Compositions and Methods for the Peripheral Targeting of Melatonin Receptor Agonists

Abstract

This specification describes a pharmaceutical composition of a melatonin receptor agonist for use in tissues outside the CNS. Also described herein are methods of using the pharmaceutical compositions described herein to improve the menopause system and to improve reproductive outcomes in polycystic ovary syndrome, endometriosis, chemotherapy-induced ovarian dysfunction, and inflammatory and metabolic diseases.

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,622, filed on July 22, 2022, which is incorporated herein by reference in its entirety.

[0002] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the incorporated publications and patents or patent applications conflict with the disclosure contained herein, this specification is intended to supersede such conflicting subject matter and / or to take precedence over the above - mentioned subject matter.

Background Art

[0003] The present disclosure relates to pharmaceutical compositions of melatonin receptor agonists that target the obliterated organ or peripheral tissue and / or pharmaceutical compositions of melatonin receptor agonists with reduced accumulation in the central nervous system after administration. The present disclosure also relates to methods for using these pharmaceutical compositions of melatonin receptor agonists for the prevention and / or treatment of symptoms related to polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, inflammation of the reproductive tract, or chemotherapy - induced ovarian dysfunction (CIOD). Background of the Invention

[0004] Melatonin, namely N-acetyl-5-methoxytryptamine, functions as a multifaceted hormone in a number of animal species. In vertebrates, the main source of melatonin is the pineal gland, which releases melatonin in a circadian production cycle that increases in the evening, reaches a peak at night, then rapidly declines throughout the morning and remains low during the day. Melatonin is a fast-acting hormone that is rapidly metabolized and has a short half-life (20 - 40 minutes) in the body. Therefore, the serum concentration of melatonin at any given time closely follows the production level of the pineal gland. Melatonin is known to function in synchronizing the circadian rhythm, and an increase in its serum concentration induces drowsiness in the central nervous system (CNS) and acts to promote sleep in diurnal vertebrate species.

[0005] In addition to its hormonal function, melatonin exhibits strong antioxidant properties. Melatonin and its metabolic derivatives have strong free radical scavenging properties against both reactive oxygen species and reactive nitrogen species. By acting to directly scavenge these free radicals, melatonin and its derivatives can prevent cellular oxidative stress, tissue oxidative stress, and organ system oxidative stress.

[0006] Melatonin also functions as a high-affinity ligand for melatonin receptor 1A (MTNR1A, MT1) and melatonin receptor 1B (MTNR1B, MT2). MTNR1A and MTNR1B are 7-transmembrane receptors coupled to G proteins and are responsible for initiating melatonin-induced signal transduction in target cells throughout the body. Melatonin-induced signal transduction mediated by MTNR1A and MTNR1B is known to regulate the mammalian circadian rhythm. In addition to its direct effect as an antioxidant, melatonin causes an indirect increase in antioxidant mechanisms in target cells. Melatonin signal transduction by MTNR1A and MTNR1B induces the expression of antioxidant enzymes such as superoxide dismutase (SOD), glutathione reductase (GSR), glutathione peroxidase (GPX), and catalase (CAT). Summary of the Invention

[0007] There remains a need to regulate phenotypes affected by melatonin in a subject. Melatonin receptors are expressed in the human ovary, and melatonin directly affects ovarian function without mediating through the hypothalamic-pituitary-gonadal (HPG) axis. In the ovary, melatonin regulates ovarian steroid production and functions to counteract the peripheral (endocrine) and local (paracrine and intracrine) effects of inflammation and oxidative stress on the maturation of ovarian somatic cells and oocytes. Melatonin signaling via receptors MT1 and MT2 regulates ovarian steroid production, inflammation, oxidative stress, and oocyte maturation in in vitro human cell assays.

[0008] In some examples, delivering melatonin or a melatonin receptor agonist results in a beneficial regulation of the subject's phenotype. However, a therapeutically effective amount of melatonin or a melatonin receptor agonist distributed systemically can cross the blood-brain barrier and may induce an unwanted neural phenotype in the subject. Therefore, delivering a therapeutically effective amount of melatonin or a melatonin receptor to a target tissue outside the CNS can result in a beneficial regulation of the subject's phenotype without inadvertently affecting CNS-mediated body functions or inducing unwanted side effects.

[0009] Due to its amphiphilic properties (high hydrophilicity and lipophilicity), melatonin can easily diffuse away from its source and may readily pass through morphological and physiological barriers, including the blood-brain barrier and cell membranes. Melatonin may be distributed to all tissues via the circulation. Extracellular melatonin rapidly equilibrates at the cytoplasmic level due to its cell-penetrating properties, leading to various functional effects such as cell signaling initiated by binding to high-affinity cell surface receptors (MT1 and MT2), as well as intracellular interactions such as direct antioxidant effects within cells and intracellular compartments. Melatonin has two functional groups that determine its specificity and amphiphilicity. The two functional groups are the 5-methoxy group and the N-acetyl side chain. Despite the characteristic of melatonin and its production to propagate extensive distribution and equilibration, the local concentration of melatonin does not always reflect the serum melatonin concentration. When synthesized by the pineal gland, melatonin is released directly into the cerebrospinal fluid (CSF) and the peripheral circulation (where approximately 70% of melatonin remains bound to serum albumin). The melatonin concentration in the third ventricle is much higher than that in other ventricular locations because it is a direct secretion from the pineal recess. Brain regions not in direct contact with the third ventricle can receive melatonin through the circulating CSF or through the blood supply where serum melatonin passes through the blood-brain barrier and enters local CNS regions. The pineal gland is not the only source of melatonin in vertebrates. Extrapineal sources of melatonin include the retina, cerebellum, Harderian gland, snail, skin, testis, ovary, bone marrow, thymus, placenta, liver, kidney, heart, chromaffin cells of the gastrointestinal tract, peripheral blood mononuclear cells, and mast cells. Except for the retina, extrapineal sources of melatonin do not appear to follow the same circadian production rhythm as in the pineal gland and do not appear to substantially contribute to circulating melatonin levels. Melatonin produced extrapineally is thought to function locally in cell types close to the site of production. Modulating the transport of melatonin can also affect local melatonin concentration or CNS bioavailability through transport across the blood-brain barrier.

[0010] This specification describes pharmaceutical compositions related to delivering a melatonin receptor agonist to tissues throughout the body of a subject. In some embodiments, the pharmaceutical composition comprises a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal or intrauterine administration. In some embodiments, intravaginal or intrauterine administration enhances the local effect of the melatonin receptor agonist. In some embodiments, the enhancement of the local effect correlates with exposure of the CNS to the melatonin receptor agonist achieved across the blood-brain barrier. In some embodiments, the pharmaceutical composition comprises a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for systemic administration with reduced accumulation in the CNS or reduced penetration across the blood-brain barrier. In some embodiments, the pharmaceutical composition comprises a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for systemic administration with reduced accumulation in the CNS or reduced penetration across the blood-brain barrier compared to an equal amount of melatonin. In some embodiments, the enhancement of the local effect by the melatonin receptor agonist that correlates with exposure of the CNS to the melatonin receptor agonist achieved across the blood-brain barrier occurs after local delivery of the melatonin receptor agonist, after delivery of the melatonin receptor agonist from the device, or after systemic delivery of the melatonin receptor agonist formulated to reduce accumulation in the CNS or formulated to reduce penetration across the blood-brain barrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a melatonin receptor agonist. In some embodiments, the therapeutically effective amount is effective to treat or alleviate polycystic ovary syndrome (PCOS), endometriosis, symptoms of menopause (e.g., decreased bone density, weight gain, hypertension, hair loss, inflammation), chemotherapy-induced ovarian insufficiency, or symptoms of inflammation of the reproductive tract in a subject in need of treatment or alleviation of polycystic ovary syndrome (PCOS), endometriosis, symptoms of menopause (e.g., decreased bone density, weight gain, hypertension, hair loss, inflammation), chemotherapy-induced ovarian insufficiency, or symptoms of inflammation of the reproductive tract.In some embodiments, the melatonin receptor agonist includes at least one of Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or a salt or derivative thereof, or a combination thereof. In some embodiments, the melatonin receptor agonist includes Circadin®. In some embodiments, the melatonin receptor agonist includes Slenyto®. In some embodiments, the melatonin receptor agonist includes ramelteon. In some embodiments, the melatonin receptor agonist includes tasimelteon. In some embodiments, the melatonin receptor agonist includes agomelatine. In some embodiments, the melatonin receptor agonist includes TIK-301. In some embodiments, the melatonin receptor agonist includes pyromelatine. In some embodiments, the melatonin receptor agonist includes N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist includes N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide. In some embodiments, the melatonin receptor agonist includes N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist non-selectively activates type 1A (MT1) and type 1B (MT2) melatonin receptors. In some embodiments, the melatonin receptor agonist preferentially activates type 1A (MT1) melatonin receptors.In some embodiments, the melatonin receptor agonist preferentially activates the type 1B (MT2) melatonin receptor. In some aspects, activation of the melatonin receptor is a means of regulating the activity of receptor interacting proteins such as TMEM33, CALR (calreticulin), CNP (cyclic nucleotide phosphodiesterase). In some embodiments, the pharmaceutical composition is formulated as a gel, cream, ointment, solution, powder, paste, or foam. In some embodiments, the pharmaceutical composition is formulated to be delivered via a drug delivery device. In some embodiments, the pharmaceutical composition is formulated to be delivered via a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, the pharmaceutical composition is formulated for delayed release, sustained release, or extended release. In some aspects, the pharmaceutical composition is used in a time-controlled release device to achieve daily or nightly release of the melatonin receptor agonist. In some embodiments, the pharmaceutical composition contains a melatonin receptor agonist in an effective amount for at least about 1 week, 2 weeks, 4 weeks, 2 months, or 6 months. In some aspects, compared to the central nervous system (CNS), the melatonin receptor agonist preferentially accumulates in the periphery. In some aspects, the concentration of the melatonin receptor agonist is higher in the periphery (e.g., plasma concentration, peripheral tissue) compared to the CNS. In some aspects, the preferential accumulation of the melatonin receptor agonist in the periphery compared to the CNS is achieved by local administration (e.g., intravaginally, intrauterinely). In some aspects, the preferential accumulation of the melatonin receptor agonist in the periphery compared to the CNS is due to the physicochemical properties of the compound. In some aspects, the preferential accumulation of the melatonin receptor agonist in the periphery compared to the CNS is due to limitations in diffusion through the blood-brain barrier (BBB). In some aspects, the preferential accumulation of the melatonin receptor agonist in the periphery compared to the CNS is due to limitations in active transport through the BBB. In some aspects, the preferential accumulation of the melatonin receptor agonist in the periphery compared to the CNS is due to efflux via the BBB efflux transporter (e.g., ABCB protein).In some embodiments, the preferential accumulation of the melatonin receptor agonist in the peripheral part compared to the CNS is due to an increase in the metabolism or excretion of the melatonin receptor agonist in the CNS. In some embodiments, the preferential accumulation of the melatonin receptor agonist in the peripheral part compared to the CNS is due to binding to proteins in the CNS that decreases the free concentration of the melatonin receptor agonist. In some embodiments, the preferential accumulation of the melatonin receptor agonist in the peripheral part compared to the CNS is due to binding to proteins in the peripheral part. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, or 10% of the pharmaceutical composition penetrates through the subject's BBB. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, or 10% of the melatonin receptor agonist penetrates through the subject's BBB. In some embodiments, a decrease in the passive diffusion of the pharmaceutical composition through the BBB results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, a decrease in the active transport through the BBB results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, an increase in the efflux from the BBB results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, an increase in the metabolism of the active ingredient of the pharmaceutical composition results in a decrease in the CNS accumulation of the melatonin receptor agonist. In some embodiments, an increase in the CNS excretion results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, binding to proteins in the CNS results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, the localization of the administration of the pharmaceutical composition results in a decrease in the CNS accumulation of the pharmaceutical composition. In some embodiments, the melatonin receptor agonist is conjugated or encapsulated with a molecule that has a low ability to pass through the BBB. In some embodiments, the melatonin receptor agonist is conjugated or encapsulated with a molecule that does not pass through the blood-brain barrier. In some embodiments, the molecule is hydrophilic and is a carbohydrate molecule, a peptide, or a synthetic molecule. In some embodiments, the melatonin receptor agonist may be less hydrophilic compared to melatonin. In some embodiments, the melatonin receptor agonist may be less lipophilic compared to melatonin.

[0011] In certain embodiments, methods are described herein for delivering a melatonin receptor agonist to tissues throughout a subject's body. In some embodiments, a method for treating or alleviating symptoms of polycystic ovary syndrome (PCOS), endometriosis, chemotherapy-induced ovarian dysfunction (CIOD), or inflammation of the reproductive tract in a subject in need thereof comprises administering to the subject a composition comprising a melatonin receptor agonist, wherein the composition is administered via a vaginal, intrauterine, or systemic route with preferential exposure at the periphery of the subject (e.g., higher plasma concentration than the CNS). In some embodiments, a method for preventing, reducing, or suppressing one or more symptoms of CIOD in a subject in need thereof comprises administering to the subject a composition comprising a melatonin receptor agonist, wherein the composition is administered via a vaginal, intrauterine, or systemic route with preferential exposure at the periphery of the subject (e.g., higher plasma concentration than the CNS). In some embodiments, the melatonin receptor agonist comprises at least one of Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or salts or derivatives thereof, or combinations thereof. In some embodiments, the melatonin receptor agonist non-selectively activates type 1A (MT1) and type 1B (MT2) melatonin receptors. In some embodiments, the melatonin receptor agonist preferentially activates the type 1A (MT1) melatonin receptor.In some embodiments, the melatonin receptor agonist preferentially activates the type 1B (MT2) melatonin receptor. In some embodiments, the composition is formulated as a gel, cream, ointment, solution, powder, paste, or foam. In some embodiments, the composition is administered by applying the composition to the dermal or transmucosal layer of the vaginal wall. In some embodiments, the composition is administered via an intrauterine device. In some embodiments, the composition is formulated to be delivered via a drug delivery device (e.g., a vaginal ring, vaginal tablet, pessary, suppository, or patch), wherein the composition is administered by placing the intravaginal device in proximity to the subject's genitalia. In some embodiments, the symptom includes abdominal pain, and the composition is administered at a dose and schedule effective to reduce the abdominal pain by at least 20%, at least 30%, or at least 40% within 24 hours, 48 hours, or 72 hours as measured by a numerical rating scale (NRS). In some embodiments, the composition is administered at least approximately daily, every other day, every three days, every seven days, every 14 days, every 28 days, or every two months. In some embodiments, administration of the melatonin receptor agonist has a limited (lower intensity and / or shorter duration) effect on melatonin receptor-mediated CNS behaviors (e.g., circadian rhythm, intoxication, sleep behavior, motor control, memory erasure, etc.) compared to melatonin. In some embodiments, the short half-life of the melatonin receptor agonist in the CNS allows the subject to experience improvement in symptoms mediated by CNS melatonin receptors without experiencing side effects caused by long-term CNS exposure.

[0012] Disclosed herein is a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration, has reduced accumulation in the central nervous system (CNS) compared to melatonin, and the therapeutically effective amount is effective for treating or alleviating symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, or inflammation of the reproductive tract in a subject in need of treatment or alleviation of symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, or inflammation of the reproductive tract. In some embodiments, the melatonin receptor agonist comprises at least one of Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or salts or derivatives thereof, or combinations thereof. In some embodiments, the melatonin receptor agonist comprises Circadin®. In some embodiments, the melatonin receptor agonist comprises Slenyto®. In some embodiments, the melatonin receptor agonist comprises ramelteon. In some embodiments, the melatonin receptor agonist comprises tasimelteon. In some embodiments, the melatonin receptor agonist comprises agomelatine. In some embodiments, the melatonin receptor agonist comprises TIK-301. In some embodiments, the melatonin receptor agonist comprises pyromelatine. In some embodiments, the melatonin receptor agonist comprises N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist comprises N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide.In some embodiments, the melatonin receptor agonist comprises N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diazas-indacen-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist non-selectively activates type 1A (MT1) and type 1B (MT2) melatonin receptors. In some embodiments, the melatonin receptor agonist preferentially activates the type 1A (MT1) melatonin receptor. In some embodiments, the melatonin receptor agonist preferentially activates the type 1B (MT2) melatonin receptor. In some embodiments, the pharmaceutical composition is formulated as a gel, ointment, solution, powder, paste, foam, cream, or lotion. In some embodiments, the pharmaceutical composition is formulated to be delivered via a drug delivery device. In some embodiments, the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, the drug delivery device is configured to be placed in proximity to the subject's genitalia. In some embodiments, a physician or qualified medical professional may place the drug delivery device in proximity to the subject's genitalia. In some embodiments, the drug delivery device is an intrauterine device and is configured to be placed in proximity to the subject's genitalia. In some embodiments, the intrauterine device is configured for time-controlled or remotely controlled release of one or more doses of the melatonin receptor agonist. In some embodiments, the pharmaceutical composition is formulated for delayed release, sustained release, extended release, long-term release, or slow release. In some embodiments, the pharmaceutical composition comprises the melatonin receptor agonist in an amount effective for at least about 1 week, 2 weeks, 4 weeks, 2 months, or 6 months. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the pharmaceutical composition accumulates in the subject's CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Circadin® accumulates in the subject's CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Slenyto® accumulates in the subject's CNS.In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of ramelteon accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of tasimelteon accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of agomelatine accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of TIK-301 accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of pyromelatonin accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide accumulates in the CNS of interest. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide accumulates in the CNS of interest. In some embodiments, the melatonin receptor agonist has a slower passive diffusion rate compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster rate of cerebrospinal fluid (CSF) efflux via the blood-brain barrier (BBB) efflux transporter compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster CNS metabolic rate compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster CNS excretion rate compared to melatonin. In some embodiments, the melatonin receptor agonist has an increased binding to one or more CNS proteins compared to melatonin. In some embodiments, the melatonin receptor agonist has an increased binding to one or more peripheral proteins compared to melatonin.In some embodiments, the melatonin receptor agonist is conjugated with or encapsulated with a molecule that has a low ability to cross the blood-brain barrier. In some embodiments, the molecule is a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule. In some embodiments, the pharmaceutical composition described herein is for use in treating polycystic ovary syndrome (PCOS) in a subject in need of treatment for polycystic ovary syndrome (PCOS). In some embodiments, the pharmaceutical composition described herein is for use in treating endometriosis in a subject in need of treatment for endometriosis. In some embodiments, the pharmaceutical composition described herein is for use in treating symptoms of menopause in a subject in need of treatment for symptoms of menopause. In some embodiments, the pharmaceutical composition described herein is for use in treating symptoms of chemotherapy-induced ovarian dysfunction (CIOD) in a subject in need of treatment for symptoms of chemotherapy-induced ovarian dysfunction (CIOD). In some embodiments, the pharmaceutical composition described herein is for use in treating inflammation of the reproductive tract in a subject in need of treatment for inflammation of the reproductive tract. In some embodiments, the pharmaceutical composition described herein is for use in treating symptoms of chemotherapy-induced ovarian failure (CIOF) in a subject in need of treatment for symptoms of chemotherapy-induced ovarian failure (CIOF). In some embodiments, the pharmaceutical composition described herein is for use in preventing symptoms of CIOD in a subject in need of prevention of symptoms of CIOD. In some embodiments, the pharmaceutical composition described herein is for use in reducing symptoms of CIOD in a subject in need of reduction of symptoms of CIOD. In some embodiments, the pharmaceutical composition described herein is for use in suppressing symptoms of CIOD in a subject in need of suppression of symptoms of CIOD.

[0013] Provided herein is a method for treating or alleviating the symptoms of polycystic ovary syndrome (PCOS), endometriosis, menopause, chemotherapy-induced ovarian insufficiency (CIOD), or inflammation of the reproductive tract in a subject in need of treatment or alleviation of the symptoms of polycystic ovary syndrome (PCOS), endometriosis, menopause, chemotherapy-induced ovarian insufficiency (CIOD), or inflammation of the reproductive tract, the method comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for vaginal, intrauterine, or systemic administration and has reduced accumulation in the central nervous system (CNS) compared to melatonin. In some embodiments, the pharmaceutical composition is administered vaginally, intrauterinely, or systemically and reduces accumulation in the subject's CNS compared to melatonin. In some embodiments, the pharmaceutical composition is administered vaginally and comprises administering the pharmaceutical composition to the dermal or transmucosal layer of the subject's vaginal wall. In some embodiments, the symptoms include abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, decreased bone density, alopecia, hypertension, or combinations thereof. In some embodiments, the administering step comprises administering at a dose and schedule effective to reduce abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, decreased bone density, alopecia, hypertension, or combinations thereof by at least 20%, at least 30%, or at least 40% within 24 hours, 48 hours, or 72 hours as measured by a numerical rating scale (NRS). In some embodiments, the administering step comprises administering at least approximately daily, every 2 days, every 3 days, every 7 days, every 14 days, every 28 days, every 2 months, or every 6 months. In some embodiments, the administering step comprises administering continuously during the treatment period. In some embodiments, the administering step comprises administering at a particular time of day or night according to the subject's circadian rhythm. In some embodiments, the pharmaceutical composition modulates the activity of melatonin receptors outside the CNS according to the subject's circadian rhythm.In some embodiments, the administering step includes administering at a specific time of day or night, regardless of the circadian variation of the melatonin level in the subject's plasma. In some embodiments, the administering step does not disrupt the circadian rhythm of the plasma melatonin level. In some embodiments, the administering step includes administering at any time during a 24-hour period. In some embodiments, the administering step has a reduced effect on melatonin receptor-mediated CNS behavior compared to administering an equal amount of melatonin. In some embodiments, the administering step has a reduced effect on melatonin receptor-mediated CNS behavior during nighttime hours compared to administering an equal amount of melatonin. In some embodiments, the melatonin receptor-mediated CNS behavior includes circadian rhythm, intoxication, sleep behavior, motor control, or memory erasure. In some aspects, the melatonin receptor agonist includes at least one of Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or salts or derivatives thereof, or combinations thereof. In some embodiments, the melatonin receptor agonist includes Circadin®. In some embodiments, the melatonin receptor agonist includes Slenyto®. In some embodiments, the melatonin receptor agonist includes ramelteon. In some embodiments, the melatonin receptor agonist includes tasimelteon. In some embodiments, the melatonin receptor agonist includes agomelatine. In some embodiments, the melatonin receptor agonist includes TIK-301. In some embodiments, the melatonin receptor agonist includes pyromelatine.In some embodiments, the melatonin receptor agonist comprises N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist comprises N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide. In some embodiments, the melatonin receptor agonist comprises N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide. In some embodiments, the melatonin receptor agonist non-selectively activates type 1A (MT1) and type 1B (MT2) melatonin receptors. In some embodiments, the melatonin receptor agonist preferentially activates the type 1A (MT1) melatonin receptor. In some embodiments, the melatonin receptor agonist preferentially activates the type 1B (MT2) melatonin receptor. In some embodiments, the pharmaceutical composition is formulated as a gel, ointment, solution, powder, paste, foam, cream, or lotion. In some embodiments, the pharmaceutical composition is formulated to be delivered via a drug delivery device. In some embodiments, the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, a physician or qualified medical professional may place the drug delivery device in proximity to the subject's genitalia. In some embodiments, administration comprises placing the drug delivery device in proximity to the subject's genitalia. In some embodiments, administration comprises placing an intrauterine device in proximity to the subject's genitalia. In some embodiments, the intrauterine device is configured for time-controlled or remote-controlled release of one or more doses of the melatonin receptor agonist. In some embodiments, the pharmaceutical composition is formulated for delayed release, sustained release, extended release, long-term release, or slow release. In some embodiments, the pharmaceutical composition comprises the melatonin receptor agonist in an amount effective for at least one week, two weeks, four weeks, two months, or six months. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the pharmaceutical composition accumulates in the subject's CNS.In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Circadin® accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Slenyto® accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of ramelteon accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of tasimelteon accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of agomelatine accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of TIK-301 accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of pyromelatonin accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide accumulates in the target CNS. In some embodiments, less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide accumulates in the target CNS. In some embodiments, the melatonin receptor agonist has a slower passive diffusion rate compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster rate of cerebrospinal fluid (CSF) efflux via the BBB efflux transporter compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster CNS metabolic rate compared to melatonin. In some embodiments, the melatonin receptor agonist has a faster CNS excretion rate compared to melatonin.In some embodiments, the melatonin receptor agonist has increased binding to one or more CNS proteins as compared to melatonin. In some embodiments, the melatonin receptor agonist has increased binding to one or more peripheral proteins as compared to melatonin. In some embodiments, the melatonin receptor agonist is conjugated or encapsulated with a molecule having low ability to cross the blood-brain barrier. In some embodiments, the molecule is a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule.

[0014] The present specification provides for the use of a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration for manufacturing a medicament for treating polycystic ovary syndrome (PCOS) in a subject in need of treatment of polycystic ovary syndrome (PCOS), and has reduced accumulation in the central nervous system (CNS) as compared to melatonin. The present specification provides for the use of a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration for manufacturing a medicament for treating endometriosis in a subject in need of treatment of endometriosis, and has reduced accumulation in the central nervous system (CNS) as compared to melatonin. The present specification provides for the use of a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration for manufacturing a medicament for treating symptoms of menopause in a subject in need of treatment of symptoms of menopause, and has reduced accumulation in the central nervous system (CNS) as compared to melatonin. The present specification provides for the use of a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration for manufacturing a medicament for treating inflammation of the reproductive tract in a subject in need of treatment of inflammation of the reproductive tract, and has reduced accumulation in the central nervous system (CNS) as compared to melatonin. The present specification provides for the use of a pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for intravaginal, intrauterine, or systemic administration for manufacturing a medicament for treating chemotherapy-induced ovarian dysfunction (CIOD) in a subject in need of treatment of chemotherapy-induced ovarian dysfunction (CIOD), and has reduced accumulation in the central nervous system (CNS) as compared to melatonin. In some embodiments, the medicament is prepared to be administered according to an administration schedule that includes administration at least approximately daily, every 2 days, every 3 days, every 7 days, every 14 days, every 28 days, every 2 months, or every 6 months.In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes a pretreatment that begins about 15 days before, 14 days before, 13 days before, 12 days before, 11 days before, 10 days before, 9 days before, 8 days before, 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 18 hours before, 12 hours before, 8 hours before, 6 hours before, 4 hours before, 2 hours before, or 1 hour before the start of chemotherapy in the subject. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes continuous administration during the treatment period. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration at a specific time of day according to the subject's circadian rhythm. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration at a specific time of day regardless of the circadian variation in plasma melatonin levels. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration without disrupting the circadian rhythm of plasma melatonin levels. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration at any time during a 24-hour period. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration with reduced impact on melatonin receptor-mediated CNS behavior compared to administration of an equal amount of melatonin. In some embodiments, the pharmaceutical is formulated to be administered according to a dosing schedule that includes administration with reduced impact on melatonin receptor-mediated CNS behavior during nighttime hours compared to administration of an equal amount of melatonin.

[0015] The present specification provides a kit comprising the pharmaceutical composition described herein and instructions for use. In some embodiments, the instructions for use specify one or more indications in a subject in need of treatment, and the one or more indications include polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian dysfunction (CIOD), chemotherapy-induced ovarian failure (CIOF), or inflammation of the reproductive tract, or combinations thereof. In some embodiments, the kit further comprises a drug delivery device for administering the pharmaceutical composition to a subject. In some embodiments, the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, the drug delivery device is configured to be disposed in proximity to the subject's genitalia. In some embodiments, the drug delivery device is an intrauterine device and is configured to be disposed in proximity to the subject's genitalia. In some embodiments, the intrauterine device is configured for time-controlled or remote-controlled release of one or more doses of a pharmaceutical composition formulated for delayed release, sustained release, extended release, long-term release, or slow release.

Brief Description of the Drawings

[0016]

Figure 1

Figure 2A

Figure 2B

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Overview In many cases, women will welcome and / or benefit from treatment to reduce the symptoms of polycystic ovary syndrome (PCOS). In many cases, in addition, effective PCOS treatment of symptoms that maintain or increase fertility would be preferred. PCOS phenotypic traits can affect many biological systems, including the endocrine, metabolic, reproductive, and immune systems. Endocrine disorders in subjects with PCOS can affect organs including the ovaries, adrenals, pituitary, and hypothalamus. Endocrine disorders in subjects with PCOS can cause elevated serum androgen levels, ovarian androgen excess, high luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio in the blood (high LH:FSH ratio), hirsutism, and acne. Abnormal interactions within the hypothalamic-pituitary-gonadal (HPG) axis can cause these disorders in subjects with PCOS. Secondary effects of disorders of this HPG axis can include adrenal androgen excess and cortisol excess. In some embodiments described herein, delivering a melatonin receptor agonist to tissues having endocrine function can alleviate PCOS symptoms including ovarian androgen excess, elevated serum androgen levels, and hirsutism. In some embodiments described herein, delivering a melatonin receptor agonist to tissues having metabolic function can alleviate PCOS symptoms including obesity and insulin resistance.

[0018] Genital disorders in subjects with PCOS mainly affect the ovaries. Ovarian dysfunction in subjects with PCOS can cause polycystic ovaries, oligoovulation, anovulation, low-quality eggs, low-quality embryos, and infertility. Ovarian insufficiency subsequently affects endometrial function. Endometrial dysfunction in PCOS can cause phenotypes including oligomenorrhea, amenorrhea, endometrial receptivity disorders, and infertility. Melatonin is concentrated in ovarian follicular fluid, and melatonin receptors are expressed in the ovaries. Subjects with PCOS have elevated serum melatonin levels and reduced melatonin levels in ovarian follicular fluid. In some embodiments, delivering a melatonin receptor agonist to ovarian tissue can alleviate PCOS symptoms, including infertility including polycystic ovaries, oligoovulation, anovulation (correction of ovulatory disorders responsible for amenorrhea or oligomenorrhea), low-quality eggs, low-quality embryos, and infertility due to disrupted endometrial receptivity intervals.

[0019] Disorders of immune system cells in subjects with PCOS affect the responsiveness of reproductive tissues and the responses of multiple tissues to systemic metabolic disorders caused by inflammation. This immune system disorder in PCOS can be presented as an overactive immune response. Furthermore, dysfunctional immune cells can cause low-grade inflammation in tissues in the subject. In some examples, this low-grade inflammation is the result of increased production of pro-inflammatory cytokines secreted by dysfunctional immune cells. In some examples, long-term inflammation of the peripheral tissue program impairs the normal function of immune cells in PCOS patients, which leads to an increase in oxidative stress in certain tissues. The resulting increase in inflammation and oxidative stress can adversely affect tissue and organ function and cause cell damage. In some embodiments, delivering a melatonin receptor agonist to immune cells and their precursors throughout the body can alleviate PCOS symptoms including low-grade inflammation and reduce oxidative stress.

[0020] In many instances, women will welcome and / or benefit from treatments that alleviate the symptoms of endometriosis. In some instances, means alternative to the surgical removal of ectopic endometrial tissue are preferred. In some instances, subjects with endometriosis present with endometriosis-associated chronic pelvic pain (EACPP). In some instances, subjects with endometriosis present with dysmenorrhea. In some instances, subjects with endometriosis present with back pain. In some instances, endometriosis can cause a decrease in fertility or infertility. In some instances, endometriosis can cause oxidative stress in the ovaries associated with endometriosis. In some instances, delivering a melatonin receptor agonist to reproductive tissue and to sites, adjacent sites, or nearby sites near endometriosis lesions or adenomyosis can slow the progression of endometriosis and help alleviate debilitation and discomfort caused by EACPP, dysmenorrhea, back pain, or combinations thereof. In some instances, delivering a melatonin receptor agonist to reproductive tissue and to sites, adjacent sites, or nearby sites near endometriosis lesions or adenomyosis can also maintain or enhance fertility in a subject.

[0021] In many instances, women will welcome and / or benefit from treatments that address idiopathic inflammation of the reproductive tract. Optionally, acute or chronic inflammation of the reproductive tract can result in ovulatory dysfunction, luteal phase defect, increased insulin resistance in ovarian tissue, hyperandrogenism, preeclampsia, folliculogenesis disorders, ovarian progesterone production disorders including luteal phase progesterone production, poor oocyte maturation, and reduced good reproductive assisted technology (ART) outcomes. In some instances, delivering a melatonin receptor agonist to the tissue of the reproductive tract can alleviate ovulatory dysfunction, luteal phase defect, increased insulin resistance in ovarian tissue, hyperandrogenism, preeclampsia, folliculogenesis disorders, ovarian progesterone production disorders including luteal phase progesterone production, poor oocyte maturation, and reduced good reproductive assisted technology (ART) outcomes.

[0022] In many instances, women will welcome and / or benefit from treatment for chemotherapy-induced ovarian dysfunction (CIOD). In some instances, CIOD can cause hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, decrease in primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, stromal tissue damage, ovarian vascular damage, ovarian inflammation, decrease in ovarian reserve, increased rate of age-dependent loss of ovarian reserve, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decrease in estrogen production, decrease in anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decrease in plasma levels of estradiol, or any combination thereof. In some instances, delivering a melatonin receptor agonist to the tissue of the reproductive tract can alleviate hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, stromal tissue damage, ovarian vascular damage, ovarian inflammation, decrease in ovarian reserve, increased rate of age-dependent loss of ovarian reserve, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decrease in estrogen production, decrease in anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decrease in plasma levels of estradiol, or any combination thereof.

[0023] In many instances, women will welcome and / or benefit from treatments that prevent, reduce, or inhibit CIOD. In some instances, CIOD can cause hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, interstitial tissue damage, ovarian vascular damage, ovarian inflammation, decreased ovarian reserve, increased age-dependent loss rate of ovarian reserve, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decreased estrogen production, decreased anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decreased plasma levels of estradiol, or any combination thereof. In some instances, delivering a melatonin receptor agonist to the tissues of the reproductive tract can mitigate the risk of onset of hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, interstitial tissue damage, ovarian vascular damage, ovarian inflammation, decreased ovarian reserve, increased age-dependent loss rate of ovarian reserve, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decreased estrogen production, decreased anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decreased plasma levels of estradiol, or any combination thereof after administration of a chemotherapy treatment. In some instances, delivering a melatonin receptor agonist to the tissues of the reproductive tract can prevent the onset of hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, interstitial tissue damage, ovarian vascular damage, ovarian inflammation, decreased ovarian reserve, increased age-dependent loss rate of ovarian reserve, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decreased estrogen production, decreased anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decreased plasma levels of estradiol, or any combination thereof after administration of a chemotherapy treatment.In some examples, delivering a melatonin receptor agonist to reproductive tract tissue may prevent the onset of hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of primordial ovarian follicle activation, follicular atresia, stromal tissue damage, ovarian vascular damage, ovarian inflammation, decreased ovarian reserve, increased age-dependent loss rate of ovarian reserve, induction of fibrosis, early menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decreased estrogen production, decreased anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decreased plasma levels of estradiol, or any combination thereof, after administration of a chemotherapy treatment.

[0024] In some examples, delivering a melatonin receptor agonist to reproductive tissue may modulate (e.g., delay, inhibit, or prevent) cellular aging of the ovary and / or control (e.g., delay, inhibit, or prevent) aging of the ovary. In many examples, ovarian aging can be caused by time, genetics, and / or environmental factors. In many examples, women with a genetic predisposition to early loss of ovarian reserve would welcome and / or benefit from a treatment that modulates (e.g., prevents, reduces, inhibits, and / or delays) depletion of ovarian reserve and / or decreases (e.g., prevents, reduces, inhibits, and / or delays) it. In some examples, for instance, women with mutations in genes important for folliculogenesis and ovarian ecology (e.g., AR, BMP15, ESR1, FIGLA, FMR1, FOXE1, FOXL2, FOXO3, FSHR, GALT, GDF9, INHA, NOBOX, NR5A1, SYCP2L, TGFBR3) would benefit from a treatment that controls (prevents, reduces, inhibits, and / or delays) depletion of ovarian reserve.

[0025] Pharmaceutical composition Melatonin receptors are 7-transmembrane cell surface receptors coupled to G proteins, which can detect extracellular ligands and regulate intracellular responses based on ligand binding. Melatonin (a primary hormone secreted by the pineal gland and also produced in some extrapineal tissues) functions as a naturally produced high-affinity ligand for melatonin receptors. Mammals have two types of melatonin receptors, designated MT1 and MT2. MT1 is encoded by the MTNR1A locus, and MT2 is encoded by the MTNR1B locus. Both MT1 and MT2 have been shown to control many melatonin-mediated biological functions, including the CNS regulation of the circadian rhythm. MT1 and MT2 are shown to be expressed in various parts of the CNS (suprachiasmatic nucleus, hippocampus, cerebellar cortex, prefrontal cortex, basal ganglia, substantia nigra, ventral tegmental area, lateral septal nucleus, as well as retinal horizontal cells, amacrine cells, ganglion cells). However, MT1 and MT2 are also expressed in cell types throughout the body (e.g., blood vessels, mammary glands, gastrointestinal tract, liver, kidney, bladder, ovary, testis, prostate, skin, and immune system) and can regulate the functions of various cell types, tissues, and organs.

[0026] The high-affinity MTNR1A (MT1) and MTNR1B (MT2) melatonin receptors are 350 and 362 amino acids long, respectively, and have a calculated molecular weight of 39 - 40 kDa. These melatonin receptors bind to pertussis toxin-sensitive G proteins, which cause inhibition of adenylyl cyclase activity. MT1 is a receptor specific to MT2 because they exhibit distinct molecular structures with only 61% amino acid identity and different chromosomal localizations. These melatonin receptors have two (MTNR1A) and one (MTNR1B) potential glycosylation sites at the N-terminus, as well as protein kinase C (PKC), casein kinase 1 (CK1), casein kinase 2 (CK2), and protein kinase A (PKA) phosphorylation sites that may be involved in their regulation. Their structure consists of seven transmembrane (TM) helices (I - VII) connected by three alternating intracellular (IL1, IL2, and IL3) and extracellular (EL1, EL2, and EL3) loops. These melatonin receptors have an asparagine-arginine-tyrosine (NRY) motif, a variant of aspartic acid-arginine-tyrosine (DRY) (or glutamic acid-arginine-tyrosine (ERY)) present in intracellular loop II of all G protein-coupled receptors, which makes them different from the superfamily members of other G protein-coupled receptors. This region is thought to be involved in signal transduction through G proteins. A mutation of asparagine 124 in the NRY motif of the MT1 melatonin receptor affects receptor transport and cell signaling. Also, the melatonin receptors have what appears to be a leucine zipper in TM IV, with seven leucines in MTNR1A and six leucines in MTNR1B, which may be involved in protein-protein interactions. At MTNR1A Gly20 (TM VI), val4 (TM IV), His7 (TM IV), Ser8 (TM III), and Ser12 (TM III) are essential for melatonin binding.In MTNR1B, it has been proposed that Cys113 (in EL1) and Cys190 (in EL2), two residues conserved in most GPCRs, form a disulfide bond essential for high-affinity melatonin binding.

[0027] Despite a large structural difference (61% amino acid identity) between the two receptors, the affinity of melatonin for both MT1 and MT2 is similar (Ki of approximately 0.1 nM). MT1 and MT2 overlap in function in some biological functions but differ in role in certain tissues or situations. Common elements of MT1 and MT2 activation include ligand-binding-mediated G i protein activation, which is accompanied by inhibition of adenylyl cyclase and subsequent decrease in intracellular cAMP levels. The distinct functions of MT1 and MT2 can be derived from tissue-specific expression patterns, differences in expression levels in certain cell types, differences in the localization and intracellular trafficking of MT1 and MT2 in certain cells, as well as distinct downstream signaling events. MT1 and MT2 can both form homo-oligomers that promote melatonin-mediated signaling. Also, MT1 and MT2 can hetero-oligomerize to promote melatonin-mediated signaling. Moreover, MT1 and MT2 have been shown to hetero-oligomerize with other receptors including 5-HT 2c receptors. Furthermore, when one receptor subtype is selectively targeted, or when dual-targeting strategies have different effects on the effects of activation downstream of specific receptors or specific receptor complexes, these different receptor complexes can not only have functional significance for signal diversification according to cell type and situation, but also present means for improving drug selectivity.

[0028] Polymorphisms in both the MTNR1A and MTNR1B genes have been shown to be associated with PCOS in case-control studies that indicate the role of MTNR1A, MTNR1B, and the melatonin signaling pathway in the symptoms and pathologies of PCOS (Yi S. et al. Biosci Rep. 2020 Jun 26;40(6)). PCOS is an endocrine disorder in which a greater than normal number of small antral follicles are formed within the ovaries. As illustrated in Figure 1, PCOS phenotypic traits associated with MTNR1A and MTNR1B can be identified as affecting the endocrine, reproductive, immune, and metabolic systems. A box surrounding specific traits that can be regulated by targeting the melatonin pathway within the affected systems is shown in Figure 1 (e.g., polycystic ovaries, oligo-ovulation, anovulation, poor-quality eggs, poor-quality embryos, and infertility within the genital system). Subjects with PCOS can exhibit dysfunction of various phenotypic traits affected in the endocrine, reproductive, immune, and metabolic systems. Furthermore, the degree of dysfunction of any particular phenotypic trait in subjects with PCOS can vary. In some examples, subjects with PCOS will benefit from treatment that equally increases signaling through both MT1 and MT2. In some examples, subjects with PCOS can benefit from treatment that targets both MT1 and MT2. In some examples, subjects with PCOS can benefit from treatment that preferentially targets MT1 over MT2. In some examples, subjects with PCOS can benefit from treatment that preferentially targets MT2 over MT1. In some examples, subjects with PCOS can benefit from treatment that targets only MT1. In some examples, subjects with PCOS can benefit from treatment that targets only MT2. In some examples, as an aspect of treatment, the degree of preferentially targeting MT1 over MT2 can result in further benefit to subjects with PCOS. In some examples, as an aspect of treatment, the degree of preferentially targeting MT2 over MT1 can result in further benefit to subjects with PCOS.

[0029] A variety of melatonin receptor agonists have been identified and clinically evaluated. Tables 1 and 2 list clinically developed melatonin receptor agonists, indications for use, and molecular characteristics. Some melatonin receptor agonists (e.g., Circadin® and Slenyto®) contain melatonin as the active substance within the formulation. Some melatonin receptor agonists (e.g., ramelteon, tasimelteon, agomelatine, TIK-301, and pyromelatine) contain chemical analogs of melatonin as the active substance within the formulation. In some embodiments, the melatonin receptor agonist can function as a dual melatonin receptor agonist. In some embodiments, the dual melatonin receptor agonist can bind with high affinity to both MT1 and MT2. In some embodiments, the high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling through both MT1 and MT2 at a concentration of the dual melatonin receptor agonist similar to the physiological concentration of melatonin found in an active signaling context. In some embodiments, the high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling through both MT1 and MT2 at a concentration of the dual melatonin receptor agonist lower than the physiological concentration of melatonin found in an active signaling context. In some embodiments, the high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling through both MT1 and MT2 to a greater extent than the same concentration of melatonin at a given concentration. In some embodiments, the high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling through both MT1 and MT2 to a lesser extent than the same concentration of melatonin at a given concentration. In some embodiments, the high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling through MT1 to a greater extent than it can activate melatonin pathway signaling through MT2.In some embodiments, a high-affinity MT1- and MT2-binding dual melatonin receptor agonist can activate melatonin pathway signaling via MT1 to a lesser extent than it can activate melatonin pathway signaling via MT2. In some embodiments, a high-affinity MT1- and MT2-binding dual melatonin receptor agonist that can activate melatonin pathway signaling via MT1 to a greater extent than it can activate melatonin pathway signaling via MT2 is preferred for treating a subject. In some embodiments, a high-affinity MT1- and MT2-binding dual melatonin receptor agonist that can activate melatonin pathway signaling via MT1 to a lesser extent than it can activate melatonin pathway signaling via MT2 is preferred for treating a subject.

[0030] In some aspects, a melatonin receptor agonist can function with an activity lower than the full agonist activity for the receptor. In some embodiments, a melatonin receptor agonist can function as a partial agonist. In some embodiments, a melatonin receptor agonist can function as a partial agonist for MT1. In some embodiments, a melatonin receptor agonist can function as a partial agonist for MT2. In some embodiments, a melatonin receptor agonist can exhibit high-affinity binding to MT1, MT2, or both MT1 and MT2, and can function as a partial agonist for MT1, MT2, or both MT1 and MT2. In some embodiments, a partial agonist for MT1, MT2, or both MT1 and MT2 can increase the overall agonism for MT1, MT2, or both MT1 and MT2 by synergizing with melatonin. In some embodiments, a melatonin receptor agonist can function as an agonist or partial agonist for MT1, MT2, or both MT1 and MT2, and 2B or 5-HT 2C can function as an antagonist for 5-HT. In some embodiments, the function as an agonist or partial agonist for MT1, MT2, or both MT1 and MT2, and 5-HT2B or 5-HT 2C Melatonin receptor agonists that can exhibit a function as an antagonist against 2B or 5-HT include agomelatine. In some embodiments, the melatonin receptor agonist can function as an antagonist and a partial agonist (AT / PA). In some embodiments, the AT / PA function can occur simultaneously. In some embodiments, the melatonin receptor agonist can function as an AT / PA having at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% PA activity.

[0031] In some embodiments, the melatonin receptor agonist has a binding affinity for MT1 or MT2 that is similar to the binding affinity of melatonin. In some embodiments, the melatonin receptor agonist has a binding affinity for MT1 or MT2 that is different from the binding affinity of melatonin. In some embodiments, the melatonin receptor agonist has a binding affinity for MT1 that is at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01%, 0.005%, 0.0001% lower than the binding affinity of melatonin for MT1. In some embodiments, the melatonin receptor agonist has a binding affinity for MT2 that is at least 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, 0.05%, 0.01%, 0.005%, 0.0001% lower than the binding affinity of melatonin for MT2. In some embodiments, the melatonin receptor agonist has a binding affinity for MT1 that is at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 17%, 20%, 22%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 1250%, 1500%, 2000%, 3000%, 5000%, 7500%, or 10000% higher than the binding affinity of melatonin for MT1.In some embodiments, the melatonin receptor agonist has a binding affinity for MT2 that is at least 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 17%, 20%, 22%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 125%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 1250%, 1500%, 2000%, 3000%, 5000%, 7500%, or 10000% higher than the binding affinity of melatonin for MT2. In some embodiments, a melatonin receptor agonist having a binding affinity for MT1 that is higher than the binding affinity of melatonin for MT1 is preferred as part of the treatment of a subject. In some embodiments, a melatonin receptor agonist having a binding affinity for MT2 that is higher than the binding affinity of melatonin for MT2 is preferred as part of the treatment of a subject. In some embodiments, a melatonin receptor agonist having a binding affinity for MT1 that is lower than the binding affinity of melatonin for MT1 is preferred as part of the treatment of a subject. In some embodiments, a melatonin receptor agonist having a binding affinity for MT2 that is lower than the binding affinity of melatonin for MT2 is preferred as part of the treatment of a subject. In some embodiments, a melatonin receptor agonist having a binding affinity for MT1 that is the same as the binding affinity of melatonin for MT1 and a binding affinity for MT2 that is higher or lower than the binding affinity of melatonin for MT2 is preferred as part of the treatment of a subject. In some embodiments, a melatonin receptor agonist having a binding affinity for MT2 that is the same as the binding affinity of melatonin for MT2 and a binding affinity for MT1 that is higher or lower than the binding affinity of melatonin for MT1 is preferred as part of the treatment of a subject. In some embodiments, the MT1 binding affinity of Circadin® or Slenyto® is at least 20% higher than the MT1 binding affinity of melatonin, and the MT2 binding affinity is at least 70% lower than the MT2 binding affinity of melatonin.In some embodiments, the MT1 binding affinity of ramelteon is at least 600% higher than the MT1 binding affinity of melatonin, and the MT2 binding affinity is the same as the MT2 binding affinity of melatonin. In some embodiments, the MT1 binding affinity of tasimelteon is at least 50% lower than the MT1 binding affinity of melatonin, and the MT2 binding affinity is at least 25% higher than the MT2 binding affinity of melatonin. In some embodiments, the MT1 binding affinity of agomelatine is at least 90% higher than the MT1 binding affinity of melatonin, and the MT2 binding affinity is the same as the MT2 binding affinity of melatonin. In some embodiments, the MT1 binding affinity of TIK-301 is at least 100% higher than the MT1 binding affinity of melatonin, and the MT2 binding affinity is at least 200% higher than the MT2 binding affinity of melatonin. In some embodiments, the MT1 binding affinity of pyrotmelatine is at least 400% higher than the MT1 binding affinity of melatonin, and the MT2 binding affinity is at least 250% higher than the MT2 binding affinity of melatonin. In some embodiments, the MT1 and MT2 binding affinities of ramelteon or agomelatine are the same as the MT1 and MT2 binding affinities of melatonin.

[0032] Melatonin receptor agonist In some aspects described herein, the pharmaceutical composition comprises a melatonin receptor agonist. In some examples, the melatonin receptor agonist comprises melatonin, Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, any of them, or a salt or derivative thereof, or a combination thereof. In some examples, the melatonin receptor agonist is melatonin. In some examples, the melatonin receptor agonist is Circadin®. In some examples, the melatonin receptor agonist is Slenyto®. In some examples, the melatonin receptor agonist is tasimelteon. In some examples, the melatonin receptor agonist is agomelatine. In some examples, the melatonin receptor agonist is β-methyl-6-chloromelatonin (TIK-301). In some embodiments, the melatonin receptor agonist is pyromelatine. In some examples, the melatonin receptor agonist is N-(2-(5-chloro-2,6-dimethoxy-1H-benzo[d]imidazol-1-yl)ethyl)acetamide (ACH000-143 (Compound 10b)). In some examples, the melatonin receptor agonist is N-(3-(5-chloro-2-ethoxy-6-methoxy-1H-benzo[d]imidazol-1-yl)propyl)acetamide (Compound 15a). In some examples, the melatonin receptor agonist is N-2-(2-methoxy-7,8-dihydro-1H-benzofuro[4,5-d]imidazol-1-yl)ethyl)acetamide (Compound 19a). In some examples, the melatonin receptor agonist is N-[2-(2-ethoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19b). In some examples, the melatonin receptor agonist is N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide. In some examples, the melatonin receptor agonist is N-[3-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)propyl]acetamide (Compound 15b).In some examples, the melatonin receptor agonist is N-[2-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]acetamide (Compound 10a). In some examples, the melatonin receptor agonist is 2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethylamine (Compound 9). In some examples, the melatonin receptor agonist is N-[2-(2-amino-5-methoxyphenylamino)ethyl]acetamide (Compound 5a). In some examples, the melatonin receptor agonist is N-[2-(6-methoxy-2-methylsulfanylbenzimidazol-1-yl)ethyl]acetamide (Compound 7). In some examples, the melatonin receptor agonist is N-[2-(6-methoxy-2-oxo-2,3-dihydrobenzimidazol-1-yl)ethyl]acetamide (Compound 6). In some examples, the melatonin receptor agonist is N-[2-(5-methoxy-2-nitrophenylamino)ethyl]acetamide (Compound 3a). In some examples, the melatonin receptor agonist is N-[2-(6-methoxybenzimidazol-1-yl)ethyl]acetamide (Compound 4). In some examples, the melatonin receptor agonist is N-[2-(2-ethoxy-5-methoxybenzimidazol-1-yl)ethyl]acetamide (Compound 8j). In some examples, the melatonin receptor agonist is N-[3-(2,6-dimethoxybenzimidazol-1-yl)propyl]acetamide (Compound 14b). In some examples, the melatonin receptor agonist is N-[3-(2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 14a). In some examples, the melatonin receptor agonist is 4-oxo-4H-pyran-2-carboxylic acid [2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]amide (Compound 8i). In some examples, the melatonin receptor agonist is cyclohexanecarboxylic acid [2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]amide (Compound 8h).In some examples, the melatonin receptor agonist is cyclopentanecarboxylic acid [2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]amide (Compound 8g). In some examples, the melatonin receptor agonist is cyclobutanecarboxylic acid [2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]amide (Compound 8f). In some examples, the melatonin receptor agonist is cyclopropanecarboxylic acid [2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]amide (Compound 8e). In some examples, the melatonin receptor agonist is N-[2-(2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (Compound 8d). In some examples, the melatonin receptor agonist is N-[2-(2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (Compound 8c). In some examples, the melatonin receptor agonist is N-[2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]propionamide (Compound 8b). In some examples, the melatonin receptor agonist is N-[2-(2-ethoxy-6-methoxybenzimidazol-1-yl)ethyl]acetamide (Compound 8a).

[0033] Topical Delivery of Pharmaceutical Compositions In some embodiments, delivery of the pharmaceutical composition is by oral, transdermal, subcutaneous, intravenous, or topical administration. In some embodiments, the pharmaceutical composition of the melatonin receptor agonist is delivered to the upper reproductive tract. In some embodiments, delivery of the pharmaceutical composition to the upper reproductive tract enables an increase in the local tissue concentration of the melatonin receptor agonist without substantially increasing the plasma concentration of the melatonin receptor agonist. In some embodiments, delivery to the upper reproductive tract includes a local tissue concentration of the melatonin receptor agonist that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, or 10,000% higher than the plasma concentration of the melatonin receptor agonist. In some embodiments, the higher the local tissue concentration of the melatonin receptor agonist, the more the occurrence or spread of an unwanted drug response in the subject's CNS or other organs is avoided. In some embodiments, the higher the local tissue concentration of the melatonin receptor agonist, the more the occurrence or spread of an unwanted drug response in the subject's CNS or other organs is avoided, and a therapeutically effective amount of the melatonin receptor agonist is delivered to the target tissue. In some embodiments, local delivery of the pharmaceutical composition is by a drug delivery device. In some embodiments, local delivery of the pharmaceutical composition is by a vaginal gel, vaginal ring, or intrauterine device. In some embodiments, local delivery includes local injection into an area near the target tissue. In some embodiments, administration of the pharmaceutical composition can include injection or infusion, including arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intravascular, intravenous, subcutaneous, inhalation, transdermal, transmucosal, sublingual, buccal, and local (including epidermal, transdermal, enema, nasal, vaginal) administration.In some exemplary embodiments, the route of administration can be via injection, such as intramuscular, intravenous, subcutaneous, or intraperitoneal injection.

[0034] Solid dosage forms for oral administration can include capsules, tablets, caplets, pills, troches, lozenges, powders, and granules. Capsules can include a core material containing the nutritional protein or nutritional composition and a shell wall encapsulating the core material. In some embodiments, the core material can include at least one of solids, liquids, and emulsions. In some embodiments, the shell wall material can include at least one of soft gelatin, hard gelatin, and polymers. Suitable polymers include cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, and sodium carboxymethylcellulose, acrylic acid polymers and copolymers (such as those sold under the trade name "Eudragit") formed from acrylic acid, methacrylic acid, methyl acrylate, ammoniomethyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer, and shellac (purified lac), but are not limited thereto. In some embodiments, at least one polymer can function as taste-masking agents.

[0035] Tablets, pills, etc. can be compressed, multi-compressed, multi-layered, and / or coated. The coating can be single or multiple. In some embodiments, the coating material can include at least one of saccharides, polysaccharides, and glycoproteins extracted from at least one of plants, fungi, and microorganisms. Non-limiting examples include corn starch, wheat starch, potato starch, tapioca starch, cellulose, hemicellulose, dextran, maltodextrin, cyclodextrin, inulin, pectin, mannan, gum arabic, locust bean gum, mesquite gum, guar gum, karaya gum, ghatti gum, tragacanth gum, funori, carrageenan, agar, alginate, chitosan, or gellan gum. In some embodiments, the coating material can include a protein. In some embodiments, the coating material can include at least one of a fat and / or an oil. In some embodiments, at least one of the fat and / or the oil can be meltable at high temperatures. In some embodiments, at least one of the fat and / or the oil can be hydrogenated or partially hydrogenated. In some embodiments, at least one of the fat and / or the oil can be derived from plants. In some embodiments, at least one of the fat and / or the oil can include at least one of glycerides, free fatty acids, and fatty acid esters. In some embodiments, the coating material can include at least one edible wax. The edible wax can be derived from animals, insects, or plants. Non-limiting examples include beeswax, lanolin, bayberry wax, carnauba wax, and rice bran wax. Tablets and pills can further be prepared using enteric coatings.

[0036] Examples of liquid formulations include syrups (e.g., oral formulations), intravenous formulations, intranasal formulations, intraocular formulations (e.g., for treating eye infections), otic formulations (e.g., ear infections), ointments, creams, aerosols, and the like. In some examples, combinations of various formulations can be administered. In some embodiments, tablets, pills, etc. can be formulated for an extended release profile.

[0037] In some examples, a melatonin receptor agonist can be administered in a composition when administered topically. When administered topically, the melatonin receptor agonist may be formulated as is known in the art for direct application to the target area. Forms mainly adjusted for topical application can be, for example, creams, milks, gels, powders, dispersions or microemulsions, thickened lotions to a certain extent, impregnated pads, ointments or sticks, aerosol formulations (e.g., sprays or foams), hydrogels, soaps, detergents, lotions or soap cakes. Other forms for this purpose include wound dressings, coated dressings or other polymer coatings, ointments, creams, lotions, pastes, jellies, sprays, and aerosols. Thus, the pharmaceutical compositions disclosed herein can be delivered via a patch or dressing for skin administration. Alternatively, the pharmaceutical compositions disclosed herein can be formulated to be part of an adhesive polymer such as a polyacrylate or acrylate / vinyl acetate copolymer. For long-term application, it may be desirable to use a microporous and / or breathable backing laminate to minimize skin hydration or maceration. The backing layer can be of any suitable thickness to provide the desired protective and supportive functions. Topical administration can also be in the form of a nail coating solution or lacquer.

[0038] Droplets, such as eye drops or nasal drops, can be formulated with one or more melatonin receptor agonists in an aqueous or non-aqueous base, which further contains one or more dispersants, solubilizers, or suspending agents. The liquid spray can be pumped or conveniently delivered from a pressurized pack. The droplets can be delivered via a plastic bottle adapted to deliver the liquid content by dropping through a simple eyedropper cap, or via a special-shaped closure.

[0039] Ointments and creams can be formulated using, for example, an aqueous or oily base to which appropriate thickening agents and / or gelling agents are added. Lotions can be formulated using an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents, or colorants.

[0040] The weight percentage of the melatonin receptor agonist in the composition can depend on various factors. In some examples, the melatonin receptor agonist can be from about 0.01 wt% to about 95 wt%, from about 0.01 wt% to about 90 wt%, from about 0.01 wt% to about 85 wt%, from about 0.01 wt% to about 80 wt%, from about 0.01 wt% to about 75 wt%, from about 0.01 wt% to about 70 wt%, from about 0.01 wt% to about 65 wt%, from about 0.01 wt% to about 60 wt%, from about 0.01 wt% to about 55 wt%, from about 0.01 wt% to about 50 wt%, from about 0.01 wt% to about 45 wt%, from about 0.01 wt% to about 40 wt%, from about 0.01 wt% to about 35 wt%, from about 0.01 wt% to about 30 wt%, from about 0.01 wt% to about 25 wt%, from about 0.01 wt% to about 20 wt%, from about 0.01 wt% to about 15 wt%, from about 0.01 wt% to about 10 wt%, from about 0.01 wt% to about 9 wt%, from about 0.01 wt% to about 8 wt%, from about 0.01 wt% to about 7 wt%, from about 0.01 wt% to about 6 wt%, from about 0.01 wt% to about 5 wt%, from about 0.01 wt% to about 4 wt%, from about 0.01 wt% to about 3 wt%, from about 0.01 wt% to about 2 wt%, from about 0.01 wt% to about 1 wt%, from about 0.01 wt% to about 0.9 wt%, from about 0.01 wt% to about 0.8 wt%, from about 0.01 wt% to about 0.7 wt%, from about 0.01 wt% to about 0.6 wt%, from about 0.01 wt% to about 0.5 wt%, from about 0.01 wt% to about 0.4 wt%, from about 0.01 wt% to about 0.3 wt%, from about 0.01 wt% to about 0.2 wt%, or from about 0.01 wt% to about 0.1 wt% based on the total weight of the composition.

[0041] In some embodiments, the pharmaceutical formulation can be in unit dose form. In some examples, the pharmaceutical formula can be lyophilized. In some exemplary embodiments, the pharmaceutical formulation is stored in a sealed container at a relative humidity of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% and a temperature of about 2°C to about 30°C, about 2°C to about 29°C, about 2°C to about 28°C, about 2°C to about 27°C, about 2°C to about 26°C, about 2°C to about 25°C, about 2°C to about 24°C, about 2°C to about 23°C, about 2°C to about 22°C, about 2°C to about 21°C, about 2°C to about 20°C, about 2°C to about 19°C, about 2°C to about 18°C, about 2°C to about 17°C, about 2°C to about 16°C, about 2°C to about 15°C, about 2°C to about 14°C, about 2°C to about 13°C, about 2°C to about 12°C, about 2°C to about 11°C, about 2°C to about 10°C, about 2°C to about 9°C, about 2°C to about 8°C, about 2°C to about 7°C, about 2°C to about 6°C, about 2°C to about 5°C, about 2°C to about 4°C, or about 2°C to about 3°C, and can be stable for at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years. Stability can be determined by determining the amount of melatonin receptor agonist remaining after a period of time. Optionally, at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% remains after the period. In some examples, the amount of melatonin receptor agonist, salt, or metabolite remaining can be determined by (a) loading a sample of the melatonin receptor agonist or its salt onto an HPLC equipped with a size exclusion column having a length of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31, 32, 33, 34, 35, or 36 inches and capable of containing silica gel, and (b) performing mass spectrometry on at least one sample eluted from the size exclusion column.Optionally, the amount of remaining melatonin receptor agonist, salt, or metabolite can be determined by performing an area under the curve (AUC) analysis of an HPLC chromatogram. Optionally, the amount of remaining melatonin receptor agonist, salt, or metabolite can be determined by performing an area under the curve (AUC) analysis of a mass spectrum.

[0042] Systemic delivery of pharmaceutical compositions In some embodiments, pharmaceutical composition delivery is effected by systemic delivery. In some embodiments, systemic delivery includes oral, transdermal, subcutaneous, intravenous, or topical administration. In some embodiments, the pharmaceutical composition has a reduced ability to accumulate in the CNS. In some embodiments, the reduced accumulation in the CNS as compared to the periphery is caused by limited diffusion across the BBB, and / or limited active transport across the BBB, and / or efflux via an ABCB protein, or other BBB efflux transporter. In some embodiments, the reduced accumulation in the CNS as compared to the periphery is caused by increased metabolism or excretion of the melatonin receptor agonist in the CNS. In some embodiments, the reduced accumulation in the CNS as compared to the periphery is caused by binding to proteins that decrease the free concentration of the compound. In some embodiments, the pharmaceutical composition has a reduced ability to affect CNS tissue. In some embodiments, the reduced accumulation of the melatonin receptor agonist in the CNS is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, or 10,000% lower than the ability of melatonin to accumulate in the CNS. In some embodiments, the reduced accumulation of the melatonin receptor agonist in the CNS after systemic administration appears as a lower concentration in the CNS and / or a shorter half-life in the CNS as compared to the periphery. In some embodiments, after systemic administration, the reduced accumulation of the melatonin receptor agonist in the CNS appears as a lower concentration of the melatonin receptor agonist in the CNS as compared to the CNS concentration after systemic administration of an equal amount of melatonin.

[0043] In some embodiments, a decrease in the ability of a melatonin receptor agonist to accumulate in the CNS avoids the occurrence or spread of an unwanted drug response in the subject's CNS. In some embodiments, a decrease in the ability of a melatonin receptor agonist to accumulate in the CNS avoids the occurrence or spread of an unwanted drug response in the subject's CNS and a therapeutically effective amount of the melatonin receptor agonist is delivered to the target tissue. In some embodiments, the formulation characteristics of the pharmaceutical composition result in a decrease in the ability of the melatonin receptor agonist to accumulate in the CNS. In some embodiments, a modification to the melatonin receptor agonist results in a decrease in the ability of the melatonin receptor agonist to accumulate in the CNS. In some embodiments, the pharmaceutical composition comprises a melatonin receptor agonist conjugate. In some embodiments, the conjugate comprises a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule that inhibits or reduces the ability of the conjugate or the melatonin receptor agonist to cross the blood-brain barrier. In some embodiments, the decrease in the ability of the melatonin receptor agonist to accumulate in the CNS is due to a reduced diffusion of the pharmaceutical composition across the BBB compared to an equal amount of melatonin. In some embodiments, the decrease in the ability of the melatonin receptor agonist to accumulate in the CNS is due to a reduced active transport of the pharmaceutical composition across the BBB compared to an equal amount of melatonin. In some embodiments, the decrease in active transport is via carrier- or receptor-mediated influx. In some embodiments, a decrease in the ability of the melatonin receptor agonist to accumulate in the CNS results in a higher degree of efflux of the melatonin receptor agonist via the BBB efflux transporter compared to the efflux of an equal amount of melatonin via the BBB efflux transporter.

[0044] In some embodiments, when comparing the dosage of a melatonin receptor agonist with an equivalent amount of melatonin, the comparison is made by comparing the dosages of the melatonin receptor agonist and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of Circadin® and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of Slenyto® and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of ramelteon and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of tasimelteon and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of agomelatine and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of TIK-301 and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of pyomelatine and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the dosages of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively.In some embodiments, when comparing the dose of a melatonin receptor agonist to an equivalent amount of melatonin, the comparison is made by comparing the doses of the melatonin receptor agonist and melatonin, each at approximately the same weight percentage, in an equivalent sample. In some embodiments, the equivalent sample contains the same components except for the presence of melatonin or the melatonin receptor agonist.

[0045] In some embodiments, the unique characteristics of a melatonin receptor agonist can induce more or less association with known melatonin receptor interacting proteins. For example, the unique characteristics can include changes associated with the recognized signaling pathway of the melatonin receptor through an inhibitory G protein-coupling interaction that functions to decrease cyclic adenosine monophosphate concentration. In some embodiments, the unique characteristics of a melatonin receptor agonist can induce more or less association with MT1, MT2, Mel1c, CAND2, VDR, QR2, MMP9, pepsin, PP2A, PEPT1, PEPT2, GLUT1, Hyp-1, LLPR-10.2B, mtPTP, serum albumin, CaM, calreticulin, or any combination thereof.

[0046] Pharmacokinetic profile Various melatonin receptor agonists with different pharmacokinetic properties are contemplated herein. In some embodiments, the melatonin receptor agonist has a binding affinity for the receptor as measured in vitro. In some embodiments, the receptor is MT1, MT2, 5-HT 2B , or 5-HT 2C . In some examples, the binding affinity of a melatonin receptor agonist for a particular receptor is measured and represented as an inhibition constant (K i ) value. In some embodiments, the K i value represents the binding affinity of the melatonin receptor agonist for the specific receptor in vivo. Tables 1 and 2 show MT1, MT2, 5-HT 2B , or 5-HT 2CEnumerate the calculated K i values for melatonin receptor agonists.

[0047] In some embodiments, the pharmaceutical compositions described herein have a desirable pharmacokinetic (PK) profile in a subject when administered to the subject. In some embodiments, the PK profile includes a lower level of melatonin receptor agonist bioavailability in the CNS than in peripheral non-CNS tissues. In some embodiments, the PK profile includes a higher level of melatonin receptor agonist bioavailability near target cells outside the CNS. In some embodiments, the PK profile includes a lower level of melatonin receptor agonist bioavailability in the CNS than near target cells outside the CNS. In some embodiments, the PK profile includes a level of melatonin receptor agonist bioavailability near target cells outside the CNS sufficient to provide a therapeutically effective treatment and a level of melatonin receptor agonist bioavailability in the CNS that does not induce an undesirable drug response in the CNS. In some embodiments, the target cells outside the CNS include cells involved in endocrine function, cells involved in reproductive function, cells involved in metabolic function, or cells involved in immune function. In some embodiments, the target cells outside the CNS include cells of the upper reproductive tract. In some embodiments, the cells of the upper reproductive tract include ovarian cells, egg cells, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, or cervical cells. In some embodiments, the cells involved in reproductive function include ovarian cells, egg cells, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, or cervical cells. In some embodiments, the target cells outside the CNS involved in endocrine function include cells of the adrenal gland, pancreatic cells, thyroid cells, parathyroid cells, or ovarian cells. In some embodiments, the target cells outside the CNS involved in metabolic function include skeletal muscle cells, hepatocytes, pancreatic cells, or adipose tissue cells. In some embodiments, the target cells outside the CNS involved in immune function include lymphocytes, neutrophils, monocytes, or macrophages. In some embodiments, the target cells outside the CNS involved in immune function include precursors of lymphocytes, neutrophils, monocytes, or macrophages. In some embodiments, the lymphocytes include T cells, B cells, or NK cells.

[0048] This specification describes, in certain embodiments, a pharmaceutical composition comprising a PK profile in a subject that delivers an effective amount of a melatonin receptor agonist molecule to target cells outside the CNS. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition induces drowsiness in the subject. In some embodiments, the PK profile indicates that the melatonin receptor agonist in the CNS does not accumulate to the extent that the pharmaceutical composition induces drowsiness in the subject. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition induces sleep. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition disrupts the subject's natural circadian rhythms. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition interferes with the function of the HPG axis. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition produces harmful neurological effects. In some embodiments, the harmful neurological effects may be a change in addiction in the subject. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition produces harmful behavioral effects. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the plasma to induce CNS effects. In some embodiments, the PK profile does not increase the level of bioavailability of the melatonin receptor agonist in the CNS to the extent that the pharmaceutical composition interferes with sleep behavior, circadian rhythm, cognitive function, processing of sensory information, motor control, memory extinction, or other neuronal functions of the CNS.In some embodiments, the PK profile of the pharmaceutical composition maintains the level of the melatonin receptor agonist in the plasma of the subject at less than about 20, 19.5, 19, 18.5, 18, 17.5, 17, 16.5, 16, 15.5, 15, 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11, 10.5, 10, 9.8, 9.6, 9.4, 9.2, 9.0, 8.8, 8.6, 8.4, 8.2, 8.0, 7.8, 7.6, 7.4, 7.2, 7.0, 6.8, 6.6, 6.4, 6.2, 6.0, 5.8, 5.6, 5.4, 5.2, 5,0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.30, 0.25, 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.005, 0.001, 0.0005, or 0.0001 pg / mL.

[0049] In some aspects, the melatonin receptor agonist has a half-life (t 1 / 2 ) that is longer than the half-life of melatonin. In some embodiments, the t 1 / 2 of the melatonin receptor agonist is the t 1 / 2At least 2.5%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, <80%, 90%, 100%, 125%, 150%, 200%, 300%, 400%, 500%, 600%, 800%, 1000%, 1250%, 1500%, 2000%, 3000%, 5000%, 10000%, 50000%, or 100000% greater than. In some embodiments, the t of Circadin®, Slenyto®, ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a) 1 / 2 is greater than the t of melatonin 1 / 2 . In some embodiments, the plasma t of the melatonin receptor agonist 1 / 2 is the t of the CNS 1 / 2Greater. Described herein are pharmaceutical compositions that, in certain embodiments, include a PK profile in a subject that delivers an effective amount of a melatonin receptor agonist to target cells outside the CNS. In some embodiments, the PK profile includes a more continuous bioavailability of the melatonin receptor agonist outside the CNS over 24 hours as compared to the natural diurnal pattern of melatonin plasma concentration in the subject. In some embodiments, the area under the curve (AUC) calculation for the combination of the melatonin receptor agonist delivered outside the CNS and native-produced melatonin includes a value greater than the AUC calculation for native-produced melatonin alone in the subject. In some embodiments, the AUC calculation for the melatonin receptor agonist delivered outside the CNS is measured over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 28, 30, 32, 34, 36, 40, 48, 56, 64, 72, 84, 96, 108, or 120 hours. In some embodiments, the AUC calculation for the melatonin receptor agonist delivered outside the CNS is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 22%, 24%, 26%, 28%, 30%, 32%, 34%, 36%, 38%, 40%, 43%, 46%, 49%, 52%, 55%, 58%, 61%, 64%, 67%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% of the calculated AUC value of native-produced melatonin in the subject. In some embodiments, the PK profile of the melatonin receptor agonist includes a delayed release, sustained release, or extended release profile. In some embodiments, the melatonin receptor agonist is released from its formulation at a first-order rate. In some embodiments, the melatonin receptor agonist is released from its formulation at a zero-order rate.

[0050] This specification describes, in certain aspects, a pharmaceutical composition comprising a melatonin receptor agonist and a PK profile in a subject for delivery to target cells outside the CNS. In some embodiments, the PK profile enables the melatonin receptor agonist to non-selectively activate MTNR1A and MTNR1B in multiple target cells outside the CNS. In some embodiments, the multiple target cells outside the CNS include endocrine cells, germ cells, metabolic cells, or immune cells, or any combination thereof. In some embodiments, the endocrine cells or germ cells are ovarian cells. In some embodiments, the PK profile enables the melatonin receptor agonist to preferentially activate the type 1A (MT1) melatonin receptor. The MT1 receptor is produced from the translation of the MTNR1A transcript. In some embodiments, the PK profile enables the melatonin receptor agonist to preferentially activate the type 1B (MT2) melatonin receptor. The MT2 receptor is produced from the translation of the MTNR1B transcript.

[0051] This specification describes, in certain embodiments, pharmaceutical compositions comprising a melatonin receptor agonist and having a PK profile in a subject for delivery to a target tissue outside the CNS. In some embodiments, the pharmaceutical composition has a reduced ability to penetrate the BBB. In some embodiments, the pharmaceutical composition has a reduced ability to be actively transported across the BBB. In some embodiments, the pharmaceutical composition has the ability to be released via a BBB efflux transporter (e.g., an ABCB protein). In some embodiments, the pharmaceutical composition is released via a BBB efflux transporter to a greater extent than an equivalent amount of systemic melatonin. In some embodiments, the pharmaceutical composition has increased metabolism and / or excretion of the compound in the CNS. In some embodiments, the pharmaceutical composition has the ability to bind to proteins in the CNS that decrease the free concentration of the compound. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition accumulates in the CNS of the subject. In some embodiments, about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist accumulates in the CNS of the subject. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition diffuses across the BBB.In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist diffuses through the BBB. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition is actively transported through the BBB. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist is actively transported through the BBB. In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition is released via a BBB efflux transporter (e.g., an ABCB protein).In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist is released via the BBB efflux transporter (e.g., ABCB protein). In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition is metabolized in the CNS. In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist is metabolized in the CNS. In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the pharmaceutical composition is bound by a protein in the CNS that reduces the free concentration of the melatonin receptor agonist.In some embodiments, more than about 80%, 75%, 70%, 65%, 60%, 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist is bound by a protein in the CNS, which reduces the free concentration of the melatonin receptor agonist.

[0052] Optionally, the melatonin receptor agonist, its salt, or the pharmaceutical composition containing the melatonin receptor agonist or its salt described herein may be administered in a dose of about 0.1 to about 1000 mg, about 1 mg to about 1000 mg, about 5 mg to about 1000 mg, about 10 mg to about 1000 mg, about 15 mg to about 1000 mg, about 20 mg to about 1000 mg, about 25 mg to about 1000 mg, about 30 mg to about 1000 mg, about 35 mg to about 1000 mg, about 40 mg to about 1000 mg, about 45 mg to about 1000 mg, about 50 mg to about 1000 mg, about 55 mg to about 1000 mg, about 60 mg to about 1000 mg, about 65 mg to about 1000 mg, about 70 mg to about 1000 mg, about 75 mg to about 1000 mg, about 80 mg to about 1000 mg, about 85 mg to about 1000 mg, about 90 mg to about 1000 mg, about 95 mg to about 1000 mg, about 100 mg to about 1000 mg, about 150 mg to about 1000 mg, about 200 mg to about 1000 mg, about 250 mg to about 1000 mg, about 300 mg to about 1000 mg, about 350 mg to about 1000 mg, about 400 mg to about 1000 mg, about 450 mg to about 1000 mg, about 500 mg to about 1000 mg, about 550 mg to about 1000 mg, about 600 mg to about 1000 mg, about 650 mg to about 1000 mg, about 700 mg to about 1000 mg, about 750 mg to about 1000 mg, about 800 mg to about 1000 mg, about 850 mg to about 1000 mg, about 900 mg to about 1000 mg, or about 950 mg to about 1000 mg.

[0053] In some cases, the melatonin receptor agonist, its salt, or the pharmaceutical composition containing the melatonin receptor agonist or its salt described in this specification may be administered at a dose of about 0.1 to about 60 mg, about 0.5 mg to about 60 mg, about 1 mg to about 60 mg, about 2 mg to about 60 mg, about 3 mg to about 60 mg, about 4 mg to about 60 mg, about 5 mg to about 60 mg, about 8 mg to about 60 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 25 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg.

[0054] In some cases, the melatonin receptor agonist, its salt, or the pharmaceutical composition containing the melatonin receptor agonist or its salt described in this specification is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 184, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640,It can be administered at a dose of 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 mg.

[0055]

Table 1-1

[0056]

Table 1-2

[0057]

Table 1-3

[0058]

Table 2

[0059] Pharmacodynamic profile In some embodiments, the pharmaceutical composition has a desired pharmacodynamic (PD) profile in a subject. In some embodiments, the pharmaceutical composition comprises a PD profile in a subject that delivers an effective amount of a melatonin receptor agonist to target cells outside the CNS. In some embodiments, the target cells outside the CNS include cells of the endocrine, reproductive, metabolic, or immune systems, or any combination thereof. In some embodiments, the target cells include ovarian cells. In some embodiments, the melatonin receptor agonist functions as a direct antioxidant. In some embodiments, the melatonin receptor agonist directly oxidizes reactive oxygen species (ROS) within the target cells, reactive nitrogen species (RNS) within the target cells, or a combination thereof. In some embodiments, the melatonin receptor agonist directly oxidizes extracellular ROS to the target cells, extracellular RNS to the target cells, or a combination thereof. In some embodiments, the melatonin receptor agonist directly oxidizes intracellular ROS within the target cells, intracellular RNS, or a combination thereof. In some embodiments, the melatonin receptor agonist directly oxidizes ROS, RNS, or a combination thereof within the target cell mitochondria. In some embodiments, the melatonin receptor agonist functions to locally upregulate melatonin receptor signaling. In some embodiments, the local upregulation of melatonin receptor signaling occurs in target cells including ovarian cells, oocytes, granulosa cells, theca cells, ovarian stromal cells, ovarian epithelial cells, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, cervical cells, adrenal cells, pancreatic cells, thyroid cells, parathyroid cells, skeletal muscle cells, hepatocytes, white adipose tissue cells, brown adipose tissue cells, osteoblasts, osteoclasts, endothelial cells, hair follicle cells, lymphocytes, neutrophils, monocytes, or macrophages, or progenitor cells of any of the above cell types. In some embodiments, the local upregulation of melatonin receptor signaling increases the expression of multiple cellular antioxidants.In some embodiments, the plurality of cellular antioxidants includes superoxide dismutase, glutathione reductase, glutathione peroxidase, or catalase, or any combination thereof. In some embodiments, the plurality of cellular antioxidants includes the genes SOD1, SOD2, GSR, GPX1, GPX2, GPX3, GPX4, GPX5, GPX6, GPX7, GPX8, or CAT. In some embodiments, local upregulation of melatonin receptor signaling increases the activity of the plurality of cellular antioxidants. In some embodiments, the plurality of cellular antioxidants includes superoxide dismutase, glutathione reductase, glutathione peroxidase, or catalase, or any combination thereof. In some embodiments, local upregulation of melatonin receptor signaling results in changes in intracellular cyclic nucleotides in a plurality of target cells. In some embodiments, the intracellular cyclic nucleotides include cAMP, cGMP, inositol 1,4,5-trisphosphate (IP3), or diacylglycerol (DAG), or any combination thereof. In some embodiments, IP3 and DAG function as messengers for the activation of the PI3K / AKT pathway. In some embodiments, local upregulation of melatonin receptor signaling results in changes in cytoplasmic calcium levels in a plurality of target cells. In some embodiments, local upregulation of melatonin receptor signaling results in changes in mitochondrial calcium levels in a plurality of target cells. In some embodiments, local upregulation of melatonin receptor signaling results in the activation of protein kinase C (PKC) subtypes in a plurality of target cells. In some embodiments, the PKC subtypes include conventional, novel, or atypical PKC subtypes. In some embodiments, local upregulation of melatonin receptor signaling results in changes in the intracellular localization of steroid hormone receptors. In some embodiments, local upregulation of melatonin receptor signaling results in changes in the expression of gonadotropin-releasing hormone receptors, luteinizing hormone receptors, and / or follicle-stimulating hormone receptors.In some embodiments, the change in the expression of the hormone receptor includes an increase in the expression level of the mRNA encoding the hormone receptor. In some embodiments, the local upregulation of melatonin receptor signaling results in a change in the secretion of progesterone from granulosa cells. In some embodiments, the change in the secretion of progesterone includes an increase in the secretion of progesterone. In some embodiments, the local upregulation of melatonin receptor signaling results in a change in the secretion of a plurality of endocrine hormones including insulin, glucagon, somatostatin, pancreatic polypeptide, cholecystokinin, secretin, amylin, gastrin, or thyroxine, or any combination thereof. In some embodiments, the local upregulation of melatonin receptor signaling results in the activation of MAPK pathway signaling. In some embodiments, the activated MAPK pathway signaling pathway is the MAPK-JNK / P38 signaling pathway. In some embodiments, the local upregulation of melatonin receptor signaling results in the activation of the G protein signaling pathway in a plurality of target cells. In some embodiments, the local upregulation of melatonin receptor signaling results in the inhibition of adenylate cyclase in a plurality of target cells. In some embodiments, the local upregulation of melatonin receptor signaling results in the activation of phospholipase C in a plurality of target cells. In some embodiments, the local upregulation of melatonin receptor signaling results in a change in lipid metabolism in a plurality of target cells. In some embodiments, the local upregulation of melatonin receptor signaling results in a change in follicular development. In some embodiments, the change in follicular development includes the prevention of granulosa cell apoptosis in a plurality of granulosa cells. In some embodiments, the prevention of granulosa cell apoptosis improves follicular development. In some embodiments, the local upregulation of melatonin receptor signaling results in an improvement in the quality of the oocyte. In some embodiments, the local upregulation of melatonin receptor signaling improves folliculogenesis and / or ovulation.

[0060] Melatonin receptor agonist formulationPharmaceutical compositions are described herein that are formulated to deliver a therapeutically effective amount of a melatonin receptor agonist to tissues of the endocrine, reproductive, metabolic, or immune systems, or any combination thereof. In some embodiments, the melatonin receptor agonist can be formulated as a gel. In some embodiments, the melatonin receptor agonist can be formulated as a cream. In some embodiments, the melatonin receptor agonist can be formulated as an ointment. In some embodiments, the melatonin receptor agonist can be formulated as a solution. In some embodiments, the melatonin receptor agonist can be formulated as a powder. In some embodiments, the melatonin receptor agonist can be formulated as a paste. In some embodiments, the melatonin receptor agonist can be formulated as a foam. In some embodiments, the melatonin receptor agonist can be formulated as an emulsion. In some embodiments, the melatonin receptor agonist can be formulated as a lotion. In some embodiments, the formulation can include polyethylene glycol (PEG). In some embodiments, the melatonin receptor agonist can include PEGylation. In some embodiments, the melatonin receptor agonist can be formulated in a hydrogel. In some embodiments, the melatonin receptor agonist formulation includes liposomes. In some embodiments, the melatonin receptor agonist loaded on liposomes provides an excellent PK profile due to the low solubility of the melatonin receptor agonist in aqueous solution. In some embodiments, the melatonin receptor agonist formulation includes nanoparticles. In some embodiments, the melatonin receptor agonist formulation includes a nanosuspension. In some embodiments, the melatonin receptor agonist formulation includes a nanoemulsion. In some embodiments, the nanoparticles include magnetic nanoparticles, zinc oxide nanoparticles, selenium-coated nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, chitosan-coated nanoparticles, polymeric micelles, cyclodextrin, or dendrimers. In some embodiments, the formulation includes a delayed release, sustained release, extended release, long-term release, or controlled release formulation.In some embodiments, the melatonin receptor agonist is at least partially encapsulated in liposomes, magnetic nanoparticles, zinc oxide nanoparticles, selenium-coated nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, chitosan-coated nanoparticles, polymeric micelles, cyclodextrin, or dendrimers. In some embodiments, the formulation protects the melatonin receptor agonist from premature oxidation. In some embodiments, protection from premature oxidation increases the efficacy of the pharmaceutical composition by retaining more of the direct antioxidant and signaling properties of the non-oxidized melatonin receptor agonist. In some embodiments, the formulation delivers a higher melatonin receptor agonist exposure after local delivery to the reproductive tract. In some embodiments, the formulation contains a melatonin receptor agonist with a slower release than conventional oral formulations. In some embodiments, the formulation contains a melatonin receptor agonist with a slower release than conventional liquid formulations. In some embodiments, the melatonin receptor agonist can be formulated as a matrix. In some embodiments, the matrix comprises a bioabsorbable polymer. In some embodiments, the bioabsorbable polymer is poly(lactic-co-glycolic acid) (PLGA). In some embodiments, the bioabsorbable polymer is poly(ethylene glycol) (PEG). In some embodiments, the bioabsorbable polymer is poly(vinyl alcohol) (PVA). In some embodiments, the bioabsorbable polymer is poly(glycolic acid) (PGA). In some embodiments, the bioabsorbable polymer is poly[2-(dimethylamino)ethyl methacrylate] (DMAEM). In some embodiments, the matrix comprises a bioinert polymer. In some embodiments, the bioinert polymer is ethylene vinyl acetate. In some embodiments, the bioinert polymer is cellulose acetate. In some embodiments, the bioinert polymer is low density polyethylene (LDPE). In some embodiments, the matrix is a solid ethylene vinyl acetate polymer matrix. In some embodiments, the matrix is a mixture of starch and a solid ethylene vinyl acetate polymer. In some embodiments, the matrix is a mixture of starch and cellulose acetate.In some embodiments, the matrix is a mixture of starch and LDPE. In some embodiments, the matrix is a mixture of starch and ethylene vinyl alcohol copolymer. In some embodiments, the matrix can release one active ingredient containing a melatonin receptor agonist. In some embodiments, the matrix can release two or more active ingredients containing a melatonin receptor agonist. In some embodiments, the matrix can release two or more active ingredients containing a plurality of melatonin receptor agonists. In some embodiments, the matrix can enable the release of a melatonin receptor agonist without the need for a membrane containing the melatonin receptor agonist. In some embodiments, the matrix can enable the release of a melatonin receptor agonist without the need for a reservoir for containing the melatonin receptor agonist. In some embodiments, the matrix can enable the delayed release of a melatonin receptor agonist. In some embodiments, the matrix can enable the sustained release of a melatonin receptor agonist. In some embodiments, the matrix can enable the extended release of a melatonin receptor agonist. In some embodiments, the matrix can enable the long-term release of a melatonin receptor agonist. In some embodiments, the matrix can enable the controlled release of a melatonin receptor agonist. In some embodiments, the matrix is contained within a drug delivery device and formulated for administration by the drug delivery device. In some embodiments, the matrix is contained within a vaginal ring and formulated for administration by the vaginal ring. In some embodiments, the matrix is contained within a vaginal tablet and formulated for administration by the vaginal tablet. In some embodiments, the matrix is contained within a pessary and formulated for administration by the pessary. In some embodiments, the matrix is contained within a suppository and formulated for administration by the suppository. In some embodiments, the matrix is contained within a patch and formulated for administration by the patch. In some embodiments, the matrix is contained within an intrauterine device and formulated for administration by the intrauterine device.

[0061] This specification describes a pharmaceutical composition formulated to deliver a therapeutically effective amount of a melatonin receptor agonist to a peripheral target tissue with a reduced ability to accumulate in the CNS. In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., oral delivery, IV administration, subcutaneous administration, etc.). In some embodiments, the formulation includes modifications that reduce lipophilicity. In some embodiments, the reduction in lipophilicity results in a decrease in cellular penetration of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in a decrease in local tissue diffusion of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in a decrease in active transport of the melatonin receptor agonist across the BBB as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in an increase in efflux from the CSF via the BBB efflux transporter of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in an increase in metabolism of the melatonin receptor agonist within the CNS as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in an increase in CNS excretion of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in lipophilicity results in a decrease in permeability of the melatonin receptor agonist across the BBB as compared to an equal amount of melatonin. In some embodiments, the formulation includes modifications that reduce hydrophilicity. In some embodiments, the reduction in hydrophilicity results in a decrease in cellular penetration of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in hydrophilicity results in a decrease in local tissue diffusion of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in hydrophilicity results in a decrease in active transport of the melatonin receptor agonist across the BBB as compared to an equal amount of melatonin. In some embodiments, the reduction in hydrophilicity results in an increase in efflux from the CSF via the BBB efflux transporter of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the reduction in hydrophilicity results in an increase in metabolism of the melatonin receptor agonist within the CNS as compared to an equal amount of melatonin.In some embodiments, the decrease in hydrophilicity results in an increase in the CNS excretion of the melatonin receptor agonist as compared to an equal amount of melatonin. In some embodiments, the decrease in hydrophilicity results in a decrease in the permeability of the melatonin receptor agonist through the BBB as compared to an equal amount of melatonin. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist included in the pharmaceutical composition penetrates the blood-brain barrier of the subject.

[0062] In some embodiments, the comparison is made by comparing the amounts of the melatonin receptor agonist and melatonin in the sample at approximately the same molar concentration, respectively, when comparing the amount of the melatonin receptor agonist to an equivalent amount of melatonin. In some embodiments, the comparison is made by comparing the amounts of Circadin® and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of Slenyto® and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of ramelteon and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of tasimelteon and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of agomelatine and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of TIK-301 and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of pyrotmelatine and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively. In some embodiments, the comparison is made by comparing the amounts of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide and melatonin in the sample at approximately the same molar concentration, respectively.

[0063] In some embodiments, the pharmaceutical composition comprises a melatonin receptor agonist conjugated to another molecule, thereby reducing the CNS accumulation of the melatonin receptor agonist as compared to an equivalent amount of melatonin. In some embodiments, the formulation comprises a modification that reduces the ability of the melatonin receptor agonist-conjugate to cross the blood-brain barrier. In some embodiments, the conjugate comprises a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule. In some embodiments, the formulation comprises a modification that prevents active transport of the agonist across the BBB. In some embodiments, the formulation comprises a modification that increases the efflux of the melatonin receptor agonist outside the CNS. In some embodiments, the formulation comprises a modification that accelerates the metabolism and / or excretion of the melatonin receptor agonist in the CNS. In some embodiments, the formulation comprises a modification that increases the binding of the melatonin receptor agonist to multiple proteins, thereby reducing its free concentration in the CNS. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS allows for a wider therapeutic dose range of the target cells in peripheral tissues. In some embodiments, the wider therapeutic dose range of the target cells in peripheral tissues does not substantially affect or impair CNS function. In some embodiments, the wider therapeutic dose range of the target cells in peripheral tissues limits the impact on CNS function. In some embodiments, the wider therapeutic dose range of the target cells in peripheral tissues can reduce potential side effects in the CNS, such as drowsiness and deficits in sleep patterns, circadian rhythms, motor control, cognitive function, or amnesia. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS can allow for higher systemic concentrations of the melatonin receptor agonist while maintaining a favorable safety profile. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS can allow for delivery by intravenous injection. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS can allow for delivery by oral administration. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS can allow for delivery by a drug delivery device such as a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device.

[0064] This specification describes types of administration of a pharmaceutical composition formulated to deliver a therapeutically effective amount of a melatonin receptor agonist to tissues of the endocrine, reproductive, metabolic, vascular, skeletal, integumentary, or immune systems, or any combination thereof. In some embodiments, the pharmaceutical composition is delivered locally near the target tissue. In some embodiments, the target tissue includes cervical tissue, myometrial tissue, or fallopian tube tissue, or any combination thereof. In some embodiments, local delivery includes local injection. In some embodiments, local delivery includes transdermal or subcutaneous delivery. In some embodiments, local delivery includes delivery through a drug delivery device. In some embodiments, local delivery includes delivery by a vaginal ring, vaginal gel, vaginal film, vaginal tablet, pessary, suppository, or patch. In some embodiments, local delivery includes intrauterine or intravaginal delivery. In some embodiments, local delivery results in a higher concentration of the melatonin receptor agonist near the delivery site than at a peripheral location far from the local delivery site. In some embodiments, local delivery includes delivery by a device. In some embodiments, the device includes an intrauterine device. In some embodiments, it is delivery by a device that enables time-controlled release of the pharmaceutical composition. In some embodiments, time-controlled release includes remotely controlled release. In some embodiments, time-controlled release enables release from an implanted chronic device that delivers the pharmaceutical composition at a desired dosing frequency. In some embodiments, the desired dosing frequency is a diurnal frequency. In some embodiments, the desired dosing frequency is a nocturnal frequency. In some embodiments, the composition is administered daily before bedtime. In some embodiments, the desired dosing frequency avoids the sedative effect of the melatonin receptor agonist. In some embodiments, the pharmaceutical composition is delivered to provide continuous exposure of the melatonin receptor agonist to a plurality of target cells. In some embodiments, the desired pattern of continuous or daily exposure to the melatonin receptor agonist for addressing the multiple phenotypes of PCOS can vary between indications.

[0065] In some embodiments, the melatonin receptor agonist delivered by a vaginal gel or drug delivery device (e.g., a vaginal ring or an intrauterine device) can achieve excellent control of PCOS symptoms derived from endocrine, inflammatory, and oxidative stress pathways and avoid the sleep induction effects associated with orally administered melatonin agonists that achieve high concentrations in the CNS.

[0066] In some embodiments, the pharmaceutical compositions described herein are administered to a subject in need thereof according to a treatment regimen. In some embodiments, the treatment regimen comprises a single administration. In some embodiments, the treatment regimen comprises at least one administration. In some embodiments, the treatment regimen comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations. In some embodiments, administration comprises delivery of an effective amount of the melatonin receptor agonist to target cells. In some embodiments, the effective amount included within a single administration is an effective amount for at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 35, 42, 49, 56, 60, 61, 62, or 90 days. In some embodiments, a single administration comprises an effective amount for at least one week, at least two weeks, at least four weeks, at least two months, or at least six months.

[0067] Use of the pharmaceutical composition In some embodiments, the pharmaceutical compositions described herein can be used to modulate a phenotype affected by melatonin in a subject. In some embodiments, the phenotype affected by melatonin is caused by melatonin system dysfunction. In some embodiments, the phenotype affected by melatonin includes symptoms that can be alleviated or treated by an increase in local melatonin concentration or activation of local melatonin receptors. In some embodiments, the phenotype affected by melatonin includes symptoms that can be alleviated or treated by activating the melatonin receptor-mediated signaling pathway. In some embodiments, the phenotype affected by melatonin is susceptible to the effects of age-related changes in melatonin distribution. In some embodiments, the age-related changes in melatonin distribution include a decrease in melatonin production. In some embodiments, the age-related changes in melatonin distribution include low melatonin levels in some peripheral tissues and normal or high plasma concentrations of melatonin. In some embodiments, the age-related changes in melatonin distribution include a decrease in extra-cranial melatonin production. In some embodiments, the age-related changes in melatonin distribution include a decrease in ovarian melatonin production.

[0068] In some embodiments, tissue damage resulting from a disease or other injury results in a phenotype affected by the subject's melatonin. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in a deceleration of disease progression. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in a halt of disease progression. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in an improvement in the manifestation of the disease. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in a alleviation or reduction in the intensity or frequency of symptoms of a disease (e.g., pain, infertility, hyperandrogenism, endocrine unbalance, ovulatory dysfunction, weight gain, insulin insensitivity, glucose intolerance, decreased bone density, hair loss, or hypertension). In some embodiments, the tissue damage occurs after administration of chemotherapy to the subject. In some embodiments, the phenotype caused by the tissue damage includes chemotherapy-induced ovarian dysfunction (CIOD). In some embodiments, the phenotype caused by the tissue damage includes chemotherapy-induced ovarian failure (CIOF). In some embodiments, CIOD or CIOF is induced in the subject by exposure to one or more chemotherapy treatments. In some aspects, CIOD includes impairment of ovarian reproductive function. In some aspects, CIOD includes impairment of ovarian endocrine function. In some aspects, CIOD includes impairment of both ovarian reproductive and endocrine functions. In some aspects, CIOF includes impairment of both ovarian reproductive and endocrine functions. Examples of chemotherapy treatment agents that can induce ovarian tissue damage in a subject include altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, temozolomide, thiotepa, and trabectedin. In some examples, the chemotherapy treatment agent is an alkylating agent.In some examples, the chemotherapeutic agent causes premature ovarian insufficiency by inducing accelerated death and / or activation of primordial follicles and / or increased closure of growing follicles. In some examples, the subject has received one or more chemotherapy treatments including administration of one or more chemotherapeutic agents. In some examples, the subject is undergoing a chemotherapy treatment including administration of one or more chemotherapeutic agents. In some examples, the subject will receive a chemotherapy treatment including administration of one or more chemotherapeutic agents. In some aspects, use of the pharmaceutical composition described herein includes administering to the subject a pharmaceutical composition comprising a melatonin receptor agonist after one or more chemotherapy treatments in the subject. In some aspects, use of the pharmaceutical composition described herein includes administering to the subject a pharmaceutical composition comprising a melatonin receptor agonist concurrently with one or more chemotherapy treatments in the subject. In some aspects, use of the pharmaceutical composition described herein includes administering to the subject a pharmaceutical composition comprising a melatonin receptor agonist prior to one or more chemotherapy treatments in the subject. In some embodiments, use of a pharmaceutical composition comprising a melatonin receptor agonist reduces cyclophosphamide-induced primordial follicle loss. In some embodiments, use of a pharmaceutical composition comprising a melatonin receptor agonist reduces cisplatin-induced primordial follicle loss. In some embodiments, use of a pharmaceutical composition comprising a melatonin receptor agonist reduces doxorubicin-induced primordial follicle loss. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist prevents primordial follicle loss due to CIOD. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist attenuates primordial follicle loss due to CIOD. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist decreases growing follicle closure due to CIOD. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist decreases ovarian mitochondrial damage due to CIOD. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces ovarian apoptosis after administration of cyclophosphamide.In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces ovarian oxidative damage after cyclophosphamide administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist preserves ovarian hormone levels after cyclophosphamide administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist improves follicle morphology after cyclophosphamide administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist preserves granulosa cell proliferation after cyclophosphamide administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist prevents the decline of ovarian reserve capacity after cisplatin administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist maintains the threshold levels of AMH and BMP15 ovarian expression after cisplatin administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist inhibits ovarian inflammation after cisplatin administration. In some embodiments, cisplatin-induced ovarian inflammation is measured by assaying the ovarian expression levels of IL-1β and / or IL-18. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist protects the ovaries of a subject from cisplatin-induced mitochondrial damage after administration of cisplatin to the subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces the levels of reactive oxygen species after cisplatin administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist increases antioxidant enzyme activity after cisplatin administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist inhibits the occurrence of mitochondrial oxidative stress after cisplatin administration. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist inhibits cisplatin-induced ovarian apoptosis. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces the degree of decrease in serum estradiol (E2) and AMH after administration of cisplatin to a subject.In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces the degree of increase in serum LH and FSH after administration of cisplatin to a subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces damage to follicles and corpora lutea after administration of cisplatin to a subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces inflammatory infiltration in the ovary after administration of cisplatin to a subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces the degree of increased ovarian collagen deposition after administration of cisplatin to a subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist prevents ovarian fibrosis after administration of cisplatin to a subject. In some embodiments, pretreatment with a pharmaceutical composition comprising a melatonin receptor agonist reduces apoptosis in granulosa cells, theca cells, stroma, and oocytes after administration of cisplatin to a subject.

[0069] In some embodiments, the phenotypes affected by melatonin in a subject include disorders in endocrine cells, germ cells, metabolic cells, vascular cells, skeletal cells, epithelial cells or immune cells, or any combination thereof. In some embodiments, the phenotypes affected by melatonin in a subject respond to treatment comprising administration of a melatonin receptor agonist. In some embodiments, the phenotypes of a subject that respond to melatonin receptor agonist therapy include ovarian phenotypes, endometrial phenotypes, inflammatory phenotypes, metabolic phenotypes, vascular phenotypes, skeletal phenotypes, epithelial phenotypes or liver phenotypes. In some embodiments, the ovarian phenotype includes abnormal or decreased folliculogenesis, altered ovarian progesterone production, altered luteal phase production of progesterone, or poor oocyte maturation. In some embodiments, the endometrial phenotype includes endometriosis, endometriosis-related ovarian oxidative stress, or adenomyosis. In some embodiments, the vascular phenotype includes abnormal blood pressure or hypertension. In some embodiments, the skeletal phenotype includes decreased bone density. In some embodiments, the epithelial phenotype includes hair loss. In some embodiments, the inflammatory phenotype includes low-grade systemic inflammation, local idiopathic inflammation, stomatitis, abnormal immune response, autoimmune damage, or embryonic developmental defects. In some embodiments, the metabolic phenotype includes increased insulin resistance, dysregulation of glucose homeostasis, excessive weight or excessive BMI, or increased oxidative stress.

[0070] In some embodiments, phenotypes of a subject that respond to a melatonin receptor agonist therapy include an indication of a particular disease or a disease aspect or symptom. In some embodiments, particular disease indications or disease aspects that respond to a melatonin receptor agonist therapy include ovulatory dysfunction, luteal phase defect, PCOS, anovulatory PCOS, insulin resistance in PCOS, glucose resistance in PCOS, risk of non-alcoholic fatty liver disease (NAFLD) in PCOS patients, weight control in PCOS, uterine inflammatory disease, inflammation in PCOS, hyperandrogenism, hirsutism, decreased uterine receptivity, ART outcomes, preeclampsia, endometriosis, endometriosis-related infertility, and endometriosis-related chronic pelvic pain (EACPP), menopause-related decrease in bone density, menopause-related hypertension, menopause-related hair loss, menopause-related weight gain, menopause-related impairment of glucose homeostasis. In some embodiments, particular disease indications or disease aspects that respond to a melatonin receptor agonist therapy include chemotherapy-induced ovarian dysfunction (CIOD).

[0071] In some embodiments, the use of the pharmaceutical compositions described herein can result in an improvement in ART outcomes. In some embodiments, the improvement in ART outcomes includes favorable embryo implantation and pregnancy continuation, higher egg quality, higher embryo quality, uterine quiescence with well-angiogenized uterus, placenta and developing embryo being able to sufficiently deliver blood at normal blood pressure, or improvement in ovarian health. In some embodiments, the improvement in ovarian health is measured by ovarian follicular reserve, follicle growth and maturation, and the frequency of regular ovulation, oocyte quality and survival rate. In some embodiments, the use of the pharmaceutical compositions described herein can enable women who are taking a melatonin receptor agonist for the treatment of PCOS, endometriosis, amenorrhea, inflammation of the reproductive tract, or symptoms of CIOD to become pregnant during treatment. Other treatment methods using oral contraceptives, clomiphene, or GnRH analog treatment in PCOS, endometriosis, amenorrhea, inflammation of the reproductive tract, or CIOD may not enable women to become pregnant during treatment. In some embodiments, the use of the pharmaceutical compositions described herein can enable women to maintain regular ovarian and menstrual cycles in long-term treatment cycles of one or two years. In some embodiments, the use of the pharmaceutical compositions described herein can result in an improvement in glucose utilization, which in turn can benefit fertility and conception.

[0072] Figure 2 shows the mode of action of melatonin receptor agonists in PCOS. Figure 2A lists diagrams associating biological systems, cell types, biological processes, and hormones that interact in the PCOS condition and symptoms and are either increased, decreased, or abnormal in PCOS. Figure 2B lists diagrams linking biological systems, cell types, biological processes, hormones that interact in PCOS conditions and symptoms, points of drug target sites, and changes induced by drug treatment in PCOS subjects treated with melatonin receptor agonists. Melatonin receptor agonist treatment can have a positive effect on the maturation and quality of oocytes and embryos. Melatonin receptor agonist treatment can result in more favorable ART outcomes. This favorable ART outcome can be attributed to both an increase in the direct ROS scavenging action of the melatonin receptor agonist in the target tissue and an increase in melatonin receptor signaling mediated by the melatonin receptor agonist in the target tissue. The increase in melatonin receptor signaling can produce anti-inflammatory and antioxidant effects in follicles that affect favorable ART outcomes as well as the maturation and quality of oocytes and embryos. The increased melatonin receptor signaling can have an anti-apoptotic effect on ovarian granulosa cells that affect favorable ART outcomes as well as the maturation and quality of oocytes and embryos. The increase in melatonin receptor signaling can help restore reproductive function through effective steroid production (e.g., regulation of progesterone production or reduction of androgen levels). This regulation of androgen levels indicates that melatonin receptor agonist treatment can improve hyperandrogenism, or hirsutism, or both, in subjects with PCOS. The increase in melatonin receptor signaling can lead to an improvement in glucose tolerance in the treated subjects. The increased melatonin receptor signaling can increase glucose turnover in adipocytes and muscle cells. In some subjects with PCOS, the increased insulin resistance can be effectively treated by increasing melatonin receptor signaling in the target cells.In some subjects with PCOS, an increase in melatonin receptor signaling can result in an increase in insulin secretion from pancreatic beta cells. In some subjects with PCOS, an increase in melatonin receptor signaling can result in improvement of the symptoms of non-alcoholic fatty liver disease (NAFLD). In some subjects with PCOS, an increase in melatonin receptor signaling can protect the subject from the onset of NAFLD. In some embodiments, an increase in melatonin receptor signaling can protect the subject from liver dysfunction. In some embodiments, an increase in melatonin receptor signaling can improve glucose metabolism in the subject.

[0073] Patient Selection and Stratification In some aspects, subjects having a genetic condition that disrupts the melatonin pathway can benefit from a treatment comprising administration of a melatonin receptor agonist. In some embodiments, subjects having a genetic condition that disrupts the melatonin pathway can include a mutation or occurrence of an allele having a minor population frequency in MTNR1A or MTNR1B. In some embodiments, subjects not having a known genetic condition that impairs the melatonin pathway can benefit from a treatment comprising administration of a melatonin receptor agonist.

[0074] Patients with PCOS or patients having a metabolic disease affecting reproduction can benefit from a treatment comprising administration of a melatonin receptor agonist. Clinical studies have demonstrated the beneficial effects of melatonin on hyperandrogenism, inflammation, ART outcomes, and metabolic function in patients with PCOS or patients having a metabolic disorder. Thus, the selection of PCOS patients having these characteristics, or the risk of these characteristics, can be considered in the decision to use a treatment comprising administration of a melatonin receptor agonist.

[0075] Patients with PCOS or patients having a metabolic condition affecting reproduction can benefit from a treatment including administration of a melatonin receptor agonist. Clinical studies have demonstrated beneficial effects of melatonin on hyperandrogenism, inflammation, ART outcomes, and metabolic function in patients with PCOS or patients having a metabolic disorder. Thus, selection of PCOS patients having these characteristics, or at risk for these characteristics, can be considered in the determination of the use of a treatment including administration of a melatonin receptor agonist.

[0076] Patients with endometriosis can benefit from a treatment including administration of a melatonin receptor agonist. Clinical trials have demonstrated beneficial effects of melatonin on pelvic pain in patients with endometriosis. Preclinical studies have demonstrated that melatonin promotes regression of endometriosis lesions in animals. Thus, in some embodiments, selection of endometriosis patients having these characteristics, or at risk for developing these characteristics, can be considered in the determination of the use of a treatment including administration of a melatonin receptor agonist.

[0077] Perimenopausal and postmenopausal women can benefit from a treatment including administration of a melatonin receptor agonist. In some embodiments, there are beneficial effects of melatonin on symptoms associated with menopause such as decreased bone density, weight gain, blood pressure regulation, hair loss, and inflammation. Thus, in some embodiments, selection of perimenopausal and postmenopausal women having these characteristics or at risk for developing these characteristics can be considered in the determination of the use of a treatment including administration of a melatonin receptor agonist.

[0078] Women who are about to receive, are currently receiving, or have previously received chemotherapy treatment can benefit from treatments that include the administration of a melatonin receptor agonist. In some embodiments, there are beneficial effects of melatonin on CIOD symptoms such as hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, stromal tissue damage, ovarian vascular damage, ovarian inflammation, decreased ovarian reserve, increased age-dependent loss rate of ovarian reserve, induction of fibrosis, early menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decreased estrogen production, decreased anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) levels, decreased plasma levels of estradiol, or any combination thereof. Thus, in some embodiments, the selection of women who are about to receive, are currently receiving, or have previously received chemotherapy treatment that have these characteristics, or a risk of developing these characteristics, may be considered in the determination of the use of treatments that include the administration of a melatonin receptor agonist.

[0079] Method of using a pharmaceutical composition of a melatonin receptor agonist This specification describes methods of using pharmaceutical compositions formulated for delivering a melatonin receptor agonist to tissues of the endocrine, reproductive, metabolic, or immune systems, or any combination thereof. In some embodiments, the method includes local delivery of the pharmaceutical composition to cells and tissues to which the pharmaceutical composition described herein is administered. In some embodiments, the method includes systemic delivery of the pharmaceutical composition described herein to a subject in which the CNS accumulation of the melatonin receptor agonist is reduced compared to the CNS accumulation of an equivalent amount of melatonin delivered systemically. In some embodiments, the reduction in CNS accumulation of the melatonin receptor agonist is due to a decrease in passive diffusion, an increase in active transport, an increase in CSF efflux via the BBB efflux transporter, an increase in CNS metabolism, an increase in CNS excretion, or modulation of protein binding of the melatonin receptor agonist, compared to an equivalent amount of melatonin delivered systemically. In some embodiments, the reduction in CNS accumulation of the melatonin receptor agonist from the pharmaceutical composition described herein results in effective delivery of the melatonin receptor agonist to the target tissue without substantially inducing undesirable functions, metabolism, or signaling in CNS tissue.

[0080] Further examples of uses include coatings containing the melatonin receptor agonist described herein. In some embodiments, coating may include coating an article such as a medical device. Optionally, the medical device may be an implantable medical device.

[0081] Route of Administration This specification describes methods of administering a pharmaceutical composition formulated to deliver a melatonin receptor agonist to tissues of the endocrine, reproductive, metabolic, vascular, skeletal, integumentary, or immune systems. In some embodiments, the method of administration delivers the melatonin receptor agonist to peripheral tissues. In some embodiments, the method includes local delivery to near the target tissue. In some embodiments, the target tissue includes cervical tissue, myometrial tissue, or fallopian tube tissue, or any combination thereof. In some embodiments, local delivery includes local injection. In some embodiments, local delivery includes transdermal delivery or subcutaneous delivery. In some embodiments, local delivery includes delivery through a drug delivery device. In some embodiments, local delivery includes delivery by a vaginal ring, vaginal gel, vaginal film, vaginal tablet, pessary, suppository, or patch. In some embodiments, local delivery includes intrauterine delivery or intravaginal delivery. In some embodiments, local delivery results in a higher concentration of the melatonin receptor agonist near the delivery site than at a peripheral location far from the local delivery site. In some embodiments, local delivery includes delivery by a device. In some embodiments, the device includes an intrauterine device. In some embodiments, it is delivery by a device that allows or enables controlled release of the pharmaceutical composition over time. In some embodiments, timed release includes remotely controlled release. In some embodiments, controlled release over time enables release from an implanted chronic device that delivers the pharmaceutical composition at a desired dosing frequency or for a desired dosing period. In some embodiments, the desired dosing frequency is a daytime frequency. In some embodiments, the desired dosing frequency avoids the sedative effect of the melatonin receptor agonist. In some embodiments, the pharmaceutical composition is delivered to provide continuous exposure of the melatonin receptor agonist to a plurality of target cells. The desired pattern of continuous or daily exposure levels to a melatonin receptor agonist for addressing the multiple phenotypes of PCOS can vary between indications.In some embodiments, the method of administration comprising delivery of the pharmaceutical composition described herein by a vaginal gel or a drug delivery device (vaginal ring or intrauterine device) can achieve excellent control of PCOS symptoms derived from endocrine, inflammatory and oxidative stress pathways and avoid the sleep induction effect associated with orally administered melatonin agonists that achieve high concentrations in the CNS.

[0082] Described herein is a method of administering a pharmaceutical composition formulated to deliver a melatonin receptor agonist with reduced ability to accumulate in the CNS to a peripheral target tissue. In some embodiments, the method includes oral administration of the pharmaceutical composition formulation. In some embodiments, the method includes reducing the permeability of the pharmaceutical composition formulation through the blood-brain barrier. In some embodiments, the method includes decreasing active transport inside the brain across the BBB. In some embodiments, the method includes increasing efflux to the outside of the brain across the BBB. In some embodiments, the method includes increasing metabolism and / or excretion of the melatonin receptor agonist in the CNS. In some embodiments, the method includes increasing binding to proteins in the CNS that decreases the free concentration of the melatonin receptor agonist. In some embodiments, less than about 50%, 45%, 40%, 35%, 30%, 25%, 22%, 20%, 18%, 15%, 13%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.75%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, 0.02%, 0.01%, 0.005%, or 0.001% of the melatonin receptor agonist included in the pharmaceutical composition accumulates in the CNS of the subject. In some embodiments, the method of administration reduces the ability of the melatonin receptor agonist to accumulate in the CNS, thereby allowing a wider therapeutic dose range for target cells in peripheral tissues. In some embodiments, the wider therapeutic dose range for target cells in peripheral tissues does not affect or impair one or more CNS functions. In some embodiments, the wider therapeutic dose range for target cells in peripheral tissues can reduce potential side effects in the CNS such as drowsiness and defects in sleep patterns, circadian rhythms, motor control, memory loss, or amnesia. In some embodiments, the reduction in the ability of the melatonin receptor agonist to cross the blood-brain barrier can allow for higher systemic concentrations of the melatonin receptor agonist while maintaining a favorable safety profile. In some embodiments, the method of administration includes delivery by intravenous injection. In some embodiments, the reduction in the ability of the melatonin receptor agonist to accumulate in the CNS can allow for delivery by intravenous injection.In some embodiments, the reduced ability of the melatonin receptor agonist to accumulate in the CNS may enable delivery by oral administration. In some embodiments, the melatonin receptor agonist is delivered to the target tissue in a therapeutically effective amount. In some embodiments, the melatonin receptor agonist is delivered to the target cells in a therapeutically effective amount.

[0083] Treatment regimen Described herein are methods of administering the pharmaceutical compositions described herein, including treatment regimens. In some embodiments, the method includes a treatment regimen for delivering a pharmaceutical composition described herein according to the needs of the subject. In some embodiments, the method includes a treatment regimen for delivering a therapeutically effective amount of a pharmaceutical composition described herein according to the needs of the subject. In some embodiments, the treatment regimen includes a single administration. In some embodiments, the treatment regimen includes at least one administration. In some embodiments, the treatment regimen includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations. In some embodiments, the administration includes delivering an effective amount of a melatonin receptor agonist to a target cell. In some embodiments, the effective amount included within a single administration is an effective amount for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 35, 42, 49, 56, 60, 61, 62, or 90 days. In some embodiments, a single administration includes an effective amount for at least one week, at least two weeks, at least four weeks, at least two months, or at least six months. In some embodiments, the method further includes a treatment cycle. In some embodiments, the treatment cycle includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more administrations of the pharmaceutical composition. In some embodiments, the treatment regimen includes a plurality of treatment cycles. In some embodiments, the plurality of treatment cycles is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more treatment cycles. In some embodiments, the treatment cycle includes a length of time. In some embodiments, the length of time includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 30, or 36 months. In some embodiments, the melatonin receptor agonist is delivered to the target tissue over a therapeutically effective period. In some embodiments, the melatonin receptor agonist is delivered to the target cell over a therapeutically effective period.

[0084] In some embodiments, the method of administering the pharmaceutical composition described herein includes the step of initiating administration at various times according to a treatment regimen. In some embodiments, the subject is pretreated by initiating administration of the pharmaceutical composition prior to receiving a chemotherapy treatment. In some embodiments, the pretreatment begins at least about 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour before the start of chemotherapy treatment in the subject. In some embodiments, the subject is treated concurrently by initiating administration of the pharmaceutical composition while receiving a chemotherapy treatment. In some embodiments, the subject is treated by maintaining administration of the pharmaceutical composition after completion of a chemotherapy treatment.

[0085] In some embodiments, the method of administering the pharmaceutical compositions described herein includes the step of administering at various times according to a treatment regimen. In some embodiments, the pharmaceutical composition is administered during a particular day or night. In some embodiments, the pharmaceutical composition is administered according to the subject's circadian rhythm. In some embodiments, the pharmaceutical composition is administered at a time in the circadian rhythm of a subject with low plasma melatonin levels. In some embodiments, the pharmaceutical composition is administered at a time in the circadian rhythm of a subject when the subject's plasma melatonin level is less than about 50 pg / mL, 45 pg / mL, 40 pg / mL, 35 pg / mL, 30 pg / mL, 25 pg / mL, 20 pg / mL, 15 pg / mL, 14 pg / mL, 13 pg / mL, 12 pg / mL, 11 pg / mL, 10 pg / mL, 9 pg / mL, 8 pg / mL, 7 pg / mL, 6 pg / mL, or 5 pg / mL. In some embodiments, the pharmaceutical composition is administered at a certain time throughout the day according to the subject's estimated circadian rhythm. In some embodiments, the pharmaceutical composition is administered at about 12:00 AM, 1:00 AM, 2:00 AM, 3:00 AM, 4:00 AM, 5:00 AM, 6:00 AM, 7:00 AM, 8:00 AM, 9:00 AM, 10:00 AM, 11:00 AM, 12:00 PM, 1:00 PM, 2:00 PM, 3:00 PM, 4:00 PM, 5:00 PM, 6:00 PM, 7:00 PM, 8:00 PM, 9:00 PM, 10:00 PM, or 11:00 PM according to the subject's current time zone. In some embodiments, the pharmaceutical composition is administered daily, every two days, every three days, every seven days, every 28 days, or every two months. In some embodiments, the method of administering the pharmaceutical composition includes continuous administration of a melatonin receptor agonist to the subject. In some embodiments, continuous administration of the pharmaceutical composition described herein to the subject includes delayed release, sustained release, extended release, long-term release, or slow release of the melatonin receptor agonist. In some embodiments, topical administration of the pharmaceutical composition described herein reduces the effect on melatonin receptor-mediated CNS behavior compared to administering an equal amount of melatonin. In some embodiments, melatonin receptor-mediated CNS behavior includes circadian rhythm, addiction, sleep behavior, motor control, or memory erasure.In some embodiments, local delivery of the pharmaceutical compositions described herein may require delivery according to the subject's peripheral circadian rhythm. In some embodiments, the peripheral circadian rhythm may act independently of the pineal gland-mediated circadian regulation of plasma melatonin levels.

[0086] In some aspects, the pharmaceutical composition is administered regardless of the subject's circadian rhythm. In some embodiments, the methods of administering the pharmaceutical compositions described herein result in greater accumulation of the melatonin receptor agonist in peripheral tissues than in CNS tissues. In some embodiments, the greater accumulation of the melatonin receptor agonist in peripheral tissues than in CNS tissues dissociates melatonin receptor-mediated CNS actions related to plasma melatonin concentration from the effects of administration of the melatonin receptor agonist. In some embodiments, the methods described herein include restriction of the melatonin receptor agonist to peripheral tissues. In some embodiments, restriction of the melatonin receptor agonist to peripheral tissues dissociates melatonin receptor-mediated CNS actions related to plasma melatonin concentration from the effects of administration of the melatonin receptor agonist. In some embodiments, the pharmaceutical compositions described herein can be administered according to a time schedule regardless of the circadian-regulated plasma melatonin levels in the subject. In some embodiments, the methods of administering the pharmaceutical compositions described herein that result in reduced CNS accumulation of the melatonin receptor agonist allow administration at any time of day. In some embodiments, the methods of administering the pharmaceutical compositions described herein that result in reduced CNS accumulation of the melatonin receptor agonist allow administration at any time without significant unwanted drug responses in the CNS. In some embodiments, the methods of administering the pharmaceutical compositions described herein that result in reduced CNS accumulation of the melatonin receptor agonist allow administration regardless of the circadian-regulated plasma melatonin levels in the subject.

[0087] Methods of generating a desired pharmacodynamic response In some embodiments, the methods described herein include administering a pharmaceutical composition described herein that provides a desired PD profile in a subject. In some embodiments, the method provides a PD profile in a subject that delivers a melatonin receptor agonist to target cells outside the CNS. In some embodiments, the method provides a PD profile in a subject that delivers an effective amount of a melatonin receptor agonist to target cells outside the CNS. In some embodiments, target cells outside the CNS include cells of the endocrine, reproductive, metabolic, vascular, skeletal, integumentary, or immune systems, or any combination thereof. In some embodiments, the target cells include ovarian cells. In some embodiments, the melatonin receptor agonist functions as a direct antioxidant. In some embodiments, the melatonin receptor agonist directly oxidizes ROS within the target cell, RNS within the target cell, or a combination thereof. In some embodiments, the melatonin receptor agonist directly oxidizes ROS within the mitochondria of the target cell, RNS within the mitochondria of the target cell, or a combination thereof. In some embodiments, the melatonin receptor agonist directly oxidizes extracellular ROS to the target cell, extracellular RNS to the target cell, or a combination thereof. In some embodiments, the melatonin receptor agonist functions to locally upregulate melatonin receptor signaling. In some embodiments, the local upregulation of melatonin receptor signaling occurs in target cells including ovarian cells, oocytes, granulosa cells, theca cells, ovarian stromal cells, ovarian epithelial cells, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, cervical cells, adrenal cells, pancreatic cells, thyroid cells, parathyroid cells, skeletal muscle cells, hepatocytes, white adipose tissue cells, brown adipose tissue cells, osteoblasts, osteoclasts, endothelial cells, hair follicle cells, lymphocytes, neutrophils, monocytes, or macrophages, or progenitor cells of any of the above cell types. In some embodiments, the local upregulation of melatonin receptor signaling increases the expression of multiple cellular antioxidants. In some embodiments, the multiple cellular antioxidants include superoxide dismutase, glutathione reductase, glutathione peroxidase, or catalase, or any combination thereof.In some embodiments, the plurality of cellular antioxidants includes the genes SOD1, SOD2, GSR, GPX1, GPX2, GPX3, GPX4, GPX5, GPX6, GPX7, GPX8, or CAT. In some embodiments, local upregulation of melatonin receptor signaling increases the activity of the plurality of cellular antioxidants. In some embodiments, the plurality of cellular antioxidants includes superoxide dismutase, glutathione reductase, glutathione peroxidase, or catalase, or any combination thereof. In some embodiments, local upregulation of melatonin receptor signaling results in changes in intracellular cyclic nucleotides in a plurality of target cells. In some embodiments, the intracellular cyclic nucleotides include cAMP, cGMP, IP3, or DAG, or any combination thereof. In some embodiments, IP3 and DAG function as messengers for activation of the PI3K / AKT pathway. In some embodiments, local upregulation of melatonin receptor signaling results in changes in cytoplasmic calcium levels in a plurality of target cells. In some embodiments, local upregulation of melatonin receptor signaling results in changes in mitochondrial calcium levels in a plurality of target cells. In some embodiments, local upregulation of melatonin receptor signaling results in activation of PKC subtypes in a plurality of target cells. In some embodiments, the PKC subtypes include conventional, novel, or atypical PKC subtypes. In some embodiments, local upregulation of melatonin receptor signaling results in changes in the intracellular localization of steroid hormone receptors. In some embodiments, local upregulation of melatonin receptor signaling results in changes in the expression of gonadotropin-releasing hormone receptor, luteinizing hormone receptor, or follicle-stimulating hormone receptor, or any combination thereof. In some embodiments, the change in the expression of the hormone receptor includes an increase in the expression level of the mRNA encoding the hormone receptor. In some embodiments, local upregulation of melatonin receptor signaling results in changes in the secretion of progesterone from granulosa cells. In some embodiments, the change in the secretion of progesterone includes an increase in the secretion of progesterone.In some embodiments, local upregulation of melatonin receptor signaling results in changes in the secretion of multiple endocrine hormones, including insulin, glucagon, somatostatin, pancreatic polypeptide, cholecystokinin, secretin, amylin, gastrin, or thyroxine, or any combination thereof. In some embodiments, local upregulation of melatonin receptor signaling results in activation of MAPK pathway signaling. In some embodiments, the activated MAPK pathway signaling pathway is the MAPK-JNK / P38 signaling pathway. In some embodiments, local upregulation of melatonin receptor signaling results in activation of the G protein signaling pathway in multiple target cells. In some embodiments, local upregulation of melatonin receptor signaling results in inhibition of adenylate cyclase in multiple target cells. In some embodiments, local upregulation of melatonin receptor signaling results in activation of phospholipase C in multiple target cells. In some embodiments, local upregulation of melatonin receptor signaling results in changes in lipid metabolism in multiple target cells. In some embodiments, local upregulation of melatonin receptor signaling results in changes in folliculogenesis. In some embodiments, the changes in folliculogenesis include prevention of granulosa cell apoptosis in multiple granulosa cells. In some embodiments, prevention of granulosa cell apoptosis improves folliculogenesis. In some embodiments, local upregulation of melatonin receptor signaling results in improvement of blood pressure regulation. In some embodiments, local upregulation of melatonin receptor signaling results in a decrease in bone density. In some embodiments, local upregulation of melatonin receptor signaling results in a decrease in hair loss.

[0088] Method for regulating phenotype This specification describes methods of administering the pharmaceutical compositions described herein that modulate a phenotype of interest. In some embodiments, the phenotype of interest is affected by melatonin. In some embodiments, the phenotype affected by melatonin is caused by melatonin system dysfunction. In some embodiments, the phenotype affected by melatonin is susceptible to the effects of age-related changes in melatonin distribution. In some embodiments, the age-related changes in melatonin distribution include a decrease in melatonin production. In some embodiments, the age-related changes in melatonin distribution include low melatonin levels in some peripheral tissues and normal or high plasma concentrations of melatonin. In some embodiments, the age-related changes in melatonin distribution include a decrease in extrapineal melatonin production. In some embodiments, the age-related changes in melatonin distribution include a decrease in ovarian melatonin production. In some embodiments, tissue damage resulting from a disease or other injury results in a phenotype of the subject that is affected by melatonin. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in a deceleration of disease progression. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in a halt of disease progression. In some embodiments, administration of a pharmaceutical composition comprising a melatonin receptor agonist to a subject whose phenotype is affected by melatonin results in an improvement in the disease aspect.

[0089] In some embodiments, the phenotypes of subjects affected by melatonin include disorders in endocrine cells, germ cells, metabolic cells, vascular cells, skeletal cells, epithelial cells, or immune cells, or any combination thereof. In some embodiments, the phenotypes of subjects affected by melatonin respond to treatments including administration of a melatonin receptor agonist. In some embodiments, the phenotypes of subjects that respond to melatonin receptor agonist treatment include ovarian phenotypes, endometrial phenotypes, vascular phenotypes, skeletal phenotypes, epithelial phenotypes, inflammatory phenotypes, metabolic phenotypes, or liver phenotypes. In some embodiments, the ovarian phenotype includes abnormal or reduced folliculogenesis, oligoovulation, anovulation, ovulatory dysfunction, altered ovarian progesterone production, altered luteal phase production of progesterone, or poor oocyte maturation. In some embodiments, the endometrial phenotype includes endometriosis, endometriosis-related ovarian oxidative stress, pelvic pain, abdominal pain, back pain, dysmenorrhea, or adenomyosis. In some embodiments, the inflammatory phenotype includes low-grade systemic inflammation, local idiopathic inflammation, stomatitis, abnormal immune response, autoimmune damage, or poor embryo development. In some embodiments, the metabolic phenotype includes increased insulin resistance, dysregulation of glucose homeostasis, excessive weight or excessive BMI, or increased oxidative stress. In some embodiments, the vascular phenotype includes abnormal blood pressure, abnormal blood pressure regulation, increased blood pressure, or hypertension. In some embodiments, the skeletal phenotype includes increased bone density loss, decreased bone density, accelerated bone density loss, or osteoporosis. In some embodiments, the epithelial phenotype includes increased hair loss, androgenetic alopecia, female pattern hair loss (FPHL), or thinning hair.

[0090] In some embodiments, the phenotypes of subjects responsive to melatonin receptor agonist treatment include aspects of the indications or conditions of certain diseases. In some embodiments, the aspects of the indications or conditions of certain diseases responsive to melatonin receptor agonist treatment are ovulatory dysfunction, luteal phase defect, PCOS, anovulatory PCOS, insulin resistance in PCOS, glucose tolerance in PCOS, risk of NAFLD in PCOS patients, weight control in PCOS, uterine inflammatory diseases, inflammation in PCOS, hyperandrogenism, hirsutism, decreased uterine receptivity, ART outcomes, abnormal blood pressure, abnormal blood pressure regulation, blood pressure elevation, hypertension, bone density loss, decreased bone mineral density, accelerated bone density loss, osteoporosis, increased hair loss, androgenetic alopecia, female pattern hair loss (FPHL), thin hair, preeclampsia, endometriosis, endometriosis-related infertility, pelvic pain, abdominal pain, back pain, dysmenorrhea, or EACPP.

[0091] Described herein are methods of administering the pharmaceutical compositions described herein that can result in an improvement in ART outcomes. In some methods, the improvement in ART outcomes includes improvement in the maturation and quality of oocytes and embryos. In some embodiments, the improvement in the maturation and quality of oocytes and embryos is due to an increase in the ROS scavenging action of the melatonin receptor agonist and / or an increase in melatonin receptor signaling in the target tissue. In some embodiments, the increase in melatonin receptor signaling in the target tissue results in an anti-inflammatory effect, an antioxidant effect, or a combination thereof. In some embodiments, the improvement in ART outcomes includes regulation of steroid production by the melatonin receptor agonist. In some embodiments, the regulation of steroid production by the melatonin receptor agonist includes regulation of progesterone production or a decrease in androgen levels.

[0092] This specification describes a method of administering the pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the method includes delivery of the pharmaceutical composition by oral, transdermal, subcutaneous, intravenous, or topical administration. In some embodiments, the method includes delivery of the pharmaceutical composition to the upper reproductive tract. In some embodiments, delivery of the pharmaceutical composition to the upper reproductive tract enables an increase in the local tissue concentration of the melatonin receptor agonist without substantially increasing the plasma concentration of the melatonin receptor agonist. In some embodiments, delivery of the pharmaceutical composition to the upper reproductive tract results in a local tissue concentration of the melatonin receptor agonist that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, or 10,000% higher than the plasma concentration of the melatonin receptor agonist. In some embodiments, delivery of the pharmaceutical composition to the upper reproductive tract results in a local tissue concentration of the melatonin receptor agonist that is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, or 10,000% higher than the concentration of the melatonin receptor agonist accumulated in the CNS. In some embodiments, the higher the local tissue concentration of the melatonin receptor agonist, the more the occurrence or spread of an unwanted drug response in the subject's CNS is avoided.In some embodiments, the higher the concentration of the melatonin receptor agonist in the local tissue, the more the occurrence or spread of an unwanted drug response in the subject's CNS is avoided, and a therapeutically effective amount of the melatonin receptor agonist is delivered to the target tissue. In some embodiments, the method includes local delivery of a pharmaceutical composition by a drug delivery device. In some embodiments, the method includes local delivery of a pharmaceutical composition by a vaginal gel, vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, local delivery includes local injection into an area near the target tissue.

[0093] This specification describes a method of administering the pharmaceutical composition described herein to a subject in need thereof. In some embodiments, the method includes delivery of the pharmaceutical composition by systemic delivery. In some embodiments, systemic delivery includes oral, transdermal, subcutaneous, intravenous, or topical administration. In some embodiments, the pharmaceutical composition has a reduced ability to accumulate in the CNS. In some embodiments, the reduction in the ability to accumulate in the CNS is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15%, 16%, 18%, 20%, 22%, 25%, 27%, 30%, 32%, 35%, 37%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, 3000%, 4000%, 5000%, or 10000% lower than the CNS accumulation of an equivalent amount of melatonin. In some embodiments, when the ability of the melatonin receptor agonist to accumulate in the CNS is reduced, the occurrence or spread of an undesired drug response in the subject's CNS is avoided. In some embodiments, when the ability of the melatonin receptor agonist to accumulate in the CNS is reduced, the occurrence or spread of an undesired drug response in the subject's CNS is avoided and a therapeutically effective amount of the melatonin receptor agonist is delivered to the target tissue. In some embodiments, one aspect of the formulation of the pharmaceutical composition results in a reduction in the ability of the melatonin receptor agonist to accumulate in the CNS. In some embodiments, modification of the melatonin receptor agonist results in a reduction in the ability of the melatonin receptor agonist to accumulate in the CNS. In some embodiments, the pharmaceutical composition includes a melatonin receptor agonist conjugate. In some embodiments, the conjugate includes a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule.

[0094] In some embodiments, the methods described herein provide a desired PK profile for a pharmaceutical composition within a subject. In some embodiments, the PK profile will include a higher level of melatonin receptor agonist bioavailability near target cells outside the CNS. In some embodiments, the PK profile will include a lower level of melatonin receptor agonist bioavailability in the CNS than near target cells outside the CNS. In some embodiments, target cells outside the CNS include cells involved in endocrine function, cells involved in reproductive function, cells involved in metabolic function, cells involved in vascular function, cells involved in skeletal function, cells involved in integumentary function, or cells involved in immune function. In some embodiments, target cells outside the CNS include cells of the upper reproductive tract. In some embodiments, cells of the upper reproductive tract include ovarian cells, oocytes, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, or cervical cells. In some embodiments, cells involved in reproductive function include ovarian cells, oocytes, granulosa cells, theca cells, ovarian stromal cells, ovarian epithelial cells, fallopian tube cells, uterine cells, endometrial cells, myometrial cells, or cervical cells. In some embodiments, target cells outside the CNS involved in endocrine function include cells of the adrenal gland, pancreatic cells, thyroid cells, parathyroid cells, or ovarian cells. In some embodiments, target cells outside the CNS involved in metabolic function include skeletal muscle cells, liver cells, pancreatic cells, or adipose tissue cells. In some embodiments, target cells outside the CNS involved in immune function include lymphocytes, neutrophils, monocytes, or macrophages. In some embodiments, target cells outside the CNS involved in immune function include precursors of lymphocytes, neutrophils, monocytes, or macrophages. In some embodiments, lymphocytes include T cells, B cells, or NK cells. In some embodiments, target cells involved in vascular function include endothelial cells. In some embodiments, target cells involved in skeletal function include osteoblasts and osteoclasts. In some embodiments, target cells involved in integumentary function include hair follicle cells.

[0095] Kit A kit is disclosed herein. The kit can include a melatonin receptor agonist, a salt thereof, a formulation, or a composition as described herein. In some embodiments, the melatonin receptor agonist, formulation, or composition can be packaged in a container. In some embodiments, the kit can further include instructions for instructing the administration of the melatonin receptor agonist, or a unit dose of the melatonin receptor agonist or formulation, to a subject. In some embodiments, the kit can include a melatonin receptor agonist disclosed herein and instructions for use thereof. In some embodiments, the instructions for use specify one or more indications in a subject in need of treatment, and the one or more indications include polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian dysfunction (CIOD), chemotherapy-induced ovarian failure (CIOF), or inflammation of the reproductive tract, or combinations thereof. In some embodiments, the kit further includes a drug delivery device for administering the pharmaceutical composition to a subject. In some embodiments, the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. In some embodiments, the drug delivery device is configured to be disposed in proximity to the subject's genitalia. In some embodiments, the drug delivery device is an intrauterine device and is configured to be disposed in proximity to the subject's genitalia. In some embodiments, the intrauterine device is configured to effect time-controlled or remote-controlled release of one or more doses of a pharmaceutical composition formulated for delayed release, sustained release, extended release, long-term release, or slow release.

[0096] A method of making a kit can include placing a melatonin receptor agonist, a salt thereof, a formulation, or a composition as described herein into a packaging container. The method can further include enclosing instructions for use. Optionally, the instructions for use can instruct the administration of the melatonin receptor agonist, or a unit dose of the melatonin receptor agonist or formulation, to a subject.

[0097] Definitions Unless otherwise defined, all terms, notations, and other technical and scientific terms and grammar used in this technical field and in this specification are intended to have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter belongs. In some cases, terms with commonly understood meanings are defined in this specification for clarity and / or ease of reference, but including such definitions in this specification should not necessarily be construed as representing a substantial difference from what is commonly understood in the art.

[0098] The use of absolute or sequential terms, such as "will", "will not", "shall", "shall not", "must", "must not", "first", "initially", "next", "subsequently", "before", "after", "lastly", and "finally", is not intended to limit the scope of the embodiments disclosed in this specification and is intended to be exemplary.

[0099] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. Further, terms such as "including", "includes", "having", "has", "with", or their variations are intended to be inclusive in the same manner as the term "comprising" to the extent used in either the detailed description and / or the claims.

[0100] As used herein, the phrases "at least one", "one or more", and "and / or" are open-ended expressions that are conjunctive and disjunctive in operation. For example, each of the expressions "at least one of A, B, and C", "at least one of A, B, or C", "one or more of A, B, and C", "one or more of A, B, or C", and "A, B, and / or C" means A alone, B alone, C alone, A and B together, A and C together, B and C together, or A, B, and C together.

[0101] As used herein, "or" refers to "and", "or", or "and / or" and can be used exclusively and inclusively. For example, "A or B" can refer to "A or B", "not A but B", "not B but A", as well as "A and B". In some cases, the context may indicate a specific meaning.

[0102] The systems, methods, software, and platforms described herein are all modular. Accordingly, terms such as "first" and "second" do not necessarily indicate priority, order of importance, or order of actions.

[0103] The terms "determining," "measuring," "evaluating," "assessing," "assaying," and "analyzing" are often used interchangeably herein to refer to forms of measurement. These terms include determining whether an element is present (e.g., detecting). These terms can include quantitative, qualitative, or both quantitative and qualitative determinations. Assessing can be relative or absolute. "Detecting the presence of" can include determining that an amount of something is present in addition to determining whether it is present or absent, depending on the context.

[0104] The terms "subject," "individual," or "patient" are often used interchangeably herein. A "subject" can be a biological entity that contains expressed genetic material. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. A subject can be a tissue, cell, and their progeny of a biological entity obtained in vivo or cultured in vitro. A subject can be a mammal. The mammal can be a human. A subject can be diagnosed as having a high risk of a disease or be suspected of having it. Optionally, a subject is not necessarily diagnosed as having a high risk of a disease or suspected of having it. The names "subject," "individual," or "patient" do not necessarily involve the supervision of medical professionals.

[0105] The term "in vivo" is used to describe events that occur in the body of a subject.

[0106] The term "in vitro" is used to describe events that occur within a container holding experimental reagents such that the experimental reagents are separated from the biological source from which the materials are obtained. In vitro assays can include cell line assays that utilize cells that are alive or dead. In vitro assays can further include cell-free assays that do not utilize intact cells.

[0107] As used herein, the terms "treatment" or "treating" are used with respect to a pharmaceutical regimen or other intervention regimen to obtain a beneficial or desired result in the subject receiving the same. Beneficial or desired results include, but are not limited to, therapeutic and / or prophylactic benefits. A therapeutic benefit may refer to the eradication or alleviation of the underlying disorder being treated. A therapeutic benefit can also be achieved by the eradication or reduction of one or more of the physiological symptoms associated with the underlying disease such that an improvement is observed in the subject, even though the subject may still suffer from the underlying disease. Prophylactic effects include delaying, preventing, or eliminating the onset of a disease or disorder, delaying or eliminating the development of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof. In the case of a prophylactic benefit, a subject at risk of developing a particular disease or reporting one or more of the physiological symptoms of a disease may be treated even if the subject has not been diagnosed with that disease.

[0108] When referring to a number or range of numbers, the term "about" means that the recited number or range of numbers is an approximation within the experimental variation (or within statistical experimental error), and the number or range of numbers can vary, for example, from 1% to 15% of the recited number or range of numbers. For example, the term "about" refers to ±10% of the recited number or value.

[0109] Throughout this application, various aspects may be presented in a range format. It should be understood that the description in range format is for convenience and brevity only and should not be construed as a rigid limitation on the scope of the present disclosure. Thus, a range description should be considered to have all of the specifically disclosed sub-ranges that could occur, as well as the individual numerical values within that range. For example, a range description such as 1-6 should be considered to have the specifically disclosed sub-ranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, as well as the individual numbers within that range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

[0110] The terms "increased", "increasing", or "increase" are used herein generally to mean an increase by a statistically significant amount. In some aspects, the terms "increased" or "increase" mean an increase of at least 10% compared to a reference level, for example, at least about 10%, at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to 100% increase, or an increase of any value between 10-100% compared to a reference level, standard, or control. Other examples of "increase" include an increase of at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or more compared to a reference level.

[0111] "Decreased," "decreasing," or "decrease" are used herein generally to mean a decrease by a statistically significant amount. In some embodiments, "decreased" or "decrease" is at least a 10% decrease as compared to a reference level, e.g., at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90%, or up to a 100% decrease (e.g., an absent level or a non-detectable level as compared to a reference level), or a decrease of any value between 10 and 100%. In terms of a marker or symptom, these terms mean a statistically significant decrease of such a level. The decrease can be, e.g., at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably decreases to a level that is within the normal range for an individual without a given disease.

[0112] The terms "follicle" and "ovarian follicle" refer to an aggregate of cells found in the ovary that contains an oocyte or immature oocyte that develops within a follicle (e.g., including a shell densely packed with somatic cells containing an immature oocyte).

[0113] The term "folliculogenesis" refers to the process by which ovarian follicles containing (immature) oocytes mature, including any stage of progression from primordial follicles to preovulatory follicles and / or from immature oocytes to eggs, or any stage thereof.

[0114] The term "oocyte" refers to a cell that is capable of maturing by meiosis into a female haploid egg cell (ovum).

[0115] The terms "menopause symptoms" and "menopausal symptoms" refer to symptoms and disorders that occur in women before, during, and after menopause that are caused at least in part by ovarian aging, hormonal changes, and / or other biological processes associated with menopause.

[0116] The term "ovarian reserve" refers to the ability of the ovaries to provide egg cells that are capable of being fertilized and of successfully achieving a healthy pregnancy, as well as ovarian follicular cells that are capable of producing ovarian hormones and signaling molecules that underlie the endocrine function of the ovaries.

[0117] The headings of the sections used in this specification are for purposes of organization only and are not to be construed as limiting the subject matter described.

[0118] Preferred embodiments of the invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. The invention is not intended to be limited by the specific examples provided within the specification. While the invention has been described with reference to the foregoing specification, the description and illustration of the embodiments herein are not intended to be construed in a limiting sense. Numerous variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. Further, it should be understood that all aspects of the invention are not limited to the specific descriptions, configurations, or relative ratios described herein, which depend on various conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be utilized in the practice of the disclosure. Therefore, it is intended that the invention include any such alternatives, modifications, variations, or equivalents. The following claims define the scope of the invention, and methods and structures within the scope of these claims and their equivalents are intended to be encompassed by the claims.

Examples

[0119] The following exemplary embodiments represent embodiments of the stimulations, systems, and methods described herein but are not intended to be limiting in any way.

[0120] Example 1: In vitro Pharmacology: Receptor Binding Assay (IC50) and In vitro Potency Assay (EC50)

[0121] Perform ligand binding assays to determine the concentrations that result in 50% inhibition of specific binding (IC50) of the control at MT1 and MT2. Incubate the compound with the cells and ligand in serial dilutions. Incubate the samples for a predetermined time at a predetermined temperature. Evaluate non-specific binding by incubation with 1 μM melatonin or a known analog for MT1 and MT2. After incubation, quantify the % of ligand binding inhibition. The dose response to the compound is measured in a cell function assay that measures cAMP levels. The EC50 is the 50% maximal antagonist response at MT1 and MT2.

[0122] Example 2: In vitro Selectivity Screening

[0123] Test the selectivity of the compound for the melatonin receptor using SelectScreen Cell-based GPCR profiling by the ThermoFisher and / or Eurofins DiscoveRx platforms against a GPCR panel. Of particular interest in the determination of selectivity are G protein-coupled receptors that have known similarities to MT1 and MT2 and known ligands used in the evaluation of selectivity. For comparison, the similarities of melatonin receptors of other species are shown in Table 3 below.

[0124] [Table 3]

[0125] Example 3: Safety Screening

[0126] Safety assessments that comply with the ICH S2A / B and ICH S7 guidelines include functional observable behaviors (FOB) (e.g., modified Irwin test), effects of the compound on the CNS, risk assessment for respiratory function, and cardiovascular assessments that include the in vitro hERG assay (to identify the potential risk of QT interval prolongation) and in vivo evaluations that are commonly performed in ICH safety assessments.

[0127] Example 4: Cell-based assay for MDR1 permeability

[0128] MDR1-expressing cells (e.g., MDR1-MDCK cells) are seeded on a Transwell filter insert and incubated with a solution containing a melatonin receptor agonist with or without an MDR1 inhibitor. After incubation for a predetermined time, samples obtained from the apical and basolateral compartments are tested for the concentration of the compound.

[0129] Example 5: Artificial gastric juice during non-fasting vs. fasting

[0130] The dissolution and absorption of drugs in the physiological environment of the gastrointestinal (GI) tract are evaluated in a biologically relevant dissolution medium. In this example, the drug refers to a selected pharmaceutical composition containing a melatonin receptor agonist.

[0131] Example 6: In vitro MTNR1A / B activation assay

[0132] In an in vitro assay, the efficacy of a compound (e.g., a melatonin receptor agonist) in MTNR1A / B activation can be determined. The effect of the compound on melatonin signaling can be examined by testing the ability of the compound to increase the following melatonin signaling readouts. Target validation can be done by examining melatonin-mediated metabolic processes that are characterized in cell lines. These include the following. · Treatment of C2C12 cell line with receptor agonist stimulates glucose uptake through activation of the PI3K pathway. This process is inhibited by co - treating the cells with ruthenium red. · Treatment of insulin - resistant 3T3 - L1 adipocytes (induced by exposure to palmitic acid) with receptor agonist stimulates an increase in glucose uptake and GLUT4 levels, as well as a decrease in phosphorylation of IRS1 at Ser307 (inhibitor). · Treatment of rat insulin - secreting cells (INS1) with receptor agonist inhibits insulin secretion. This process is decreased by the use of ruthenium red. · Treatment of granulosa cells (KGN or primary cells) with melatonin increases the expression of some cyclic nucleotide phosphodiesterase isoforms, phosphorylation of protein kinase B, and expression of SIRT1, and inhibits the measurement of oxidative phosphorylation and mitochondrial dysfunction [Source: PMCID: PMC8950389, PMCID: PMC8582167]. · Treatment of macrophages (RAW264.7 or primary cells) with LPS induces the expression of pro - inflammatory molecules (e.g., TNFα, IL1B, IL6, IL8), and melatonin decreases their LPS - induced expression.

[0133] Example 7: In vivo pharmacology

[0134] Determine the concentrations of the compound in the brain, cerebrospinal fluid (CNF), plasma, and peripheral tissues at consecutive time points after oral administration and / or i.v. administration and / or topical administration of the compound to rats and / or mice. Analyze the samples by LC - MS and / or microdialysis. Evaluate the bound and free concentrations of the compound in different samples at different time points.

[0135] Example 8: In vivo disease model

[0136] Melatonin has been shown to improve metabolic and reproductive traits in PCOS animal models. Compounds that function as melatonin receptor agonists produce one or more of the following phenotypic changes in PCOS rat / mouse models (the effects of melatonin were tested using both DHT-induced models and continuous light stimulation models). · Interrupt long estrous cycles · Increase the number of corpora lutea · Decrease the number of cystic follicles · Reduce the levels of testosterone and AMH · Improve glucose tolerance and increase glucose uptake · Reduce leptin levels · Alleviate hyperinsulinemia · Reduce serum TNFα levels · Increase antioxidant capacity (e.g., superoxide dismutase, catalase, and glutathione reductase activities, reducing power (GSH / GSSG ratio))

[0137] To determine the effects of melatonin receptor agonist treatment, the following PCOS animal models are provided.

[0138] In the PCOS mouse model, on day 0, mice are treated by local injection of a melatonin receptor agonist or saline vehicle into the myometrium of the mouse uterus (ultrasound-guided or visually guided after laparotomy). The mice are divided into groups 1-7 according to this example, and the treatment groups follow the animal model experimental groups and treatment dose designs listed in Table 4. On days 1, 2, 3, 7, 10, 14, 17, 21, 24, 28, and / or 35, the mice are assayed for the above characteristics.

[0139] Induction of PCOS in androgen-induced models:

[0140] In the induction of PCOS in an androgen-induced model using rats, the following protocol is implemented. Polycystic ovary syndrome (PCOS) is induced in mice by daily subcutaneous administration of testosterone propionate (TP) (10 mg / kg) for 35 days. Groups 2 - 7 have disease induction. Group 1 is a vehicle control.

[0141] Preventive treatment is administered from day 1 to day 35 of the test design. On day 0, rats are randomly assigned by birth weight (BW) and allocated to groups 1 - 7. All treatments (days 1 - 35) are initiated when the rats are 21 days old and are performed once daily by oral gavage for 35 consecutive days. In animals in the treatment groups receiving once-daily (QD) treatment, the melatonin analog is administered by oral gavage 1 hour after the onset of darkness. In animals in the treatment groups receiving twice-daily (BID) treatment, the melatonin analog is first administered by oral gavage 1 hour after the onset of darkness and then again by oral gavage approximately 5 hours after the first administration. In the androgen-induced PCOS model, the animals are maintained on a 12-hour light / 12-hour dark light schedule.

[0142] Induction of PCOS in a light-induced (or dark-induced) model:

[0143] PCOS is induced in rats by exposure to constant light (or constant darkness) for 8 weeks. Groups 2 - 7 have disease induction. Group 1 is a vehicle control.

[0144] All treatments are initiated when the rats are 5 weeks old and are performed once daily for 8 weeks. Preventive treatment is administered from day 1 to day 56 (random assignment by BW on day 0) of the test design. The melatonin analog is administered by oral gavage at the same time on the treatment days (days 1 - 56).

[0145] In both androgen-induced PCOS induction and light-induced (or dark-induced) PCOS induction, groups 1-7 are treated according to the experimental groups listed in Table 4 on the treatment test design day. Animals in group 1 receive a vehicle control treatment of sunflower oil according to the treatment test design day. Animals in the androgen-induced PCOS induction model of group 2 receive TP administration for disease induction but no treatment. Animals in the light-induced (or dark-induced) PCOS induction model of group 2 are subjected to PCOS induction but receive no treatment. Animals in group 3 receive metformin hydrochloride treatment daily as a positive control for the treatment of metabolic symptoms according to the treatment test design day. Animals in group 4 receive low-dose melatonin analog treatment once a day (QD) according to the treatment test design day. Animals in group 5 receive high-dose melatonin analog treatment once a day (QD) according to the treatment test design day. Animals in group 6 receive melatonin analog treatment twice a day (BID) according to the treatment test design day. Animals in group 7 receive melatonin treatment daily according to the treatment test design day.

[0146]

Table 4

[0147] The following administration routes are used according to the drug to be administered to the subject. Oral gavage nutrition (metformin, melatonin, melatonin analog), subcutaneous (sunflower oil, TP). The melatonin analog administered to the animals in groups 4-6 on the treatment test design day is N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143) (Compound 10b). The treatment doses for each implementation of the treatment for groups 3-7 are listed in Table 4

[0148] On the 1st, 2nd, 3rd, 7th, 10th, 14th, 17th, 21st, 24th, 28th, and / or 35th day, the androgen-induced PCOS induction model animals of groups 1 - 7 are assayed for the changes in the PCOS phenotypes listed above in this example. At the end of the test, the remaining animals in groups 1 - 7 are assayed for the changes in the PCOS phenotypes and the degree of symptoms listed above in this example.

[0149] PCOS induction for the photo-induced (or dark-induced) model animals from groups 1 - 7 is assayed for the changes in the PCOS phenotypes listed above in this example on the 1st, 2nd, 3rd, 7th, 10th, 14th, 17th, 21st, 24th, 28th, 35th, 42nd, 49th, and / or 56th day. At the end of the test, the remaining animals in groups 1 - 7 are assayed for the changes in the PCOS phenotypes and the degree of symptoms listed above in this example. The animals are further assayed according to the parameters listed in the In vivo pharmacology of Example 7. Table 5 lists the expected results for the PCOS control animals and the experimental groups that received melatonin analog treatment.

[0150]

Table 5

[0151] An in vivo pharmacology test is performed on one or more PCOS induction models. The concentrations of the assayed compounds in the brain, cerebrospinal fluid (CNF), plasma, and peripheral tissues at consecutive time points are determined after oral administration and / or i.v. administration and / or topical administration of melatonin analogs to rats and / or mice. The samples are analyzed by LC-MS and / or microdialysis. The bound and free concentrations of the melatonin analogs in different samples at different time points are evaluated. The in vivo pharmacology test is performed using i) subjects without disease induction (e.g., wild-type mice or wild-type rats), and ii) subjects with PCOS induction shown in this example. The following data are collected during the pharmacology test. · In-life anthropometric parameters (BMI, abdominal circumference to thoracic circumference (AC / TC) ratio) · In vivo colpocytological examination (estrous cycle) · PK profiling (T0, 30 seconds, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours) · Serum biomarkers: FSH, LH, testosterone, CRP, insulin, glucose · Tissue examination: ovaries, uterus, and IAF on the final day of the test (gross morphology + ovarian tissue and follicle count)

[0152] The expected results in the PCOS induction model on the final day of the test are listed in Table 5.

[0153] Conclusion: Preventive treatment with a melatonin analog for the subjects prevents the induction of changes in the PCOS phenotype and the degree of symptoms compared to the subjects with PCOS disease control. Preventive and concurrent treatment with a melatonin analog for the subjects improves the induced PCOS phenotype changes and symptoms compared to the subjects with PCOS disease control. Preventive and concurrent treatment with a melatonin analog for the subjects improves at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or all 15 of the induced PCOS phenotype changes, symptoms, or outcomes listed in Table 5 compared to the subjects with PCOS disease control.

[0154] Endometriosis model:

[0155] A mouse model of endometriosis is created by inoculating endometrial fragments collected from donor mice into the abdominal cavity of recipient mice. The endometriosis mice are treated with a melatonin receptor agonist for a predetermined period (e.g., 10, 15, 20, 30 days), and the effect of the treatment is measured by evaluating the following. · Regression of lesions · Decrease in the level, and / or expression, and / or activity of proMMP9 · Increase in the TIMP1 level, and / or expression, and / or activity, and / or decrease in the proMMP9 / TIMP1 ratio ·Decrease in the level, and / or expression, and / or activity of proMMP3 ·Decrease in the expression and / or level of TNFα ·Increase in apoptosis and / or apoptosis markers (e.g., caspase 3, caspase 9) ·Reduction in pain and / or hyperalgesia and / or allodynia ·Decrease in inflammation and / or inflammation biomarkers

[0156] Mice are assigned to groups 1 - 6 (randomized by BW on day 0). Groups 2 - 6 have disease induction. Group 1 is a vehicle control. Groups 1 - 6 are treated on the test design day of treatment by the experimental groups listed in Table 6.

[0157]

Table 6

[0158] At the end of the test, the remaining animals in groups 1 - 6 are assayed for the changes in the endometriosis phenotype and the degree of symptoms listed above in this example.

[0159] Example 9: In vivo Chemotherapy - Induced Ovarian Dysfunction Model

[0160] Melatonin has been shown to reduce and protect metabolic and reproductive traits in animal models of tissue damage by chemotherapy. Compounds that function as melatonin receptor agonists produce one or more of the following phenotypic changes in the CIOD rat / mouse model. ·Attenuation of CIOD - induced primordial follicle loss ·Decrease in growing follicle atresia ·Decrease in CIOD - induced mitochondrial damage ·Normalization of inflammatory biomarkers (C - reactive protein (CRP), IL1, and TNF expression and plasma malondialdehyde (MDA) levels) and antioxidant biomarkers (total antioxidant capacity (TAC) level and total glutathione (GSH) after chemotherapy administration) ·Reduction in the scope of CIOD-induced ovarian apoptosis ·Reduction in the scope of CIOD-induced oxidative damage ·Normalization of sex hormone levels ·Improvement of follicular morphology ·Normalization of granulosa cell proliferation ·Reduction in the loss of fertility after CIOD ·Prevention of chemotherapy-induced ovarian reserve decline ·Protection from chemotherapy-induced mitochondrial damage in the ovary ·Recovery of ovarian mitochondrial function ·Reduction in ovarian collagen deposition

[0161] On day 1, a simultaneous-treatment CIOD model is created by a single administration of cisplatin (7 mg per kg of body weight, i.p. injection) to female rats. The test animals are further treated once or twice daily for 7 consecutive days starting from day 1 with a melatonin receptor agonist (30 or 60 mg per kg of body weight by oral administration). Control animals do not receive the treatment with the melatonin receptor agonist. All animals are maintained on a 12-hour light / 12-hour dark cycle starting at 6:00 am. After all the treatments are completed, blood samples are collected from all animals on day 8 and assayed for serum hormone levels, inflammatory biomarkers, and antioxidant biomarkers. After the collection of the blood samples, the animals are sacrificed and the ovarian cells and tissue morphology are assayed by histological analysis to enable the measurement of the degree of tissue damage and the CIOD phenotype.

[0162] A pretreatment CIOD model is prepared. In test animals, female mice are pretreated once or twice a day for 3 days with a melatonin receptor agonist (30 or 60 mg per kg of body weight by oral administration). On the 3rd day, a single dose of cyclophosphamide (200 mg per kg of body weight by i.p. injection) is administered to all mice. The test animals receive cyclophosphamide administration 30 minutes after receiving the final melatonin receptor agonist pretreatment. All animals are maintained on a 12-hour light / 12-hour dark cycle starting at 6:00 am. On the 10th day, blood samples are collected from all animals and assayed for serum hormone levels, inflammatory biomarkers, and antioxidant biomarkers. After collection of the blood samples, the animals are sacrificed and ovarian cells and tissue morphology are assayed by histological analysis to enable measurement of the degree of tissue damage and the CIOD phenotype.

[0163] From the results, it will be recognized that both co-treatment and pretreatment with a melatonin receptor agonist reduce the effect of CIOD.

[0164] Example 10: Patient Selection and Stratification and Biomarker Evaluation

[0165] In PCOS patients or patients with metabolic disorders, beneficial effects of melatonin on hyperandrogenism, inflammation, ART outcome, and metabolic function are recognized. PCOS patients with these characteristics are considered for treatment.

[0166] Biochemical evaluation items: Evaluation of melatonin receptor activation can be evaluated by confirming the following. · Normalization of metabolic phenotype biomarkers including HbA1c, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMO-IR), and lipid profile measurement · Improvement of hyperandrogenism Normalization of inflammatory biomarkers (C-reactive protein (CRP), IL1 and TNF expression, and plasma malondialdehyde (MDA) levels) and antioxidant biomarkers (total antioxidant capacity (TAC) levels and total glutathione (GSH)) · Improvement of ovulation disorders that can be expected considering the positive effect of melatonin on ART outcomes and the improvement of ovarian function in vitro.

[0167] From the results, PCOS patients with at least one of hyperandrogenism, inflammation, unsuccessful ART outcomes, or metabolic disorders will be recognized to benefit by receiving treatment including administering a melatonin receptor agonist in a therapeutically effective amount according to a dosing regimen that continues until at least the patient shows improvement in biochemical evaluation items. This improvement includes improvement in at least one of the characteristics selected by the patient. Non-limiting examples of improvement include improvement of characteristics of hyperandrogenism, normalization of one or more inflammatory biomarkers (e.g., C-reactive protein (CRP), IL1 and TNF expression, and plasma malondialdehyde (MDA) levels), normalization of one or more antioxidant biomarkers (e.g., total antioxidant capacity (TAC) levels and total glutathione (GSH)), improvement of ovulation disorders leading to an improved chance of successful ART outcomes, normalization of metabolic phenotype markers (e.g., HbA1c, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMO-IR)), or normalization of lipid profile measurements, or any combination thereof.

[0168] The foregoing disclosure has been described in some detail for purposes of clarity and understanding, but it will be apparent to those skilled in the art upon reading this disclosure that various changes in form and detail can be made without departing from the proper scope of the disclosure. For example, all of the techniques and apparatus described above can be used in various combinations. All publications, patents, patent applications, and / or other documents cited in this application are hereby incorporated by reference in their entirety to the same extent as if each individual publication, patent, patent application, and / or other document were individually and separately indicated to be incorporated by reference for all purposes.

[0169] Aspect Some embodiments relate to any one of the following aspects. Aspect 1: A pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is a. formulated for intravaginal, b. intrauterine, or c. formulated for systemic administration and has reduced accumulation in the central nervous system (CNS) compared to melatonin, and the therapeutically effective amount is effective for treating or alleviating symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in a subject in need of treatment or alleviation of symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract. Aspect 2: A pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is a. formulated for intravaginal, b. intrauterine, or c. formulated for systemic administration and has reduced accumulation in the central nervous system (CNS) compared to melatonin, and the therapeutically effective amount is effective for preventing, reducing, or suppressing one or more symptoms associated with chemotherapy-induced ovarian insufficiency in a subject in need of prevention, reduction, or suppression of one or more symptoms associated with chemotherapy-induced ovarian insufficiency. Aspect 3: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises at least one of Circadin (registered trademark), Slenyto (registered trademark), ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or a salt or derivative thereof, or a combination thereof. Aspect 4: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises Circadin (registered trademark). Aspect 5: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises Slenyto (registered trademark). Aspect 6: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises ramelteon. Aspect 7: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises tasimelteon. Aspect 8: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises agomelatine. Aspect 9: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises TIK-301. Aspect 10: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises pyromelatine. Aspect 11: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide. Aspect 12: The pharmaceutical composition according to Aspect 1 or 2, wherein the melatonin receptor agonist comprises N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide. Aspect 13: The pharmaceutical composition according to aspect 1 or 2, wherein the melatonin receptor agonist comprises N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide. Aspect 14: The pharmaceutical composition according to any one of aspects 1 to 13, wherein the melatonin receptor agonist non-selectively activates type 1A (MT1) and type 1B (MT2) melatonin receptors. Aspect 15: The pharmaceutical composition according to any one of aspects 1 to 13, wherein the melatonin receptor agonist preferentially activates type 1A (MT1) melatonin receptors. Aspect 16: The pharmaceutical composition according to any one of aspects 1 to 13, wherein the melatonin receptor agonist preferentially activates type 1B (MT2) melatonin receptors. Aspect 17: The pharmaceutical composition according to any one of aspects 1 to 16, formulated as a gel, ointment, solution, powder, paste, foam, cream, or lotion. Aspect 18: The pharmaceutical composition according to any one of aspects 1 to 16, formulated to be delivered via a drug delivery device. Aspect 19: The pharmaceutical composition according to aspect 18, wherein the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. Aspect 20: The pharmaceutical composition according to aspect 18 or 19, wherein the drug delivery device is configured to be placed in proximity to the genitalia of the subject. Aspect 21: The pharmaceutical composition according to aspect 19 or 20, wherein the drug delivery device is the intrauterine device and is configured to be placed in proximity to the genitalia of the subject. Aspect 22: The pharmaceutical composition according to aspect 21, wherein the intrauterine device is configured for time-controlled or remotely controlled release of one or more doses of the melatonin receptor agonist. Aspect 23: The pharmaceutical composition according to any one of aspects 1 to 22, formulated for delayed release, sustained release, extended release, long-term release, or slow release. Aspect 24: The pharmaceutical composition according to any one of Aspects 1 to 23, comprising the melatonin receptor agonist in an effective amount for at least about 1 week, 2 weeks, 4 weeks, 2 months, or 6 months. Aspect 25: The pharmaceutical composition according to any one of Aspects 1 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the pharmaceutical composition accumulates in the CNS of the subject. Aspect 26: The pharmaceutical composition according to any one of Aspects 4 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Circadin® accumulates in the CNS of the subject. Aspect 27: The pharmaceutical composition according to any one of Aspects 5 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of Slenyto® accumulates in the CNS of the subject. Aspect 28: The pharmaceutical composition according to any one of Aspects 6 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of ramelteon accumulates in the CNS of the subject. Aspect 29: The pharmaceutical composition according to any one of Aspects 7 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of tasimelteon accumulates in the CNS of the subject. Aspect 30: The pharmaceutical composition according to any one of Aspects 8 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of agomelatine accumulates in the CNS of the subject. Aspect 31: The pharmaceutical composition according to any one of Aspects 9 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of TIK-301 accumulates in the CNS of the subject. Aspect 32: The pharmaceutical composition according to any one of Aspects 10 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of pyromelatine accumulates in the CNS of the subject. Aspect 33: The pharmaceutical composition according to any one of Aspects 11 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide accumulates in the CNS of the subject. Aspect 34: The pharmaceutical composition according to any one of Aspects 12 or 14 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide accumulates in the CNS of the subject. Aspect 35: The pharmaceutical composition according to any one of Aspects 13 to 24, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide accumulates in the CNS of the subject. Aspect 36: The pharmaceutical composition according to any one of Aspects 1 to 35, wherein the melatonin receptor agonist has a slower passive diffusion rate compared to melatonin. Aspect 37: The pharmaceutical composition according to any one of Aspects 1 to 36, wherein the melatonin receptor agonist has a faster rate of cerebrospinal fluid (CSF) outflow via the blood-brain barrier (BBB) efflux transporter compared to melatonin. Aspect 38: The pharmaceutical composition according to any one of Aspects 1 to 37, wherein the melatonin receptor agonist has a faster CNS metabolic rate compared to melatonin. Aspect 39: The pharmaceutical composition according to any one of Aspects 1 to 38, wherein the melatonin receptor agonist has a faster CNS excretion rate compared to melatonin. Aspect 40: The pharmaceutical composition according to any one of Aspects 1 to 39, wherein the melatonin receptor agonist has an increased binding to one or more CNS proteins compared to melatonin. Aspect 41: The pharmaceutical composition according to any one of Aspects 1 to 40, wherein the melatonin receptor agonist has an increased binding to one or more peripheral proteins compared to melatonin. Aspect 42: The pharmaceutical composition according to any one of Aspects 1 to 41, wherein the melatonin receptor agonist is conjugated with or encapsulated with a molecule having a low ability to cross the blood-brain barrier. Aspect 43: The pharmaceutical composition according to Aspect 42, wherein the molecule is a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule. Aspect 44: The pharmaceutical composition according to any one of Aspects 1 or 3 to 43, for use in the treatment of polycystic ovary syndrome (PCOS) in a subject in need of treatment for polycystic ovary syndrome (PCOS). Aspect 45: The pharmaceutical composition according to any one of Aspects 1 or 3 to 43, for use in the treatment of endometriosis in a subject in need of treatment for endometriosis. Aspect 46: The pharmaceutical composition according to any one of Aspects 1 or 3 to 43, for use in the treatment of symptoms of menopause in a subject in need of treatment for symptoms of menopause. Aspect 47: The pharmaceutical composition according to any one of Aspects 1 to 43, for use in the treatment of symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of treatment for symptoms of chemotherapy-induced ovarian insufficiency. Aspect 48: The pharmaceutical composition according to any one of Aspects 2 to 43, for use in the prevention of symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of prevention of symptoms of chemotherapy-induced ovarian insufficiency. Aspect 49: The pharmaceutical composition according to any one of Aspects 2 to 43, for use in reducing symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of reducing symptoms of chemotherapy-induced ovarian insufficiency. Aspect 50: The pharmaceutical composition according to any one of Aspects 2 to 43, for use in suppressing symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of suppressing symptoms of chemotherapy-induced ovarian insufficiency. Aspect 51: The pharmaceutical composition according to any one of Aspects 1 to 43, for use in the treatment of inflammation of the reproductive tract in a subject in need of treatment for inflammation of the reproductive tract. Aspect 52: The pharmaceutical composition according to any one of Aspects 1 to 51, wherein when the therapeutically effective amount is administered to the subject, it is effective for preventing, reducing, or suppressing one or more symptoms associated with polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in the subject. Aspect 53: A pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is a. formulated for intravaginal, b. intrauterine, or c. systemic administration, and has a reduced accumulation in the central nervous system (CNS) compared to melatonin, and the therapeutically effective amount is effective for preventing, reducing, or suppressing one or more symptoms associated with chemotherapy-induced ovarian insufficiency in a subject in need of preventing, reducing, or suppressing one or more symptoms associated with chemotherapy-induced ovarian insufficiency. Aspect 54: A method for treating or alleviating the symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in a subject in need thereof, comprising administering to the subject in need of treating or alleviating these symptoms a pharmaceutical composition according to any one of Aspects 1 to 52. Aspect 55: The method according to Aspect 54, wherein the pharmaceutical composition reduces the accumulation in the CNS of the subject compared to melatonin and is administered intravaginally, intrauterinely, or systemically. Aspect 56: The method according to Aspect 54 or 55, wherein the pharmaceutical composition is administered intravaginally and comprises administering the pharmaceutical composition to the dermal layer or transmucosal layer of the vaginal wall of the subject. Aspect 57: The method according to any one of Aspects 54 to 56, wherein the symptoms include abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, decreased bone density, hair loss, hypertension, or a combination thereof. Aspect 58: The method according to any one of Aspects 54 to 57, wherein the symptoms include hot flashes, osteoporosis, risk of infertility, infertility, sleep disorders, joint pain, anxiety, depression, sexual dysfunction, increased risk of cardiovascular disease, loss of primordial ovarian follicles, promotion of activation of primordial ovarian follicles, follicular atresia, stromal tissue damage, ovarian vascular damage, ovarian inflammation, decline in ovarian reserve capacity, increase in the age-dependent loss rate of ovarian reserve capacity, induction of fibrosis, premature menopause, premature ovarian insufficiency, premature ovarian failure, induction of apoptosis in mature ovarian follicles, decrease in estrogen production, decrease in anti-Müllerian hormone (AMH) production, follicle-stimulating hormone (FSH) level, decrease in plasma level of estradiol, or any combination thereof. Aspect 59: The method according to any one of Aspects 54 to 58, wherein the step of administering is carried out according to a dosage and schedule effective to reduce abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, bone density loss, hair loss, hypertension, or a combination thereof, by at least 20%, at least 30%, or at least 40% within 24 hours, 48 hours, or 72 hours as measured by a numerical rating scale (NRS). Aspect 60: The method according to any one of Aspects 54 to 59, wherein the step of administering includes administering at least approximately daily, every 2 days, every 3 days, every 7 days, every 14 days, every 28 days, every 2 months, or every 6 months. Aspect 61: The method according to any one of Aspects 54 to 60, wherein the step of administering includes administering continuously during the treatment period. Aspect 62: The method according to any one of Aspects 54 to 61, wherein the step of administering is started about 15 days before, about 14 days before, about 13 days before, about 12 days before, about 11 days before, about 10 days before, about 9 days before, about 8 days before, about 7 days before, about 6 days before, about 5 days before, about 4 days before, about 3 days before, about 2 days before, about 1 day before, about 18 hours before, about 12 hours before, about 8 hours before, about 6 hours before, about 4 hours before, about 2 hours before, or about 1 hour before the start of chemotherapy in the subject. Aspect 63: The method according to any one of Aspects 54 to 62, wherein the administering step includes administering at a specific time of day or night according to the circadian rhythm of the subject. Aspect 64: The method according to any one of Aspects 54 to 63, wherein the pharmaceutical composition regulates the activity of melatonin receptors outside the CNS according to the circadian rhythm of the subject. Aspect 65: The method according to any one of Aspects 54 to 64, wherein the administering step includes administering at a specific time of day or night regardless of the circadian variation in the plasma melatonin level of the subject. Aspect 66: The method according to any one of Aspects 54 to 65, wherein the administering step does not disrupt the circadian rhythm of the plasma melatonin level of the subject. Aspect 67: The method according to any one of Aspects 54 to 66, wherein the administering step includes administering at any time during a 24-hour period. Aspect 68: The method according to any one of Aspects 54 to 67, wherein the administering step has a reduced effect on melatonin receptor-mediated CNS behavior compared to the case of administering an equal amount of melatonin. Aspect 69: The method according to any one of Aspects 54 to 68, wherein the administering step has a reduced effect on melatonin receptor-mediated CNS behavior during the night time compared to the case of administering an equal amount of melatonin. Aspect 70: The method according to Aspect 68 or 69, wherein the melatonin receptor-mediated CNS behavior includes circadian rhythm, intoxication, sleep behavior, motor control, or memory erasure. Aspect 71: Use of the pharmaceutical composition according to any one of Aspects 1 to 52 for the manufacture of a medicament for treating polycystic ovary syndrome (PCOS) in a subject in need of treatment for polycystic ovary syndrome (PCOS). Aspect 72: Use of the pharmaceutical composition according to any one of Aspects 1 to 52 for the manufacture of a medicament for treating endometriosis in a subject in need of treatment for endometriosis. Aspect 73: Use of the pharmaceutical composition according to any one of Aspects 1 to 52 for the manufacture of a medicament for treating symptoms of menopause in a subject in need of treatment for symptoms of menopause. Use of the pharmaceutical composition according to any one of Aspects 1 to 53 for the manufacture of a medicament for treating chemotherapy-induced ovarian insufficiency in a subject in need of treatment for chemotherapy-induced ovarian insufficiency. Aspect 75: Use of the pharmaceutical composition according to any one of Aspects 1 to 53 for the manufacture of a medicament for treating symptoms of menopause in a subject in need of treatment for symptoms of menopause. Aspect 76: Use of the pharmaceutical composition according to any one of Aspects 1 to 53 for the manufacture of a medicament for treating inflammation of the reproductive tract in a subject in need of treatment for inflammation of the reproductive tract. Aspect 77: The use according to any one of Aspects 70 to 75, wherein the medicament is prepared to be administered according to a dosing schedule including administration at least approximately daily, every 2 days, every 3 days, every 7 days, every 14 days, every 28 days, every 2 months, or every 6 months. Aspect 78: The use according to any one of Aspects 71 to 77, wherein the medicament is prepared to be administered according to a dosing schedule including continuous administration during the treatment period. Aspect 79: The use according to any one of Aspects 71 to 78, wherein the medicament is prepared to be administered according to a dosing schedule including starting administration about 15 days before, 14 days before, 13 days before, 12 days before, 11 days before, 10 days before, 9 days before, 8 days before, 7 days before, 6 days before, 5 days before, 4 days before, 3 days before, 2 days before, 1 day before, 18 hours before, 12 hours before, 8 hours before, 6 hours before, 4 hours before, 2 hours before, or 1 hour before the start of chemotherapy in the subject. Aspect 80: The use according to any one of Aspects 71 to 79, wherein the medicament is prepared to be administered according to a dosing schedule including administration at a specific time of day and night according to the circadian rhythm of the subject. Aspect 81: The use according to any one of Aspects 71 to 79, wherein the medicament is prepared to be administered according to a dosing schedule including administration at a specific time of day and night regardless of the circadian variation in plasma melatonin levels. Aspect 82: The use according to any one of Aspects 71 to 81, wherein the medicament is prepared to be administered according to a dosing schedule including administration without disturbing the circadian rhythm of plasma melatonin levels. Aspect 83: Use according to any one of Aspects 71 - 82, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration at any time during a 24 - hour period. Aspect 84: Use according to any one of Aspects 71 - 83, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration in a manner that reduces the impact on melatonin receptor - mediated CNS behavior compared to when an equal amount of melatonin is administered. Aspect 85: Use according to any one of Aspects 70 - 84, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration in a manner that reduces the impact on melatonin receptor - mediated CNS behavior during nighttime hours compared to when an equal amount of melatonin is administered. Aspect 86: A kit comprising the pharmaceutical composition according to any one of Aspects 1 - 52 and an instruction manual. Aspect 87: The kit according to Aspect 86, wherein the instruction manual specifies one or more indications in a subject in need of treatment, and the one or more indications include polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy - induced ovarian dysfunction (CIOD), or inflammation of the reproductive tract. Aspect 88: The kit according to Aspect 86 or 87, further comprising a drug delivery device for administering the pharmaceutical composition to a subject. Aspect 89: The kit according to any one of Aspects 86 - 88, wherein the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device. Aspect 90: The kit according to any one of Aspects 86 - 89, wherein the drug delivery device is configured to be placed in proximity to the genitalia of the subject. Aspect 91: The kit according to any one of Aspects 86 - 90, wherein the drug delivery device is an intrauterine device and is configured to be placed in proximity to the genitalia of the subject. Aspect 92: The kit according to any one of Aspects 86 - 91, wherein the intrauterine device is configured for time - controlled release or remote - controlled release of one or more doses of the pharmaceutical composition.

Claims

1. A pharmaceutical composition comprising a therapeutically effective amount of a melatonin receptor agonist, wherein the pharmaceutical composition is formulated for a. intravaginal, b. intrauterine, or c. systemic administration, and has a reduced accumulation in the central nervous system (CNS) compared to melatonin, wherein the therapeutically effective amount is effective for treating or alleviating symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in a subject in need of treatment or alleviation of symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract.

2. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises at least one of Circadin (registered trademark), Slenyto (registered trademark), ramelteon, tasimelteon, agomelatine, TIK-301, pyromelatine, N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide (ACH000-143, (Compound 10b)), N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide (Compound 15a), N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide (Compound 19a), or a salt or derivative thereof, or a combination thereof.

3. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises Circadin (registered trademark).

4. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises Slenyto (registered trademark).

5. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises ramelteon.

6. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises tasimelteon.

7. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises agomelatine.

8. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises TIK-301.

9. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises pyromelatine.

10. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide.

11. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide.

12. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist comprises N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide.

13. The melatonin receptor agonist is a type 1A (MT １ ), and a type 1B (MT ２ ), and non-selectively activates melatonin receptors. The pharmaceutical composition according to claim 1.

14. The melatonin receptor agonist preferentially activates the type 1A (MT １ ) melatonin receptor, and the pharmaceutical composition according to claim 1.

15. The melatonin receptor agonist preferentially activates the type 1B (MT ２ ) melatonin receptor, and the pharmaceutical composition according to claim 1.

16. The pharmaceutical composition according to claim 1, formulated as a gel, ointment, solution, powder, paste, foam, cream, or lotion.

17. The pharmaceutical composition according to claim 1, formulated to be delivered via a drug delivery device.

18. The pharmaceutical composition according to claim 17, wherein the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device.

19. The pharmaceutical composition according to claim 18, wherein the drug delivery device is configured to be placed in proximity to the genitalia of the subject.

20. The pharmaceutical composition according to claim 18, wherein the drug delivery device is the intrauterine device and is configured to be placed in proximity to the genitalia of the subject.

21. The pharmaceutical composition according to claim 20, wherein the intrauterine device is configured for time-controlled or remote-controlled release of one or more doses of the melatonin receptor agonist.

22. The pharmaceutical composition according to claim 17, formulated for delayed release, sustained release, extended release, long-term release, or slow release.

23. The pharmaceutical composition according to claim 1, comprising the melatonin receptor agonist in an effective amount for at least about 1 week, 2 weeks, 4 weeks, 2 months, or 6 months.

24. The pharmaceutical composition according to claim 1, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the pharmaceutical composition accumulates in the CNS of the subject.

25. The pharmaceutical composition according to claim 3, wherein less than about 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, or less than 5% of Circadin (registered trademark) accumulates in the CNS of the subject.

26. The pharmaceutical composition according to claim 4, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of Slenyto (registered trademark) accumulates in the CNS of the subject.

27. The pharmaceutical composition according to claim 5, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of ramelteon accumulates in the CNS of the subject.

28. The pharmaceutical composition according to claim 6, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of tasimelteon accumulates in the CNS of the subject.

29. The pharmaceutical composition according to claim 7, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of agomelatine accumulates in the CNS of the subject.

30. The pharmaceutical composition according to claim 8, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of TIK-301 accumulates in the CNS of the subject.

31. The pharmaceutical composition according to claim 9, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of pyromelatine accumulates in the CNS of the subject.

32. The pharmaceutical composition according to claim 10, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of N-[2-(5-chloro-2,6-dimethoxybenzimidazol-1-yl)ethyl]acetamide accumulates in the CNS of the subject.

33. The pharmaceutical composition according to claim 11, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of N-[3-(5-chloro-2-ethoxy-6-methoxybenzimidazol-1-yl)propyl]acetamide accumulates in the CNS of the subject.

34. The pharmaceutical composition according to claim 12, wherein less than about 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of N-[2-(2-methoxy-7,8-dihydro-6-oxa-1,3-diaza-as-indacen-1-yl)ethyl]acetamide accumulates in the CNS of the subject.

35. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has a slower passive diffusion rate compared to melatonin.

36. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has a faster cerebrospinal fluid (CSF) outflow rate via the blood-brain barrier (BBB) efflux transporter as compared with melatonin.

37. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has a faster CNS metabolic rate as compared with melatonin.

38. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has a faster CNS excretion rate as compared with melatonin.

39. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has an increased binding to one or more CNS proteins as compared with melatonin.

40. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist has an increased binding to one or more peripheral proteins as compared with melatonin.

41. The pharmaceutical composition according to claim 1, wherein the melatonin receptor agonist is conjugated or encapsulated with a molecule having a low ability to cross the blood-brain barrier.

42. The pharmaceutical composition according to claim 41, wherein the molecule is a hydrophilic molecule, a carbohydrate molecule, a peptide, or a synthetic molecule.

43. The pharmaceutical composition according to claim 1, for use in the treatment of polycystic ovary syndrome (PCOS) in a subject in need thereof.

44. The pharmaceutical composition according to claim 1, for use in the treatment of endometriosis in a subject in need thereof.

45. The pharmaceutical composition according to claim 1, for use in the treatment of symptoms of menopause in a subject in need thereof.

46. The pharmaceutical composition according to claim 1, for use in the treatment of symptoms of chemotherapy-induced ovarian dysfunction (CIOD) in a subject in need thereof.

47. The pharmaceutical composition according to claim 1, for use in the treatment of inflammation of the reproductive tract in a subject in need thereof.

48. The pharmaceutical composition according to claim 1, for use in the treatment of symptoms of chemotherapy-induced ovarian failure (CIOF) in a subject in need thereof.

49. The pharmaceutical composition according to claim 1 for use in preventing symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of preventing symptoms of chemotherapy-induced ovarian insufficiency.

50. The pharmaceutical composition according to claim 1 for use in reducing symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of reducing symptoms of chemotherapy-induced ovarian insufficiency.

51. The pharmaceutical composition according to claim 1 for use in suppressing symptoms of chemotherapy-induced ovarian insufficiency in a subject in need of suppressing symptoms of chemotherapy-induced ovarian insufficiency.

52. When the therapeutically effective amount is administered to the subject, it is effective to prevent, reduce, or suppress one or more symptoms associated with polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in the subject. The pharmaceutical composition according to any one of claims 1 to 51.

53. A method for treating or alleviating symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract in a subject in need of treatment or alleviation of symptoms of polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian insufficiency, or inflammation of the reproductive tract, comprising the step of administering to the subject in need of treatment or alleviation of these symptoms a pharmaceutical composition according to any one of claims 1 to 52.

54. The method according to claim 53, wherein the pharmaceutical composition is administered vaginally, intrauterinely, or systemically with reduced accumulation in the CNS of the subject compared to melatonin.

55. The method according to claim 54, wherein the pharmaceutical composition is administered vaginally, and administering the pharmaceutical composition to the dermal layer or transmucosal layer of the vaginal wall of the subject.

56. The symptoms include abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, decreased bone density, alopecia, hypertension, or combinations thereof. The method according to any one of claims 53 to 55.

57. The method according to any one of claims 53 to 56, wherein the administering step comprises administering at a dose and schedule effective to reduce abdominal pain, back pain, chronic pelvic pain, dysmenorrhea, amenorrhea, oligomenorrhea, glucose intolerance, insulin resistance, hyperandrogenemia, hepatic steatosis, hirsutism, infertility, weight gain, bone density loss, hair loss, hypertension, or combinations thereof, by at least 20%, at least 30%, or at least 40% within 24 hours, 48 hours, or 72 hours as measured by a numerical rating scale (NRS).

58. The method according to any one of claims 53 to 57, wherein the administering step comprises administering at least approximately daily, every 2 days, every 3 days, every 7 days, every 14 days, every 28 days, every 2 months, or every 6 months.

59. The method according to any one of claims 53 to 58, wherein the administering step comprises administering continuously during the treatment period.

60. The method according to any one of claims 53 to 59, wherein the administering step comprises administering at a specific time of day or night according to the circadian rhythm of the subject.

61. The method according to claim 60, wherein the pharmaceutical composition modulates the activity of melatonin receptors outside the CNS according to the circadian rhythm of the subject.

62. The method according to any one of claims 53 to 61, wherein the administering step comprises administering at a specific time of day or night regardless of the circadian variation in plasma melatonin levels of the subject.

63. The method according to any one of claims 53 to 62, wherein the administering step does not disrupt the circadian rhythm of the plasma melatonin levels of the subject.

64. The method according to any one of claims 53 to 63, wherein the administering step comprises administering at any time during a 24-hour period.

65. The method according to any one of claims 53 to 64, wherein the administering step has a reduced effect on melatonin receptor-mediated CNS behavior compared to administering an equal amount of melatonin.

66. The method according to any one of claims 53 to 65, wherein the administering step has a reduced effect on melatonin receptor-mediated CNS behavior during nighttime hours compared to administering an equal amount of melatonin.

67. The method according to claim 65 or 66, wherein the melatonin receptor-mediated CNS behavior comprises a circadian rhythm, addiction, sleep behavior, motor control, or memory extinction.

68. Use of a pharmaceutical composition according to any one of claims 1 to 52 for the manufacture of a medicament for treating polycystic ovary syndrome (PCOS) in a subject in need of treatment for polycystic ovary syndrome (PCOS).

69. Use of a pharmaceutical composition according to any one of claims 1 to 52 for the manufacture of a medicament for treating endometriosis in a subject in need of treatment for endometriosis.

70. Use of a pharmaceutical composition according to any one of claims 1 to 52 for the manufacture of a medicament for treating symptoms of menopause in a subject in need of treatment for symptoms of menopause.

71. Use of a pharmaceutical composition according to any one of claims 1 to 52 for the manufacture of a medicament for treating inflammation of the reproductive tract in a subject in need of treatment for inflammation of the reproductive tract.

72. Use of a pharmaceutical composition according to any one of claims 1 to 52 for the manufacture of a medicament for treating chemotherapy-induced ovarian dysfunction (CIOD) in a subject in need of treatment for chemotherapy-induced ovarian dysfunction (CIOD).

73. The use according to any one of claims 68 to 72, wherein the medicament is prepared to be administered according to a dosing schedule that includes administration at least approximately daily, every two days, every three days, every seven days, every fourteen days, every twenty-eight days, every two months, or every six months.

74. The use according to any one of claims 68 to 73, wherein the medicament is prepared to be administered according to a dosing schedule that includes a pretreatment that begins about 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 18 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour before the start of chemotherapy in the subject.

75. The use according to any one of claims 68 to 74, wherein the medicament is prepared to be administered according to a dosing schedule that includes continuous administration during the treatment period.

76. The use according to any one of claims 68 to 75, wherein the medicament is prepared to be administered according to a dosing schedule that includes administration at a specific time of day and night according to the circadian rhythm of the subject.

77. The use according to any one of claims 68 to 76, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration at a specific time of day or night, regardless of the circadian variation in plasma melatonin levels.

78. The use according to any one of claims 68 to 77, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration without disturbing the circadian rhythm of plasma melatonin levels.

79. The use according to any one of claims 68 to 78, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration at any time during a 24-hour period.

80. The use according to any one of claims 68 to 79, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration with a reduced impact on melatonin receptor-mediated CNS behavior compared to administration of an equal amount of melatonin.

81. The use according to any one of claims 68 to 80, wherein the pharmaceutical is prepared to be administered according to an administration schedule that includes administration with a reduced impact on melatonin receptor-mediated CNS behavior during nighttime hours compared to administration of an equal amount of melatonin.

82. A kit comprising the pharmaceutical composition according to any one of claims 1 to 52 and a package insert.

83. The kit according to claim 82, wherein the package insert designates one or more indications in a subject in need of treatment, and the one or more indications include polycystic ovary syndrome (PCOS), endometriosis, amenorrhea, chemotherapy-induced ovarian dysfunction (CIOD), chemotherapy-induced ovarian failure (CIOF), or inflammation of the reproductive tract.

84. The kit according to claim 82 or 83, further comprising a drug delivery device for administering the pharmaceutical composition to a subject.

85. The kit according to claim 84, wherein the drug delivery device is a vaginal ring, vaginal tablet, pessary, suppository, patch, or intrauterine device.

86. The kit according to claim 84 or 85, wherein the drug delivery device is configured to be placed in proximity to the genitalia of the subject.

87. The kit according to any one of claims 84 to 86, wherein the drug delivery device is an intrauterine device and is configured to be placed in proximity to the genitalia of the subject.

88. The kit according to any one of claims 84 to 87, wherein the intrauterine device is configured for time-controlled release or remote-controlled release of one or more doses of the pharmaceutical composition formulated for delayed release, sustained release, extended release, long-term release, or slow release.

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