods. In addition, women who are diagnosed with endometriosis may have painful bladder syndrome, digestive or gastrointestinal symptoms similar to a bowel disorder, fatigue, tiredness, or lack of energy.

[0008] At present, there is no curative treatment for endometriosis, and clinical management of symptoms such as pain management occurs through medical or surgical treatments, or a combination of the two. These interventions have limited efficacy with numerous side effects. Medical therapies treat endometriosis by targeting the estrogen production pathways (GnRH agonists, Danazol) or by suppressing the menstrual cycle (hormonal contraceptives, progestogens). An issue with these approaches is that women experience relief only while using the therapies and recurrence is common upon termination of therapy. An additional limitation of these therapies is that fertility is suppressed for the duration of their use. Endometriosis recurrence occurs by the time the woman is ready for conception, limiting the window of opportunity for conception. Surgical interventions provide symptomatic relief but are expensive and do not guarantee against recurrence of either the disease or its symptoms. Surgical treatment aims to remove bulky endometriotic lesions, or, in more complex cases, complete excision of the pelvic organs. Moreover, surgery can be locally destructive to vital organs, the ovaries, bowels, bladder, urethra, and may compromise fertility. Further, new occurrence of lesion can happen elsewhere or at the same site. Neither the medical management nor the surgery turns out to give relief in the long term or is universally acceptable for the patients. Therefore, there exists an unmet need for a novel, effective, and well-tolerated non-invasive treatment.

[0009] According to their physiopathology and their localization, ectopic endometrial lesions, consisting of endometrial glands and stroma, can be divided into three primary types: superficial peritoneal lesions or endometriosis (SPE), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE).

[0010] Superficial peritoneal endometriosis occurs in 15-50% of all women diagnosed with endometriosis. (Hudelist G. el al., Transvaginal sonography vs. clinical examination in the preoperative diagnosis of deep infdtrating endometriosis, 37 Ultrasound Obstet. Gynecol. 480 (2011)). Superficial lesions of endometriosis are typically located on the pelvic organs or pelvic peritoneum. Nisolle and Donnez classified the peritoneal lesions into three different kinds: red, bluish or blue-black “powder-bum” lesions, and white. (Nisolle M. and Donnez J., Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities, 68 Fertil. Steril. 585 (1997)). Red lesions represent the first step of peritoneal endometriosis and are highly vascularized and active lesions. Black / blue black or powder lesions represent the second step, advanced endometriosis, may be associated with hemosiderin deposits and finally, white lesions are quiescent endometriosis or healed endometriosis, or latent lesions. To date, laparoscopy is the most common standard to detect peritoneal endometriotic lesions. Transvaginal ultrasound and magnetic resonance imaging are associated with poor sensitivity and specificity and remains a challenge.

[0011] Ovarian endometrioma can be found in 2-10% of women of childbearing age and 50% of women treated for infertility. (Vercellini P. et al., Endometriosis: Pathogenesis and treatment, 10 Nat. Rev. Endocrinol. 261 (2014)). Endometriomas contain a dense, brown, chocolate-like fluid and are pseudocysts formed by the invagination of endometriosis within the ovarian cortex. Adhesions are usually associated with endometriomas and attach them to nearby pelvic structures. Ovarian endometrioma can also be detected by transvaginal ultrasound and MRI. To date, three different laparoscopic surgical approaches are proposed in the literature for treating ovarian endometrioma, including surgical excision (cystectomy), drainage with coagulation of the cystic wall, and drainage followed by CO2 laser vaporization of the cystic wall. Cystectomy is deemed superior for pain and recurrence in endometrioma >3 cm. (Hart R.J. et al., Excisional surgery versus ablative surgery for ovarian endometriomata, Cochrane Database Syst. Rev. CD004992 (2008)). However, it poses fertility risks, with a chance of ovarian failure after bilateral ovarian endometrioma removal. Surgery for recurrent endometriomas is more damaging to healthy ovarian tissue and ovarian reserve than primary surgery. In order to preserve the ovarian reserve, nonsurgical treatment of ovarian endometriomas, such as aspiration or sclerotherapy, has been studied. This technique consists of injecting a sclerosing agent into the cyst cavity. Nonsurgical treatments like sclerotherapy aim to preserve ovarian reserve but have not gained widespread use due to higher recurrence rates.

[0012] Deep infiltrating endometriosis (DIE) is a nodular blend of fibromuscular tissue and adenomyosis, characterized by a specifical histologic pattern that includes well -differentiated glandular cells, pure stromal cells, glandular or mixed differentiated cells, and pure undifferentiated glandular cells. (Abrao M. et al, Histological classification of endometriosis as a predictor of response to treatment, 82 Int. J. Gynecol. Obstet. 31 (2003)). These lesions are primarily affecting several pelvic organs such as uterosacral ligaments, vagina, rectovaginal septum, pelvic side walls, ureter, bladder, or bowel. Patients with DIE may present with deep dyspareunia and various bowel symptoms from diarrhoea to dyschezia during menses, depending on the location of the deep lesions. When surgical treatment is required, and excision of these lesions is needed, the surgeon is faced with a difficult challenge mainly because of the heterogenicity of the localization of the lesions. That leads to the difficulty of reproducing the same type of surgical technique each time.

[0013] The continuous supply of estrogen from multiple sources is a major cause of endometriotic lesion growth and persistence. The ovary is the primary site of estrogen synthesis and secretion. The maturing follicles secrete estrogen, which cause the endometriotic lesions to grow and proliferate. Endometriotic lesions have also been shown to contain a high concentration of aromatase enzyme, which converts androgen from the adrenal / ovaries into estrogen, resulting in significant amounts of estrogen being produced locally in the lesion.

[0014] The biological rationale for using standard of care products (progestins / GnRH analogues / OCPs) to treat endometriosis is that they inhibit the hypothalamic-pituitary-ovarian (HPO) axis and cause anovulation, reducing the systemic supply of estrogen. These therapies, however, are ineffective in preventing local estrogen production.

[0015] Progesterone / progestins when used in high concentration locally at the endometriotic lesion will have a better effect on negating the effect of estrogen on the lesion.

[0016] Progestogen (also called progestagen, gestagen, or gestogen) refers to a broad class of both natural progesterone and the synthetic progestogens called as progestins that shows similar effects as progesterone, binds to the progesterone receptor, and acts as an agonist. Progestins used for the treatment of endometriosis include dienogest (DNG), medroxyprogesterone acetate (MPA), norethindrone acetate (NETA) also known as norethisterone acetate, Cyproterone acetate, dydrogesterone, Lynestrenol, Megestrol acetate, Desogestrel, Levonorgestrel (LNG), Gestrinone, and Etonogestrel (ENG), Gestodene, norgestimate and norgestrel. Progestogens are available in several dosage forms such as soft gel capsules for oral administration, in the form of cream, pessaries, or gels for vaginal administration, and as intramuscular injections. Progestogens are widely used in different gynaecological and obstetrical conditions. The major drawback with existing progestogen containing products is inadequate concentration of drug levels at the site of the endometriotic lesion.

[0017] Orally administered progesterone undergoes first pass metabolism resulting in low bioavailability. Although micronized formulations of progesterone in vaginal and parenteral dosage forms have solved this problem to some extent, low target tissue concentration still remains an issue to be resolved. Systemic administration through parenteral route results in high serum drug levels and lower intralesional levels, resulting in higher incidence of systemic side effects and inadequate effect at the site of the lesion. The intravaginal route is unlikely to achieve adequate intralesional therapeutic levels. Because the majority of infiltrative lesions are surrounded by dense fibrotic tissues caused by chronic inflammation, which prevents the drug from penetrating into the endometriotic lesion. Any effort to increase the target tissue concentration by increasing the dose would result in higher systemic exposure and would lead to side effects related to overdose of progesterone.

[0018] High doses of progesterone are needed to eliminate or reduce lesions, and it is very difficult to successfully supply such high doses without undesirable effects through any known routes of administration other than the proposed intralesional route. For example, if progesterone is administered orally, some of the progesterone will be metabolized before it reaches the site of action, so a greater dose must be administered in order to ensure a therapeutically effective amount of drug reaches the site of action. These greater doses than therapeutically necessary can result in undesirable side effects, and there is no guarantee that the administered drug will reach the site of action after it enters systemic circulation.

[0019] Pelvic lesions are fibrotic due to chronic inflammation and do not allow easy permeation of these medications, and therefore limit the access of systemically administered drugs. Progestogens cannot cross the barrier of the fibrotic cyst wall; thus, oral and parenteral administration of Progestogens typically do not have an effect on the inner surface of the cyst containing the active endometriotic layer. Further, when the cyst structure or morphology is complex, entry of drug in the desired concentration through systemic administration is difficult.

[0020] As a result, delivery of a high-concentration drug at the target site with low systemic exposure is an unmet need in the treatment of endometriosis.

[0021] Previous applications US 9532995, US 9468647, IN1038 / DELNP / 2006 and IN7561 / DELNP / 2009 disclose methods for the treatment of endometriosis comprising direct administration of progestogen into or within an endometriotic lesion at a dose which will be dependent on the size of lesion. By administering the progestogen intralesionally, higher concentration of progestogen will be made available to directly act on the endometrial tissue and less systemic exposure. The applications further disclose the use of surfactants and cosolvents such as, polysorbates and polyethylene glycols, to prepare effective formulations of progesterone for intralesional administration. The inventors of the present disclosure executed several commercial trials using formulations disclosed in these patents containing polysorbates and polyethylene glycols along with Sodium CMC as a viscosity building agent. However, the inventors discovered there was significant fall in pH during the evaluation of these injectable suspension batches. The inventors also discovered a previously unknown significant fall in the viscosity of the injectable suspension product from its initial level, which in turn, also resulted in changes in rate of settling of suspended particles. Changes in viscosity led to non-uniformity of active drug. Hence, there remained unmet need to develop physically and chemically stable intralesional formulations.

[0022] For endometriosis, treatment of different size, type and severity of lesions, different doses typically may be needed to be administered intralesional route ranging from 0.2 mg to 5 g. Further, endometriosis is associated with large ovarian cyst or multiple lesions at various part of the reproductive tract. If there are multiple lesions present, dosage will be delivered in the multiples of 0.2 mg to 5 g during one treatment session.

[0023] However, administering larger doses of the drug ranging from 0.2 mg to 5 g intralesionally will be a limitation on the injection volume that can be administered. Hence, the drug concentration disclosed in the current disclosure embodiments can range from 2 mg / mL to 1000 mg / mL of progesterone.

[0024] There is a need in the art for high concentrated injectable formulation of progesterone so that higher doses can be administered in smaller injection volumes, thereby improving the patient experience and flexibility in dosing.

[0025] US20130245570A1 discloses compositions containing progesterone with vitamin E and / or conjugated linoleic acid.

[0026] WO / 2011074931 discloses parenteral pharmaceutical formulation in suspension, of sustained release, containing suspended particles of estradiol and progesterone for hormonal replacement in female mammals in low and ultra-low doses, in the form of an injectable suspension composed of estradiol particles, progesterone particles, a surface-active agent, an isosmotic agent, a viscous agent and one or more preservatives.

[0027] WO / 2002055020 discloses topical testosterone formulation which may include a therapeutically effective amount of micronized testosterone, an arginine ingredient, and a tocopherol ingredient admixed with a poloxamer lecithin organogel. Additional ingredients may be included, such as melatonin, oxytocin, DHEA, and progesterone.

[0028] None of these references provide stable pharmaceutical progesterone formulations suitable for intralesional injection. Additionally, none of these references address the problems associated with pH and viscosity stability of progesterone formulations.

[0029] Sometimes, even in the presence of proper suspending and wetting agents, a drug suspension is not stable for a long time, and it is necessary to store the drug long-term as a lyophilized powder and prepare the suspension just before administration. This is described, for example, in the case described by Geller and co-workers in the US Patent U.S. 5,002,940. This greatly increases the cost of to manufacture the drug since an additional freeze-drying process is mandatory.

[0030] One of the major problems in the development of high concentrations injectable drug products as suspensions is the elevated viscosity of resulting formulations, especially at high concentrations. Highly concentrated injectable suspensions usually show the tendency to form particulates during processing and / or storage, which makes dosing difficult.

[0031] Injectable suspensions are heterogeneous systems that typically consist of a solid phase dispersed in a liquid phase, with the liquid phase being aqueous or non-aqueous. It was observed that the administration of suspensions by intralesional injection may present numerous challenges. For instance, the suspension product typically should be suitable for uniform-dosing of product, should be sterile, stable, syringeable, injectable, isotonic, and non-irritating. The suspension should be stable during storage and should be readily resuspended or re-dispersed at the time of administration. The drug suspension should be uniform and capable of delivery through a needle without clogging and without the need to use excessive force for the injection. The foregoing administration, manufacturing, storage, and usage requirements make injectable suspensions difficult dosage forms to develop. Accordingly, the present disclosure provides stable, highly concentrated injectable, pharmaceutical formulations of progesterone suitable for intralesional administration.

[0032] Oil based dosage forms can cause irritation in the tissues, which if untreated or treatment is discontinued may lead to necrosis and finally to fibrosis. Therefore, in some embodiments, the proposed formulation has been formulated as an aqueous suspension in order to have a physiological pH which is suitable for intralesional administration for treatment of endometriosis effectively. This physiological pH provides protection from irritation in the adjoining tissues. The pH also contributes to stability and physical attributes of the formulation. Further, this physiological pH maintains the natural microbiome of the organ systems. The progesterone injection suspensions of the present disclosure exhibit improved physical parameters, such as fewer drug aggregates, desired viscosity, and reduced degree of flocculation and settling time. The present disclosure also provides methods, kits, compositions, combinations for treatment of endometriosis and related disorders and conditions employing said stable formulation of progesterone. The disclosure also provides simple, reproducible and cost-effective methods of preparing pharmaceutical formulations of progesterone. Administration by intralesional route provides the benefit to administering high doses of Progestogens while avoiding metabolism of the drug after entry into systemic circulation. The present disclosure causes the drug to remain in situ at the site of the lesion and to be locally absorbed because of the rigid and fibrotic nature of the endometrial cyst / lesion and the cyst wall do not allow the drug to percolate outside the lesion.

[0033] SUMMARY OF THE DISCLOSURE

[0034] In some embodiments, the present disclosure relates to stable pharmaceutical formulations of progesterone. In some embodiments, the disclosure provides formulations of progesterone as injectable suspensions which are well suited for intralesional injection, especially to the lesions of different sizes as per desired injection dosages.

[0035] In some embodiments, the disclosure provides concentrated progesterone injectable suspension formulations with desired viscosity range, which are particularly suitable for intralesional administration.

[0036] In some embodiments, the disclosure discloses highly concentrated injectable suspension pharmaceutical formulations of progesterone ranging from 2 mg / ml to 1000 mg / ml.

[0037] In some embodiments, the disclosure discloses highly concentrated injectable suspension pharmaceutical formulations of progesterone ranging from 2 mg / ml, 5mg / ml, lOmg / ml, 20mg / ml, 40mg / ml, 50mg / ml, lOOmg / ml, 150mg / ml, 200mg / ml, 250mg / ml, 300mg / ml, 350mg / ml, 400mg / ml, 450mg / ml, 500mg / ml, 550mg / ml, 600mg / ml, 650mg / ml, 700mg / ml, 750mg / ml, 800mg / ml, 850mg / ml, 900mg / ml, 950mg / ml to 1000 mg / ml. In some embodiments, the disclosure provides a progesterone injection suspension with improved physical parameters, such as fewer drug aggregates, desired viscosity range, and reduced degree of flocculation and settling time so that the injectable suspensions can be packaged in a suitable container in a cost-effective manner.

[0038] In some embodiments, the disclosure provides simple, reproducible and cost-effective methods of preparing pharmaceutical formulations of progesterone. In some embodiments, the disclosure also provides methods of preparing stable pharmaceutical suspension formulations of progesterone.

[0039] In some embodiments, the progesterone is progestogen, for example, it can be a natural progesterone or one or more of synthetic progestins, that are used for the treatment of endometriosis which include but not limited to natural micronized progesterone, Dienogest, Medroxyprogesterone acetate (MPA) and Norethindrone / norethisterone acetate (NETA), Cyproterone acetate, Dydrogesterone, Lynestrenol, Megestrol acetate, Desogestrel, Levonorgestrel (LNG), Gestrinone, Etonogestrel (ENG), Gestodene, norgestimate and norgestrel. In some embodiments, progestin is a term used to describe a synthetic progestogen. In some embodiments, the amount of progestogen administered per lesion typically is equivalent in activity to 0.2 mg to 5 g of progesterone.

[0040] In some embodiments the disclosure provides injectable suspension formulations which are sterile, free of pyrogens, stable, syringeable, injectable, isotonic, non-irritating, and ensure dose uniformity.

[0041] In some embodiments, "endometriosis" refers to the presence of endometrium like tissue — epithelium and stroma — that develops outside of the uterine cavity.

[0042] In some embodiments, endometriotic lesions or the endometriotic cyst / implants include superficial peritoneal lesions, ovarian endometriomas and deeply infiltrating endometriosis (DIE).

[0043] In some embodiments, endometriosis occurs in the pelvic region: on the ovaries, uterus, fallopian tubes, uterosacral ligaments, broad ligaments, round ligaments, cul-de-sac or ovarian fossa, appendix, large bowel, ureters, bladder, or rectovaginal septum.

[0044] In some embodiments, endometriosis is found in extra-pelvic locations, such as the upper abdomen, diaphragm, abdominal wall or abdominal scar tissue.

[0045] In some embodiments the method of intralesional administration or delivery depends on the location of the lesion, size, type and severity of the lesion and procedure used to access the lesion. In some embodiments, depending on the location of the lesion, drug may be administered transvaginally, during a laparoscopic procedure, or using endoscopic or open surgical administration, such as a laparotomy. In some embodiments, the intralesional injections are administered once. In some embodiments, patients may receive repeated administration of the drug.

[0046] In some embodiments the dose may vary depending upon the size, location, type and severity of endometriotic lesion, which can vary from a few millimetres in diameter to a few centimetres. In some embodiments, the dose ranges from 0.2 mg to 5 grams intralesionally. If there are multiple lesions present, dosage is administered in the multiples of 0.2 mg to 5 grams depending on the number of lesions present.

[0047] In some embodiments, ovarian endometriomas are treated either transvaginally guided by ultrasound or during a laparoscopic procedure. In transvaginally ultrasound guided treatment of ovarian endometriomas, a suitable needle is inserted into the cyst cavity. Cyst contents are aspirated followed by sterile washing and administration of the drug. Under laparoscopic visual guidance, a suitable needle inserted into the cyst, the contents of the cyst are aspirated followed by intracystic wash using normal saline and the drug is administered through the same or a different needle.

[0048] In some embodiments, when surface peritoneal lesion (Flat surface lesions) is visualized during laparoscopy, sub peritoneal or intralesional injection can be administered. In some embodiments, smaller dosages are administered for smaller lesions.

[0049] In some embodiments, when treating scar endometriosis (episiotomy scar, LSCS / hysterotomy scar), the drug is administered using a suitable needle into the lesion with or without ultrasound guidance.

[0050] If the uterosacral nodules seen during laparoscopy are close to important structures, using a cautery could be risky. In some embodiments, in these situations, local administration of the formulation is given.

[0051] In some embodiments, if uterosacral nodules are palpated clinically during vaginal examination, intralesional administration is carried out visually or using a vaginal probe and ultrasound.

[0052] In some embodiments, adenomyoma is treated by administering the drug under ultrasound or laparoscopic guidance using a suitable needle. In some embodiments, scar and umbilical lesions are treated by administering the drug directly or through ultrasound or laparoscopic guided.

[0053] In some embodiments, the dose amount may vary depending upon the location of the lesion, size, type, and severity of the endometriotic lesion, and the size of endometriotic lesions which can vary from a few millimetres to a few centimetres in diameter. In some embodiments the dose ranges from 0.2 mg to 5 grams, administered directly into the endometriotic lesion under ultrasound or laparoscopic or MRI guidance using a suitable needle. In some embodiments, if there are multiple lesions present, doses are delivered in the multiples of 0.2 mg to 5 grams depending on the number of lesions present.

[0054] In some embodiments, the patient exhibits positive outcomes with treatment of the formulations containing progesterone as intralesional injections.

[0055] In some embodiments the disclosure provides methods for treatment of endometriosis and related disorders and conditions, including but not limited to endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, endometriotic or adenomyotic nodules of the uterosacral ligaments and endometriotic nodules elsewhere such as scar endometriosis.

[0056] In some embodiments the disclosure provides a medicament comprising an effective amount of progestogen to be administered intralesionally for treatment of endometriosis and related disorders and conditions. The medicament is formulated for intralesional delivery and contains a progestogen as an active ingredient. In some embodiments, the medicament is a suspension, such as a non-oil-based suspension, of the active ingredient. Other formulations are also contemplated. In some embodiments, the medicament is formulated to increase retention of the drug at the site of injection and to minimize any inflammatory response thereto. In some embodiments, the formulations disclosed herein can also be used for the treatment of fibroids by intralesional administration.

[0057] In some embodiments, the progestogen input API used will be micronized or nanosized to the desired particle size range suitable for intralesional administration by injection.

[0058] In some embodiments, the disclosure provides kits, compositions and combinations comprising progesterone for treatment of endometriosis and related disorders and conditions.

[0059] In some embodiments, the disclosure provides an aqueous pharmaceutical formulation comprising a progestogen, and at least one buffering agent, wherein the formulation maintains a stable pH and viscosity during storage, wherein the formulation is suitable for intralesional administration, and wherein the progestogen is present in a concentration from 2 mg / ml to 1000 mg / ml. In some embodiments, the progestogen is present in a concentration of 2 mg / ml to 500 mg / ml. In some embodiments, the progestogen is present in a concentration of about 2 mg / ml, 5 mg / ml, 10 mg / ml, 20 mg / ml, 40 mg / ml, 50 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 350 mg / ml, 400 mg / ml, 450 mg / ml, 500 mg / ml, 550 mg / ml, 600 mg / ml, 650 mg / ml, 700 mg / ml, 750 mg / ml, 800 mg / ml, 850 mg / ml, 900 mg / ml, 950 mg / ml, or 1000 mg / ml.

[0060] In some embodiments, the progestogen comprises natural micronized progesterone, Dienogest, Medroxyprogesterone acetate (MPA), Norethindrone / norethisterone acetate (NETA), Cyproterone acetate, Dydrogesterone, Lynestrenol, Megestrol acetate, Desogestrel, Levonorgestrel (LNG), Gestrinone, Etonogestrel (ENG), Gestodene, norgestimate, or norgestrel.

[0061] In some embodiments, the at least one buffering agent is selected from alkali or alkaline earth salts of acetic, aconitic, citric, glutaric, lactic, malic, succinic, phosphate and carbonic acids, or derivatives thereof, preferably sodium phosphate or sodium citrate, more preferably sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tri-sodium phosphate, tri-potassium phosphate alone or in combination. In some embodiments, the formulation comprises at least two buffering agents, wherein a first buffering agent is present in about 0.01% to 0.20% w / v and a second buffering agent is present in about 0.01% to 0.80% w / v of the formulation.

[0062] In some embodiments, the formulation further comprises at least one viscosity agent, and / or at least one wetting agent. In some embodiments, the viscosity agent comprises cellulose, methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, gelatin and acacia, preferably methyl cellulose, sodium carboxymethylcellulose, or sodium hyaluronate, or derivatives thereof. In some embodiments, the viscosity agent is about 0.05% w / v to 20% w / v of the formulation. In some embodiments, the wetting agent is selected from polysorbate, poloxamer, docusate sodium and sodium hyaluronate. In some embodiments, the wetting agent is about 0.01% w / v to 5.0% w / v of the formulation.

[0063] In some embodiments, the formulation further comprises at least one pharmaceutically acceptable additive, wherein said pharmaceutically acceptable additives are one or more of at least at least one tonicity agent, and at least one preservative agent. In some embodiments, the tonicity agent comprises sodium chloride, potassium chloride, sodium sulfate, dextrose, mannitol, or glycerol. In some embodiments, the tonicity agent is about 0.01% w / v to 30% w / v of the formulation. In some embodiments, the preservative agent comprises phenol, chlorobutanol, benzyl alcohol, methyl paraben, propyl paraben, benzalkonium chloride, or cetylpyridinium chloride. In some embodiments, the preservative agent is from about 0.01% w / v to 2.0% w / v of the formulation.

[0064] In some embodiments, the formulation has a viscosity ranging from about 1 to 300 cps. In some embodiments, the formulation has a pH from about in the range from about pH 3.0 to pH 8.0, preferably from about pH 4.0 to pH 7.5, more preferably from about pH 6.0 to pH 7.5. In some embodiments, the progesterone has particle size in range of about D90 of 20-150 pm. In some embodiments, the formulation further comprising at least one metal chelating agent. In some embodiments, the metal chelating agent comprises ethylenediaminetetraacetic acid or salts thereof.

[0065] In some embodiments, the aqueous pharmaceutical formulation exhibits a pH that does not dramatically decrease during storage and is maintained closer to its initial value, a viscosity that does not significantly fall from its initial level during storage, a dissolution profile of not more than 75% in 2 hrs, and impurity levels complying with ICH guidelines.

[0066] In some embodiments, the aqueous pharmaceutical formulation comprises about 1 to 50% w / v of progesterone, about 0.02% to 0.90% of at least one buffering agent, about 0.05% w / v to 20% w / v of at least one viscosity agent, about 0.01% w / v to 30% w / v of at least one tonicity agent, about 0.01% w / v to 5.0%w / v of at least one wetting agent, and about 0.01% w / v to 2.0% w / v of at least one preservative agent, wherein the formulation has a viscosity ranging from about 1 to 300 cps, and wherein the buffering agent is sodium dihydrogen phosphate dihydrate and / or di-sodium hydrogen phosphate.

[0067] In some embodiments, disclosed herein are uses of formulations and methods for treatment of endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE) or powder lesions, deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis in a subject in need thereof, comprising administering to the subject the progestogen formulation disclosed herein. In some embodiments, the amount of progestogen administered per lesion is equivalent in activity to 0.2 mg to 5 g of progesterone.

[0068] In some embodiments, disclosed herein is a method for preparation of an aqueous pharmaceutical formulation of progesterone comprising: a. adding one or more viscosity agents, one or more one tonicity agents and at least one pH buffering agent in a suitable aqueous solvent and mixing by continuous stirring using suitable means to obtain a clear aqueous solution; b. adding one or more wetting agents in an aqueous solution obtained in step (a) to obtain a clear solution; c. adding desired quantity of progesterone having particle size in range of about D90 of 20-150 pm to the solution of step (b) to obtain a suspension; and d. stirring the suspension of step (c) for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation comprising about 2 mg / ml to 1000 mg / ml of progesterone.

[0069] In some embodiments, disclosed herein is a method for preparation of an aqueous pharmaceutical formulation of progesterone comprising: a) dissolving required amount of one or more preservatives in required volume of water and heating at suitable temperature range of 22-28°C for suitable period until the one or more preservatives dissolves completely to obtain a clear solution; b) adding required quantity of at least one buffering agent to the clear solution obtained in step a) in small increments with continuous mixing until a clear solution is obtained; c) adding required quantity of one or more viscosity agents to the clear solution obtained in step b) under continuous stirring for required period of time until a clear lump free viscous solution is obtained; d) dissolving required quantity of one or more wetting agent in required quantity of water in a separate container of suitable size until clear solution is obtained to obtain surfactant solution; e) adding the wetting agent solution obtained in step d) into the clear solution obtained in step c) by mixing for suitable period as per batch size under suitable conditions until it mixes uniformly to obtain a bulk solution; f) adding required quantity of progesterone as per batch size into bulk solution obtained in step e) and stirring well for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation; g) optionally, sterilizing the compounded bulk suspension obtained in step f) by using temperature range of about 122°C to 125°C for at least 15 minutes and a FO value > 12 minutes to obtain sterilized bulk suspension; h) optionally, cooling the sterilized bulk suspension of step g) to room temperature and making final weight of the cooled bulk suspension with water and adjusting pH by using 0.1 N HC1 or 0.1 N NaOH to desired value; i) optionally, filling the compounded and sterilized bulk suspension of any one of step f) to step h) aseptically into suitable containers under suitable conditions.

[0070] In some embodiments, disclosed herein is a pharmaceutical composition for the treatment of endometriosis, including endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and endometriotic nodules, such as scar endometriosis, comprising from about 2 mg / ml, 5mg / ml, lOmg / ml, 20mg / ml, 40mg / ml, 50mg / ml, lOOmg / ml, 150mg / ml, 200mg / ml, 250mg / ml, 300mg / ml, 350mg / ml, 400mg / ml, 450mg / ml, 500mg / ml, 550mg / ml, 600mg / ml, 650mg / ml, 700mg / ml, 750mg / ml, 800mg / ml, 850mg / ml, 900mg / ml, 950mg / ml or 1000 mg / ml of progesterone, at least one buffering agent, at least one viscosity agent, at least one tonicity agent, at least one wetting agent and at least one preservative agent and one or more other pharmaceutically acceptable excipients, wherein the composition has a viscosity ranging from about 1 to 300 cps and pH from about 4.0 to 7.5.

[0071] The foregoing description and following description are exemplary and explanatory and are intended to provide explanation of the disclosure. Other embodiments, aspects, advantages, and features will be readily apparent to those skilled in the art from the following disclosure. DETAILED DESCRIPTION

[0072] Definitions

[0073] The term "lesions" used throughout the specification shall apply to all types of lesions or implants or cysts that are associated with "endometriosis" and refers to the presence of endometrium-like tissue that is present outside of the uterine cavity and can be used interchangeably.

[0074] Types of endometriotic lesions or the endometriotic cyst / implants include but not limited to superficial peritoneal lesions, ovarian endometriomas and deeply infiltrating endometriosis (DIE).

[0075] The term “endometriosis” used throughout the specification shall apply to all types of endometriosis characterized by the presence of endometrium-like tissue outside the uterus including but not limited to endometriosis externa, endometrioma, adenomyosis, adenomyomas, adenomyotic nodules of the uterosacral ligaments, and endometriotic nodules elsewhere such as scar endometriosis, and the like.

[0076] The term “progestogens” refers to both the natural female sex hormones Progesterone and 17-hydroxy Progesterone (17P) as well as several synthetic progestins, all displaying the ability to bind Progesterone receptors.

[0077] The term “progesterone” and “progestogen” used throughout the specification are used interchangeably and shall apply to all types of progestogens, for example, it can be a natural progesterone or one or more of synthetic progestins, that are used for the treatment of endometriosis which include but not limited to natural micronized progesterone, Dienogest, Medroxyprogesterone acetate (MPA) and Norethindrone / nor ethisterone acetate (NETA), Cyproterone acetate, Dydrogesterone, Lynestrenol, Megestrol acetate, Desogestrel, Levonorgestrel (LNG), Gestrinone, Etonogestrel (ENG), Gestodene, norgestimate and norgestrel.

[0078] Some chemical compounds or agents may act as “wetting agent” as well as “surfactants”. Accordingly, terms “wetting agent” as well as “surfactants” have been used for same compound or class of compounds and have been used inter-changeably in the description.

[0079] A “pharmaceutically acceptable additive or excipient” means an additive or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes an additive or an excipient that is acceptable for veterinary use as well as human pharmaceutical use. “A pharmaceutically acceptable additive / excipient” as used in the specification and claims includes both one and more than one such excipient.

[0080] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.

[0081] “Treating” or “treatment” of a disease or condition includes:

[0082] (1) preventing the disease or condition, i.e. causing the clinical symptoms of the disease or condition not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease or condition;

[0083] (2) inhibiting the disease or condition, i.e., arresting or reducing the development of the disease or condition or clinical symptoms thereof; or

[0084] (3) relieving the disease or condition, i.e., causing regression of the disease or condition or clinical symptoms thereof.

[0085] A “therapeutically effective amount” means the amount of formation or composition of the present disclosure that, when administered to a patient for treating a disease or condition, is sufficient to effect such treatment for the disease or condition. The “therapeutically effective amount” will vary depending on the formulation, the disease, the condition and severity of the disease or the condition and age, weight, etc., of the mammal to be treated.

[0086] Syringeability describes the ability of an injectable suspension to pass easily through a hypodermic needle on transfer from a vial prior to injection. It includes characteristics such as ease of withdrawal, absence of clogging and foaming tendencies, and accuracy of dose measurements. As described in Injectable Emulsions and Suspensions. Floyd, A.G.; Jain, S. Pharmaceutical Dosage Forms: Disperse Systems. Marcel Dekker, 1996, vol. 2, an increase in the viscosity, density, particle size, and concentration of solids in suspension may hinder the syringeability of suspensions.

[0087] Injectability refers to the performance of the suspension during injection. Injectability includes factors such as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging.

[0088] Clogging refers to the blockage of syringe needles while administering a suspension. It may occur because of a single large particle, or a drug aggregate that blocks the lumen of the needle due to a bridging effect of the particles. Clogging at or near the needle end may cause restricted flow of the suspension. This may involve a number of factors, such as the injection vehicle, wetting of particles, particle size and distribution, particle shape, viscosity, and flow characteristics of the suspension.

[0089] Re-suspendability describes the ability of the suspension to uniformly disperse with minimal shaking after it has stood for some time. Re-suspendability can be a problem for suspensions that undergo "caking' due to settling of the deflocculated particles. "Caking' refers to a process by which the particles undergo growth and fusion to form a non- dispersible mass of material.

[0090] Viscosity describes the resistance that a liquid system offers to flow when it is subjected to an applied shear stress. A more viscous system requires greater force or stress to make it flow at the same rate as a less viscous system. A liquid system will exhibit either Newtonian or non-Newtonian flow based on a linear or a non-linear increase, respectively, in the rate of shear with the shearing stress. Structured vehicles used in suspensions exhibit nonNewtonian flow and are typically plastic, pseudoplastic, or shear-thinning with some thixotropy (exhibiting a decrease in viscosity with an increase in the rate of shear).

[0091] Intralesional administration means administration into or within a pathological area. Administration is affected by injection into a lesion and / or by instillation into a pre-existing cavity, such as in endometrioma (a cystic mass localized to an ovary). Intralesional administration also includes administration into tissue in such close proximity to the endometriotic tissue such that the progestogen acts directly on the endometriotic tissue, but does not include administration to tissue remote from the endometriotic tissue that the progestogen acts on the endometriotic tissue through systemic circulation.

[0092] Intralesional administration or delivery includes transvaginal, endoscopic or open surgical administration including, but are not limited to, via laparotomy.

[0093] The methods, formulations, kits, compositions and / or combinations of the present disclosure comprise at least one progestogen which can be progesterone or one or more of synthetic progestins. The methods, formulations, kits, compositions and / or combinations of the present disclosure comprise at least one progestogen which can be progesterone or one or more of synthetic progestins including, but not limited to, dienogest, MPA, NETA, cyproterone acetate, dydrogesterone, lynestrenol, megestrol acetate, desogestrel, LNG, gestrinone, ENG, gestodene, norgestimate and norgestrel.

[0094] Thus, progestogen is a broad class that includes natural and potent synthetic progestins. The doses of progesterone and synthetic progestins vary according to their potency of binding to their receptors. For example, norethindrone and levonorgestrel have highest potency for their receptors, whereas the potency of MPA is about one-tenth that of norethindrone, followed by a lower potency of dydrogesterone and even lower for progesterone. A higher potency progestin may be used in a much smaller dose and thus be equivalent to a larger dose of a less potent progestin. Thus, dosage of progestogen in the prepared formulations can vary and be easily evaluated according to type of progestogen. Accordingly, the approved therapeutic doses for different synthetic progestins vary from as low as 0.1 mg to 0.5 mg for LNG, 0.5 to 1 mg for Norethindrone, 2 mg for Dienogest, 10 to 20 mg for dydrogestrone and as high as 100 to 1000 mg for natural progesterone per ml of the formulation. The amount of progestogen administered per lesion typically is equivalent in activity to 0.2 mg to 5 g of progesterone. Depending upon size of lesion, higher concentration injectable strength of about 100 mg / ml, 500 mg / ml or more can be administered.

[0095] The prepared formulations are suitable for parenteral route of administration and can be administered intralesionally to treat endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis. The prepared formulations relive pain associated with endometriosis, eliminate lesions, reduce size of the lesions, prevent recurrence and have potential to improve management of endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis and related infertility thereby improving quality of life.

[0096] Further, the proposed formulation delivered intralesionally may obviate the need for surgery, facilitate easier surgery when used preoperatively as it will decrease the size and vascularity of the lesion, and can also be used post - operatively where total surgical eradication is not technically feasible.

[0097] Injectable Formulations

[0098] In initial development studies, several trials were undertaken using suitable suspending agents along with one or more suitable surfactants and co-solvents such as, polysorbates and polyethylene glycols, respectively. The suspension formulations were prepared as described in the applications IN1038 / DELNP / 2006 and IN7561 / DELNP / 2009, the contents of which are incorporated herein by reference. During these trials, a significant fall in pH during the evaluation of the initial injectable suspension batches containing progesterone was observed. Additionally, a significant fall in the viscosity of the suspension product from its initial level was observed, resulting in changes in rate of settling of suspended particles which lead to non-uniform dosing of active drug on administration as injection dosage forms. The values of pH and viscosity over a course of time are provided below in Table 1 of Example 1.

[0099] In order to resolve the reduction in pH and viscosity values during storage for improving commercial viability of the prepared suspension formulations, the inventors of the present disclosure undertook several trials using different buffering agents with varying concentrations until injectable suspensions having substantially stabilized pH was obtained.

[0100] The inventors of the disclosure surprisingly and unexpectedly found that adding one or more buffering agents lessen the observed viscosity decrease during storage throughout the shelf life of the disclosed suspensions comprising progesterone, in addition to controlling the pH of the suspensions. The stability data for representative formulations containing different concentrations of buffering agents compared to a formulation without buffering agents is presented below in Table 10.

[0101] In some embodiments, the suspendability and syringeability of the drug suspension also stabilized throughout the shelf life of the product, which in the formulations without buffering agent showed significant fall in viscosity as described above and in Table 1 of Example 1 during the initial development studies.

[0102] In some embodiments, one or more suitable buffering agents, such as inorganic acid salts, are used in appropriate concentrations in order to maintain the buffering capacity of the resulting formulation.

[0103] In some embodiments, the use of inorganic acid salts as buffering agents offers both advantages and disadvantages. In fact, on one hand if a careful control of pH of formulations is achieved, on the other hand, when suspension formulations are concerned, ionic species tend to destabilize the formulations with detrimental effects on the re-suspendability and on the controlled flocculation of the formulation. Thus, the use of inorganic acid salt based buffering systems into the formulations is to be minimized.

[0104] In some embodiments, the present disclosure provides that the pH of these stabilized systemic aqueous suspensions does not dramatically decrease during storage but, on the contrary, is maintained closer to the initial value. In some embodiments, there is no significant change in the pH of the injectable suspension in the formulations containing buffering agent during shelf life of the formulation. Therefore, these stabilized suspensions can be safely administered and ensure longer shelf life of the developed formulation.

[0105] In some embodiments, the disclosure provides a pharmaceutical formulation comprising therapeutically effective amount of progesterone, at least one buffering agent, and pharmaceutically acceptable additives, wherein said at least one buffering agent is about 0.01 to % 0.90% w / v of the formulation.

[0106] The formulation of disclosure comprises progesterone in amount of about 2 mg / ml, 5mg / ml, lOmg / ml, 20mg / ml, 40mg / ml, 50mg / ml, lOOmg / ml, 150mg / ml, 200mg / ml, 250mg / ml, 300mg / ml, 350mg / ml, 400mg / ml, 450mg / ml, 500mg / ml, 550mg / ml, 600mg / ml, 650mg / ml, 700mg / ml, 750mg / ml, 800mg / ml, 850mg / ml, 900mg / ml, 950mg / ml, or 1000 mg / ml of the formulation, preferably about 50 mg / ml to 400 mg / ml of the formulation.

[0107] The formulation has a viscosity ranging from about 1 to 300 cps. The formulation is in form of an injectable suspension. The formulation comprises progesterone having particle size in range of about D90 of 20-150 pm.

[0108] In some embodiments, the buffering agents include, but not limited to, those derived from acetic, aconitic, citric, glutaric, lactic, malic, succinic, phosphate and carbonic acids, as known in the art. In some embodiments, the buffering agent includes an alkali or alkaline earth salt of one of the aforementioned acids, the examples include but not limited to sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate, disodium hydrogen phosphate and dipotassium hydrogen phosphate tri-sodium phosphate, tri-potassium phosphate alone or in combination. In some embodiments, the buffering agent is a phosphate and citrate buffer, such as phosphoric acid or a pharmaceutically acceptable salt thereof, or citric acid or a pharmaceutically acceptable salt thereof.

[0109] The formulation comprises at least two buffering agents, wherein a first buffering agent is about 0.01% to 0.20% of the formulation and wherein a second buffering agent is about 0.01% to 0.80% of the formulation. The two buffering agents are selected from alkali or alkaline earth salts of acetic, aconitic, citric, glutaric, lactic, malic, succinic, phosphate and carbonic acids, or derivatives thereof, preferably sodium phosphate or sodium citrate, more preferably sodium dihydrogen phosphate, disodium hydrogen phosphate alone or in combination. In some embodiments, the buffering agent is sodium phosphate or sodium citrate.

[0110] In some embodiments, the pharmaceutically acceptable additives are one or more of at least one viscosity agent, at least one tonicity agent, at least one wetting agent and at least one preservative agent. The viscosity agent is selected from cellulose, methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, gelatin and acacia, preferably methyl cellulose, sodium carboxymethylcellulose and sodium hyaluronate, or derivatives thereof. The tonicity agent is selected from sodium chloride, potassium chloride, sodium sulfate, dextrose, mannitol and glycerol. The wetting agent is selected from polysorbate, poloxamer and docusate sodium. The preservative agent is selected form phenol, chlorobutanol, benzyl alcohol, methyl paraben, propyl paraben, benzalkonium chloride and cetylpyridinium chloride. The viscosity agent is about 0.05% w / v to 20% w / v of the formulation. The tonicity agent is about 0.01% w / v to 30% w / v of the formulation. The wetting agent is about 0.01% w / v to 5.0% w / v of the formulation. The preservative agent is from about 0.01% w / v to 02.0% w / v of the formulation.

[0111] The pharmaceutical aqueous suspension, according to the disclosure, may additionally include, at least one metal chelating agent.

[0112] In some embodiments, suitable thickening or viscosity agents comprise well known cellulose derivatives (e.g., methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose), gelatin and acacia. In some embodiments, the viscosity agent is Sodium CMC 7MF, Sodium CMC DV SPL, Sodium hyaluronate alone or in combination.

[0113] In some embodiments, the formulations of the present disclosure may also include one or more metal chelating agents, and / or one or more preservatives.

[0114] In some embodiments, suitable metal chelating agents may include, but not limited to, ethylenediamine-tetracetic acid or salts thereof (e.g., edetate disodium).

[0115] In some embodiments, suitable preservative agents comprise phenol, chlorobutanol, benzyl alcohol, methyl paraben, propyl paraben, benzalkonium chloride, cetylpyridinium chloride and the likes.

[0116] In some embodiments, the formulations may comprise one or more wetting agent such as, but not limited to, polysorbates such as polysorbate 20, polysorbate 80 and poloxamer or the likes along with other one or more suitable surfactant in suitable ratios. In some embodiments, the suspension formulations comprise at least 0.01% w / v wetting agent.

[0117] In some embodiments, the formulations of the disclosure may also include one or more tonicity adjusting agents. Suitable tonicity adjusting agents are for instance, but not limited to, sodium chloride, sodium sulfate, dextrose, mannitol, glycerol and the likes.

[0118] In some embodiments, the formulations of the disclosure may include water as dispersion base of the disclosed injectable compositions. In some embodiments, the formulations of the disclosure may include water, propylene glycol, polyethylene glycol, alcohol alone or in combination as dispersion base of the disclosed injectable compositions. In some embodiments, the pH of pharmaceutical compositions in the present disclosure may range from about pH 3.5 to pH 10. In some embodiments, the pH is about pH 4.0 to pH 7.5. In some embodiments, the pH is about pH 5.0 to pH 7.5.

[0119] In some embodiments of the disclosure, the pH of the stabilized suspension does not dramatically decrease during storage. In some embodiments, the pH of the suspension is maintained closer to the initial value. Therefore, the stabilized suspensions can be safely administered. This also ensures longer shelf life of the developed formulations.

[0120] In some embodiments, intralesional injections of high concentration injectable suspension formulations of the disclosure can be directly injected into the lesions, thereby allowing higher concentration of the drugs at the administration site and further minimizing the side effects in patients without permeating drug out from the lesions, thereby ensuring targeted treatment of lesions.

[0121] In some embodiments, the dispersed phase produces suspension formulations having optimum physical, chemical, and pharmacological properties. Particle size distribution, specific surface area, inhibition of crystal growth, and changes in the polymorphic form are of special significance and it is to be ensured that these and other properties of the formulations do not change significantly during storage to adversely affect performance of the suspensions with storage (aging).

[0122] In some embodiments, the disclosure provides concentrated progesterone injectable suspension formulations with desired viscosity range, which are particularly suitable for intralesional administration. In some embodiments, the developed formulations are able to resolve usual issues of injectability and syringeability of high concentration injection suspension formulations. In some embodiments, the developed formulations are able to inject higher dosages in the minimum volumes. Thus, they are suitable for intralesional administration in varying lesion sizes as per recommended dosages by clinicians.

[0123] In some embodiments, the developed formulations are stable and are easily redispersible with reduced tendency of agglomeration or hard caking during storage throughout the shelf life.

[0124] In some embodiments, injectable suspension formulations of the disclosure possess desirable qualities, such as, the suspended materials do not settle rapidly; the particles that do settle to the bottom of the container do not form a hard cake; settled contents are readily re- dispersed into a uniform mixture when the container is shaken; the suspension has desired viscosity and is pourable freely from the orifice of a syringe needle.

[0125] In some embodiments, the formulations of the disclosure may have a nitrogen blanket, overlay on the head-space of the vial. Additionally, the formulations of the present disclosure may include purging the formulation with one or more of helium, argon, or nitrogen or the likes.

[0126] In some embodiments, the viscosity of injectable suspension formulations is up to 300 cps when measured by using suitable device such as Brookfield viscometer. This, the developed formulations have high viscosity ranging up to 300 cps without any concerns in the syringebility aspects of the final injectable suspension product.

[0127] Method of preparation of stable formulations of progesterone

[0128] The development of injectable preparations, especially aqueous suspensions for parenteral administration, is known in the field. Parenteral suspensions are often prepared as flocculated or deflocculated suspensions. In the flocculated suspensions, the “controlled flocculation” approach is used. In this approach, the application of known principles of formulation chemistry is used to produce vehicles which permit drug flocs to form and settle. However, they are easily re-suspended with slight agitation and remain uniformly dispersed or suspended during the period of therapeutic administration.

[0129] Specifically, it is well known that one of the main difficulties in formulating parenteral aqueous suspensions of steroids such as progesterone, is to overcome their hydrophobicity, that significantly reduce the wettability, suspendability or re-suspendibility of the active in aqueous media. Both wetting and suspending agents are needed in order to achieve desired formulation suspendability and re-suspendability of the active compound.

[0130] In some embodiments, the present disclosure provides simple, reproducible, and cost- effective manufacturing processes for preparing stable high dose injectable suspensions of the formulations of progesterone.

[0131] In some embodiments, the method of preparing a pharmaceutical suspension formulation comprises:

[0132] (a) adding one or more viscosity agents, one or more tonicity agents and one or more pH buffering agents in a suitable aqueous solvent and mixing by continuous stirring using suitable means to obtain a clear aqueous solution;

[0133] (b) adding one or more wetting agents in the aqueous solution obtained in step (a) to obtain a clear solution; (c) adding desired quantity of at least one progestogen having suitable particle size to the solution obtained in step (b) to obtain a suspension followed by adjusting volume to make up target concentration; and

[0134] (d) stirring the suspension of step (c) for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation.

[0135] The above method may optionally comprise sterilization step for the suspension formulation and filling the sterilized suspension formulation into suitable containers under suitable conditions.

[0136] In some embodiments, a further method of preparing the formulations of the present disclosure using water in a suitable container as per target batch size comprises the following steps:

[0137] (a) dissolving an amount of one or more preservatives in a volume of water and heating at suitable temperature for suitable period of time until the one or more preservatives dissolves completely to obtain a clear solution;

[0138] (b) adding a quantity of one or more buffering agents to the clear solution obtained in step (a) in small increments with continuous mixing until a clear solution is obtained;

[0139] (c) adding a quantity of one or more viscosity agents to the clear solution obtained in step

[0140] (b) under continuous stirring for a period of time until a clear, lump free viscous solution is obtained;

[0141] (d) dissolving a quantity of one or more wetting agent in a quantity of water in a separate container of suitable size until clear solution is obtained to obtain surfactant solution;

[0142] (e) adding the wetting agent solution obtained in step (d into the clear solution obtained in step (c) by mixing for a suitable period of time as per batch size under suitable conditions until it mixes uniformly to obtain a bulk solution;

[0143] (f) adding a quantity of progesterone as per batch size into the bulk solution obtained in step (e) and stirring for suitable period of time until it disperses uniformly to obtain compounded bulk suspension.

[0144] The above method may optionally comprise an additional step of soaking one or more viscosity agents overnight in water to ensure ease of dispersion prior to step (c).

[0145] The above method may comprise sterilizing the compounded bulk suspension obtained in step (f) by suitable means to obtain sterilized bulk suspension. The sterilization may be followed by optional cooling of the sterilized bulk suspension to room temperature and making final weight of the cooled bulk suspension with water and adjusting pH to desired value. The method may also comprise a step of filling the compounded and sterilized bulk suspension aseptically into suitable containers under suitable conditions. The entire batch of finished drug product underwent manual visual inspection for defects and then was stored in quarantine area until released.

[0146] The above method parameters and steps may be arrived and / or modified in accordance with target batch size. In some embodiments, for a batch size of 1.0 Kg, the mixing in step (e) may be done for nearly about 60 minutes. In some embodiments, the mixing in step (e) may be done for about 30-45 minutes.

[0147] Example 1: Initial development studies

[0148] As mentioned above, the formulations for initial developmental studies were prepared by using suitable suspending agents along with surfactants and co-solvents such as, polysorbates and polyethylene glycols, respectively in accordance with patent applications IN1038 / DELNP / 2006 and IN7561 / DELNP / 2009. A significant fall in pH and viscosity of the prepared suspension formulations from initial levels is observed. The observed values of pH and viscosity up to six months of storage under temperature conditions of 40°C / 75%RH and 25°C / 65%RH (accelerated storage conditions and normal storage conditions, respectively) are provided in Table 1.

[0149] Table 1: Values of pH and viscosity of formulations under normal and accelerated conditions of storage The values in Table 1 show that pH and viscosity reduction occur both at accelerated testing conditions (40°C / 75%RH) and at controlled room temperature (25°C / 65%RH). Considering that after only 6 months at room temperature a significant decrease of approximately near to 2.0 pH unit is observed, very low pH values (close to 3.0) are anticipated after long-term storage, for instance after 1 to 2 years. The change in pH and viscosity is the reason for reduced shelf-life of injectable suspension.

[0150] Example 2: Method for preparation of formulations of progesterone

[0151] The formulations of the disclosure can be prepared by the method comprising the following steps:

[0152] (a) adding about 0.05% w / v to 20% w / v of one or more viscosity agents, about 0.01% w / v to 30% w / v of one or more one tonicity agents and about 0.02 % w / v to 0.90% w / v of at least two pH buffering agents in a suitable aqueous solvent and mixing by continuous stirring using suitable means to obtain a clear aqueous solution;

[0153] (b) adding about 0.01% w / v to 5.0 %w / v of one or more wetting agents in an aqueous solution obtained in step (a) to obtain a clear solution;

[0154] (c) adding desired concentration of progesterone having particle size in range of about D90 of 20-150 pm to the solution obtained in step (b) to obtain a suspension followed by adjusting volume to obtain target concentration; and

[0155] (d) stirring the suspension of step (c) for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation comprising about 2 mg / ml to 1000 mg / ml of progesterone.

[0156] Example 3: Method for preparation of formulations of progesterone

[0157] The formulations of the present disclosure are prepared by using water for injection (WFI) in a suitable size SS (stainless steel) tank as per target batch size. The method comprises the following steps:

[0158] 1. dissolving 0.01% w / v to 2.0% w / v of one or more preservatives in required volume of water and heating at temperature range of 22-28°C for suitable period of time until the one or more preservatives dissolves completely to obtain a clear solution;

[0159] 2. adding about 0.02 % w / v to 0.90% w / v of at least two buffering agents to the clear solution obtained in step 1) in small increments with continuous mixing until a clear solution is obtained; 3 adding about 0.05% w / v to 20 % w / v of one or more viscosity or one or more suspending agents to the clear solution obtained in step 2) under continuous stirring for required period of time until a clear lump free viscous solution is obtained;

[0160] 4. dissolving about 0.01% w / v to 5.0% w / v of one or more wetting agent in required quantity of water in a separate container of suitable size until clear solution is obtained to obtain wetting agent solution;

[0161] 5. adding the wetting agent solution obtained in step 4) into the clear solution obtained in step 3) by mixing for a suitable period of time as per batch size under suitable conditions until it mixes uniformly to obtain a bulk solution;

[0162] 6. adding required quantity of progesterone as per batch size into bulk solution obtained in step 5) and stirring well for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation;

[0163] 7. optionally, sterilizing the compounded bulk suspension obtained in step 6) by using temperature range of about 122°C to 125°C for at least 15 minutes and a F0 value > 12 minutes to obtain sterilized bulk suspension;

[0164] 8. optionally, cooling the sterilized bulk suspension of Step 7 to room temperature and making final weight of the cooled bulk suspension with water and adjusting pH by using 0.1 N HC1 or 0.1 N NaOH to desired value;

[0165] 9 optionally, filling the compounded and sterilized bulk suspension of Step 6 aseptically into suitable containers under suitable conditions.

[0166] The above method may optionally comprise soaking one or more viscosity agents overnight in required quantity of water to ensure ease of dispersion prior to step 3).

[0167] The suitable container in the step 9) of the above method is depyrogenated USP Type 1 glass vials capped with pre-sterilized rubber stopper and flip-off aluminium seal. The entire batch of finished drug product underwent manual visual inspection for defects and then was stored in quarantine area until released.

[0168] The following exemplary formulations comprising progesterone were prepared by preparation methods illustrated herein above by employing varying amounts of the excipients and additives.

[0169] The following examples are offered for illustrative purposes, and are not intended to limit the disclosure in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results.

[0170] The prepared formulations were evaluated for chemical stability under accelerated stability conditions. The observed impurity levels, as illustrated in Table 11 of Example 13 below, in the resultant liquid suspension product comply to target limits for impurities as per ICH (the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guideline.

[0171] As representative suitable formulations consistent with the objects, features and advantages of the present disclosure, the following non-limiting examples are provided.

[0172] Example 4: An exemplary formulation of progesterone in below Table 2 prepared using method of preparation steps disclosed in Example 2

[0173] Table 2: Formulation comprising progesterone

[0174] Example 5: An exemplary formulation of progesterone in below Table 3 prepared using method of preparation steps disclosed in Example 3

[0175] Table 3: Formulation comprising progesterone

[0176] Example 6: An exemplary formulation of progesterone in below Table 4 prepared using method of preparation steps disclosed in Example 2

[0177] Table 4: Formulation comprising progesterone

[0178] Example 7: An exemplary formulation of progesterone in below Table 5 prepared using method of preparation steps disclosed in Example 2

[0179] Table 5: Formulation comprising progesterone Example 8: An exemplary formulation of progesterone in below Table 6 prepared using method of preparation steps disclosed in Example 2

[0180] Table 6: Formulation comprising progesterone

[0181] Example 9: An exemplary formulation of progesterone in below Table 7 prepared using method of preparation steps disclosed in Example 2

[0182] Table 7: Formulation comprising progesterone Example 10: Formulation of progesterone in below Table 8 prepared using method of preparation steps disclosed in Example 2

[0183] Table 8: Formulation comprising progesterone

[0184] Example 11: Formulation of progesterone in below Table 9 prepared using method of preparation steps disclosed in Example 2

[0185] Table 9: Formulation comprising progesterone Example 12: An exemplary formulation of progesterone in below Table 10 prepared using method of preparation steps disclosed in Example 2

[0186] Table 10: Formulation comprising progesterone

[0187] Example 13: Formulation of progesterone in below Table 11 prepared using method of preparation steps disclosed in Example 3

[0188] Table 11: Formulation comprising progesterone Example 14: Formulation of progesterone in below Table 12 prepared using method of preparation steps disclosed in Example 3

[0189] Table 12: Formulation comprising progesterone

[0190] Example 15: An exemplary formulation of progesterone in below Table 13 prepared using method of preparation steps disclosed in Example 2

[0191] Table 13: Formulation comprising progesterone Example 16: An exemplary formulation of progesterone in below Table 14 prepared using method of preparation steps disclosed in Example 2

[0192] Table 14: Formulation comprising progesterone

[0193] The various formulations illustrated above were prepared using conventional methods of manufacturing with equipment’s routinely used in the field which are apparent to a person skilled in the art.

[0194] Example 17: The developed formulations were further evaluated for drug release studies compared to formulations comprising PEG or polysorbates

[0195] Table 15: Drug release profile for the formulations comprising progesterone of the present disclosure and formulations of progesterone known in the field

[0196] 25 As evident from above data in Table 15, the drug release is significantly reduced when formulated using present disclosure formulation compared to the previously disclosed composition of PEG / Polysorbate based formulation. Thus, there will be less chance of the drug permeating out of the lesions for the formulations of the disclosure, thereby ensuring target treatment with lesser side effects.

[0197] Example 18: Stability data for formulation comprising buffering agents compared to formulation not comprising buffering agents

[0198] A representative pharmaceutical formulation of the disclosure as illustrated in Example 6 comprising progesterone and specific buffering agents, particularly sodium dihydrogen phosphate dihydrate and di-sodium hydrogen phosphate, at specific concentrations was evaluated for changes in values of pH and viscosity in normal (25°C / 65%RH) and accelerated (40°C / 75%RH) storage conditions for up to three months. A comparative formulation without buffering agents (as prepared and disclosed in IN1038 / DELNP / 2006) was also evaluated for changes in values of pH and viscosity under same storage conditions.

[0199] The values of pH and viscosity of the formulations at the end of three months’ period are provided herein below in Table 16. The observed values of pH and viscosity show that the formulation of the disclosure is able to resist substantial decrease in pH and viscosity values during storage throughout the shelf life of the formulation vis-a-vis comparative formulation without buffering agent showed significant reduction in values of pH and viscosity during storage. Thus, the formulation of the disclosure surprisingly and unexpectedly exhibited excellent product stability during both normal and accelerated storage conditions. Table 16: Stability data for one of the representative formulations of the disclosure containing buffering agents and comparative formulation without buffering agents Example 19: Stability data

[0200] The developed pharmaceutical formulations demonstrate good chemical stability as per currently available accelerated stability data. The developed pharmaceutical formulations demonstrate good chemical as well as physical stability as per currently available accelerated stability data as per ICH (International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines (40°C ± 2°C / 75% RH ± 5% RH). The observed impurity levels in the resultant product were complying with target limits for impurities as per ICH guideline (Table 17) for representative formulation illustrated in Example 6.

[0201] Table 17: Stability data for one of the representative formulations of the disclosure under accelerated storage conditions Example 20: Safety and efficacy studies

[0202] A validated preclinical model will be employed to assess the safety, efficacy, and pharmacokinetic advantages of a newly developed stable aqueous intralesional (IL) progesterone formulation compared to conventional intramuscular (IM) progesterone administration. The IL route is anticipated to deliver higher concentrations of progesterone directly to endometriotic lesions, while maintaining significantly lower systemic plasma levels (Cmax). This targeted approach is expected to minimize systemic side effects commonly associated with parenteral progesterone. Given the fibrotic nature and limited permeability of endometriotic tissue, intralesional administration is projected to enhance local drug delivery, promote greater reduction in lesion size, and provide more effective pain relief, all while supporting a favorable safety and efficacy profile.

[0203] The formulations of the present disclosure and methods for preparation thereof as set forth in the present application describe the efficacy and utility of these formulations and methods for preparation thereof to restore healthy functioning in humans and treat the conditions and disorders in humans as identified and described in this patent application.

[0204] Certain exemplary advantages of pharmaceutical formulations according to some embodiments include: i) the suspended material does not settle rapidly; ii) the particles that do settle to the bottom of the container do not form a hard cake; iii) the settled content is readily re-dispersed into a uniform mixture on shaking; iv) the suspension has suitable viscosity and is pourable freely from the orifice of a syringe needle; v) the formulations are stable, high dose injectable suspensions prepared by using simple, reproducible and cost-effective process; vi) the concentrated progesterone injectable suspension formulations have desired viscosity range, which are particularly suitable for intralesional administration; vii) the formulations are able to resolve usual issues of injectability and syringeability of highly concentrated injection suspension formulations; viii) the developed formulations are able to inject higher dosages in the minimum volumes, hence suitable for intralesional administration in varying lesion sizes as per recommended dosages by clinicians; ix) the formulations are physically stable and easily re-dispersible with reduced tendency of agglomeration or hard caking during storage throughout the shelf life. It will be obvious to those skilled in the art to make various changes, modifications and alterations to the disclosure described herein. To the extent that these various changes, modifications and alteration do not depart from scope of the present disclosure, they are intended to be encompassed therein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims. In addition, where this application has listed the steps of a method or procedure in a specific order, it may be possible, or even expedient in certain circumstances, to change the order in which some steps are performed, and it is intended that the particular steps of the method or procedure claims set forth herein below not be construed as being order-specific unless such order specificity is expressly stated in the claim.

[0205] Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. For illustrative purpose, the formulations, combinations and compositions of the present disclosure preferably comprise progesterone with specific excipients. However, those skilled in the art would appreciate that scope of the present disclosure would extend to formulations, combinations and compositions comprising other steroids, progestagens and additives known in the field of art.

Claims

CLAIMSWe claim:

1. An aqueous pharmaceutical formulation comprising: a) a progestogen; and b) at least one buffering agent; wherein the formulation maintains a stable pH and viscosity during storage, wherein the formulation is suitable for intralesional administration, and wherein the progestogen is present in a concentration from 2 mg / ml to 1000 mg / ml.

2. The aqueous pharmaceutical formulation of claim 1, wherein the progestogen is present in a concentration of 2 mg / ml to 500 mg / ml.

3. The aqueous pharmaceutical formulation of claim 1, wherein the progestogen is present in a concentration of about 2 mg / ml, 5 mg / ml, 10 mg / ml, 20 mg / ml, 40 mg / ml, 50 mg / ml, 100 mg / ml, 150 mg / ml, 200 mg / ml, 250 mg / ml, 300 mg / ml, 350 mg / ml, 400 mg / ml, 450 mg / ml, 500 mg / ml, 550 mg / ml, 600 mg / ml, 650 mg / ml, 700 mg / ml, 750 mg / ml, 800 mg / ml, 850 mg / ml, 900 mg / ml, 950 mg / ml, or 1000 mg / ml.

4. The aqueous pharmaceutical formulation of claim 3, wherein the progestogen is present in a concentration of about 250 mg / ml, 300mg / mL, 400 mg / mL or 500 mg / mL.

5. The aqueous pharmaceutical formulation of any one of claims 1-4, wherein the progestogen comprises natural micronized progesterone, Dienogest, Medroxyprogesterone acetate (MPA), Norethindrone / norethisterone acetate (NETA), Cyproterone acetate, Dydrogesterone, Lynestrenol, Megestrol acetate, Desogestrel, Levonorgestrel (LNG), Gestrinone, Etonogestrel (ENG), Gestodene, norgestimate, or norgestrel.

6. The aqueous pharmaceutical formulation of claim 5, wherein the progestogen comprises natural micronized progesterone.

7. The aqueous pharmaceutical formulation of any one of claims 1-6, wherein the at least one buffering agent is selected from alkali or alkaline earth salts of acetic, aconitic, citric, glutaric, lactic, malic, succinic, phosphate and carbonic acids, or derivatives thereof, preferably sodium phosphate or sodium citrate, more preferably sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tri-sodium phosphate, tri-potassium phosphate alone or in combination.

8. The aqueous pharmaceutical formulation of claim 7, wherein the buffering agent is present in about 0.02% to 0.90% w / v of the formulation.

9. The aqueous pharmaceutical formulation of claim 7, comprising at least two buffering agents, wherein a first buffering agent is present in about 0.01% to 0.20% w / v and a second buffering agent is present in about 0.01% to 0.80% w / v of the formulation.

10. The aqueous pharmaceutical formulation of any one of claims 1-9, further comprising at least one viscosity agent, and / or at least one wetting agent.

11. The aqueous pharmaceutical formulation of claim 10, wherein the viscosity agent comprises cellulose, methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose, gelatin and acacia, preferably methyl cellulose, sodium carboxymethylcellulose, or sodium hyaluronate, or derivatives thereof.

12. The aqueous pharmaceutical formulation of claim 10 or 11, wherein the viscosity agent is about 0.05% w / v to 20% w / v of the formulation.

13. The aqueous pharmaceutical formulation of claim 10, wherein the wetting agent is selected from polysorbate, poloxamer, docusate sodium and sodium hyaluronate.

14. The aqueous pharmaceutical formulation of claim 10 or 13, wherein the wetting agent is about 0.01% w / v to 5.0% w / v of the formulation.

15. The aqueous pharmaceutical formulation of any one of claims 1-14, further comprises at least one pharmaceutically acceptable additive, wherein said pharmaceuticallyacceptable additives are one or more of at least at least one tonicity agent, and at least one preservative agent.

16. The aqueous pharmaceutical formulation of claim 15, wherein the tonicity agent comprises sodium chloride, potassium chloride, sodium sulfate, dextrose, mannitol, or glycerol.

17. The aqueous pharmaceutical formulation of claim 15 or 16, wherein the tonicity agent is about 0.01% w / v to 30% w / v of the formulation.

18. The aqueous pharmaceutical formulation of claim 15, wherein the preservative agent comprises phenol, chlorobutanol, benzyl alcohol, methyl paraben, propyl paraben, benzalkonium chloride, or cetylpyridinium chloride.

19. The aqueous pharmaceutical formulation of claim 15 or 18, wherein the preservative agent is from about 0.01% w / v to 2.0% w / v of the formulation.

20. The aqueous pharmaceutical formulation of any one of claims 1-19, wherein the formulation has a viscosity ranging from about 1 to 300 cps.

21. The aqueous pharmaceutical formulation of any one of claims 1-20, wherein the formulation has a pH from about in the range from about pH 3.0 to pH 8.0, preferably from about pH 4.0 to pH 7.5, more preferably from about pH 6.0 to pH 7.5.

22. The aqueous pharmaceutical formulation of any one of claims 1-21, wherein the progesterone has particle size in range of about D90 of 20-150 pm.

23. The aqueous pharmaceutical formulation of any one of claims 1-22, further comprising at least one metal chelating agent.

24. The aqueous pharmaceutical formulation of claim 23, wherein the metal chelating agent comprises ethylenediamine-tetraacetic acid or salts thereof.

25. The aqueous pharmaceutical formulation of any one of claims 1-24, wherein the formulation exhibits: a) a pH that does not dramatically decrease during storage and is maintained closer to its initial value; b) a viscosity that does not significantly fall from its initial level during storage; c) dissolution profile of not more than 75% in 2 hrs and d) impurity levels complying with ICH guidelines.

26. An aqueous pharmaceutical formulation comprising about 1 to 50% w / v of progesterone, about 0.02% to 0.90% of at least one buffering agent, about 0.05% w / v to 20% w / v of at least one viscosity agent, about 0.01% w / v to 30% w / v of at least one tonicity agent, about 0.01% w / v to 5.0%w / v of at least one wetting agent, and about 0.01% w / v to 2.0% w / v of at least one preservative agent, wherein the formulation has a viscosity ranging from about 1 to 300 cps, and wherein the buffering agent is sodium dihydrogen phosphate dihydrate and / or di-sodium hydrogen phosphate.

27. A method for treatment of endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE) or powder lesions, deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis in a subject in need thereof, comprising administering to the subject the formulation as claimed in any one of the claims 1 to 26.

28. Use of the formulation as claimed in any one of claims 1 to 26 for treating endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis, comprising administering the formulation to the subject.

29. A formulation as claimed in any one of claims 1 to 26 for use in treatment of endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas,adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis.

30. A formulation as claimed in any one of claims 1 to 26 for use in the manufacture of a medicament for the treatment of endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis.

31. A method comprising administering a therapeutic formulation as claimed in any one of claims 1 to 26 to a subject, wherein said subject is suffering from endometriosis, endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and / or endometriotic nodules, such as scar endometriosis.

32. The formulation of any one of claims 25, 26, 29, or 30, the method of any one of claims 27 or 31, or the use of claim 28, wherein the amount of progestogen administered per lesion is equivalent in activity to 0.2 mg to 5 g of progesterone.

33. A method for preparation of an aqueous pharmaceutical formulation of progesterone comprising: a. adding one or more viscosity agents, one or more one tonicity agents and at least one pH buffering agent in a suitable aqueous solvent and mixing by continuous stirring using suitable means to obtain a clear aqueous solution; b. adding one or more wetting agents in an aqueous solution obtained in step (a) to obtain a clear solution; c. adding desired quantity of progesterone having particle size in range of about D90 of 20-150 pm to the solution of step (b) to obtain a suspension; and d. stirring the suspension of step (c) for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation comprising about 2 mg / ml to 1000 mg / ml of progesterone.

34. A method for preparation of an aqueous pharmaceutical formulation of progesterone comprising:1) dissolving required amount of one or more preservatives in required volume of water and heating at suitable temperature range of 22-28°C for suitable period until the one or more preservatives dissolves completely to obtain a clear solution;2) adding required quantity of at least one buffering agent to the clear solution obtained in step a) in small increments with continuous mixing until a clear solution is obtained;3) adding required quantity of one or more viscosity agents to the clear solution obtained in step b) under continuous stirring for required period of time until a clear lump free viscous solution is obtained;4) dissolving required quantity of one or more wetting agent in required quantity of water in a separate container of suitable size until clear solution is obtained to obtain surfactant solution;5) adding the wetting agent solution obtained in step d) into the clear solution obtained in step c) by mixing for suitable period as per batch size under suitable conditions until it mixes uniformly to obtain a bulk solution;6) adding required quantity of progesterone as per batch size into bulk solution obtained in step e) and stirring well for suitable period of time until it disperses uniformly to obtain compounded bulk suspension formulation;7) optionally, sterilizing the compounded bulk suspension obtained in step f) by using temperature range of about 122°C to 125°C for at least 15 minutes and a FO value > 12 minutes to obtain sterilized bulk suspension;8) optionally, cooling the sterilized bulk suspension of step g) to room temperature and making final weight of the cooled bulk suspension with water and adjusting pH by using 0.1 N HC1 or 0.1 N NaOH to desired value;9) optionally, filling the compounded and sterilized bulk suspension of any one of step f) to step h) aseptically into suitable containers under suitable conditions.

35. The method of claim 34, optionally comprising soaking one or more viscosity agents overnight in water to ensure ease of dispersion prior to step c).

36. A pharmaceutical composition for the treatment of endometriosis, including endometriosis externa, endometrioma, superficial peritoneal lesions (SPE), deep infiltrating endometriosis (DIE), adenomyosis, adenomyomas, adenomyotic nodules of uterosacral ligaments, and endometriotic nodules, such as scar endometriosis, comprising from about 2 mg / ml, 5mg / ml, lOmg / ml, 20mg / ml, 40mg / ml, 50mg / ml,lOOmg / ml, 150mg / ml, 200mg / ml, 250mg / ml, 300mg / ml, 350mg / ml, 400mg / ml, 450mg / ml, 500mg / ml, 550mg / ml, 600mg / ml, 650mg / ml, 700mg / ml, 750mg / ml, 800mg / ml, 850mg / ml, 900mg / ml, 950mg / ml or 1000 mg / ml of progesterone, at least one buffering agent, at least one viscosity agent, at least one tonicity agent, at least one wetting agent and at least one preservative agent and one or more other pharmaceutically acceptable excipients, wherein the composition has a viscosity ranging from about 1 to 300 cps and pH from about 4.0 to 7.5.

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