Formulations and methods for treating symptoms of menopause

Abstract

The present disclosure relates to an aqueous topical formulation comprising at least one TRPV1 antagonist and at least one specific plant extract. Also disclosed herein is a method for treating at least one symptom of menopause, comprising topically administering an effective amount of the disclosed formulation.

Description

[Technical field]

[0001] Disclosed herein are aqueous topical formulations comprising at least one TRPV1 antagonist and at least one botanical extract, and methods of treating menopause-related symptoms with the formulations disclosed herein. [Background technology]

[0002] Perimenopause and menopause can be caused by a variety of events, including naturally declining reproductive hormones, surgery to remove ovaries, chemotherapy, radiation therapy, lactation, hypothalamic dysfunction, and premature ovarian failure. Regardless of the onset event, women experiencing perimenopause and menopause have declining estrogen levels that can lead to a collection of physical symptoms, including hot flashes, night sweats, and a syndrome that has recently been called genitourinary syndrome associated with menopause (GSM). Women experiencing GSM can exhibit a variety of problems related to physical changes in the vulva, vagina, and lower urinary tract, including vaginal dryness and irritation, burning sensation, dyspareunia, pain, palpitations, itching, stinging, frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty in sexual arousal, insufficient lubrication during sexual arousal, vaginal bleeding from fragile atrophic skin, and dry labia. Wanczyk-Baszak et al., Menopause Rev 2018;17(4):180-184.

[0003] Vulvovaginal atrophy (VVA) and vulvodynia (VVD) have symptoms that may be components of GSM or may be attributed to separate individual diagnoses. Vulvovaginal atrophy is characterized by thinning of the vaginal wall, dryness, inflammation, decreased lubrication, and impaired skin barrier function. Vulvodynia is characterized by painful burning, stinging, rawness, soreness, palpitation, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule. Due to overlapping symptoms (e.g., inflammation, dyspareunia, burning, vulvar pruritus), misdiagnosis of one for the other is understandable and common. Mitro et al., Women's Midlife Health (2016) 2:4. However, misdiagnosis and treatment of VVA when a subject actually has VVD not only fails to treat the true cause of discomfort and reduce symptoms, but may additionally lead to worsening of symptoms. For example, formulations designed for VVA may not be stable at the pH of the vagina with VVD, and thus exposure to formulations that may contain components that are unstable in the environment in which they are applied may result in further irritation and / or worsening of symptoms instead of relief.

[0004] Further complicating symptom-based diagnosis is the role that estrogen plays in supporting the regulation of healthy vaginal pH in women. As previously described herein, women undergoing perimenopause and menopause have declining estrogen levels. Thus, as estrogen declines through perimenopause and menopause, vaginal pH shifts from acidic to alkaline. Endrocinology (2005) Feb; 146 (2): 816-824. Given the variation in vaginal pH throughout the menopausal experience, pH is an important consideration in topical formulations. Certain ingredients that may be standard in vulvar and vaginal formulations, such as niacinamide, may degrade in environments with a pH higher or lower than 6. Thus, the degradation of ingredients in formulations intended to alleviate or minimize discomfort may instead cause irritation. Application of currently existing topical formulations to already sensitive vulvovaginal tissues in people experiencing VVD or VVA has been shown to exacerbate existing irritation caused by these conditions.

[0005] Observations from rodent models and human patients appear to indicate a link between hormone levels and the establishment of vaginal hypersensitivity, with altered sensitivity accompanying proliferation of sensory nerves in vaginal tissue. Ting et al., Bio.Of Reproduction, 71, 1397-1404 (2004). Also, one study found that subjects suffering from vulvodynia had increased expression and showed increased activity of, among others, the Transient Receptor Potential Vanilloid Type 1 (TRPV1) receptor. Tympanidis et al., European J.of Pain 8 (2004) 129-133. TRPV1 receptors are expressed by nociceptive fibers and are elicited by capsaicin, noxious heat, protons, and chemicals produced during inflammation. Id. TRPV1 receptors are ion channels involved in the transmission and regulation of heat pain sensation from sensory neurons to the brain. Thus, treatments for subjects suffering from what may be vulvodynia may benefit from more specific targeting of pain receptors, including TRVP1, for example, where reduced estrogen leads to further activation of TRPV1 in vaginal tissue.

[0006] Accordingly, the present disclosure provides a method for treating or preventing the inflammatory bowel disease by administering to the patient an effective amount of at least one TRPV1 antagonist and at least one of the following compounds: chamomilla recutita flower extract, sapindus trifoliatus fruit extract, aloe leaf juice, cucumber extract, hydrolyzed quinoa, hamamelis virginiana leaf extract, oat grain extract, oat grain flour, coconut extract, rosa damascena flower extract, microalgae extract, akebia japonica extract, rhodosorus marinus extract, phaeodactylum tricornutum extract, coniferous tree extract, blumea balsamifera extract, kaempferia galanga extract, coriander extract, coriandrum sativum extract, sweet orange extract, citrus aurantium bergamia extract, citrus serrata ... sinensis extract, lavender extract, English lavender (lavandula angustifolia) extract, bay laurel extract, sweet basil extract, basil (ocimum basilicum) extract, basil (ocimum tenuiflorum) extract, mint extract, peppermint (mentha piperita) extract, peppermint (mentha spicata) extract, peppermint (mentha haplocalyx) extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, cymbopogon citratus extract, lemon eucalyptus (corymbia citriodora) extract, prunus mandschurica extract, apple leaf extract, cinnamon bark extract, strawberry extract, angelica sinensis extract, acai oil extract, mangifera indica extract, fumaria officinalis extract, rumex japonicus extract, guaiac wood extract, guaiaicumofficinale extract, guaiacum sanctum extract, lemongrass extract, citrus oil extract, bergamot extract, vanilla planifolia extract, vanilla tahitensis extract, vanilla pompona extract, theobroma cacao extract, pomegranate extract, myrciaria dubia extract, houttuynia cordata extract, sea lettuce extract, ulva compressa extract, agathosma betulina extract, mentha canadensis extract, eclipta prostrate extract, calendula extract, milk thistle extract marianum extract, cydonia oblonga extract, oenothera biennis extract, lepidium meyenii extract, ulmus rubra extract, olea europaea extract, acmella oleracea extract, humulus lupulus extract, nicotiana sylvestris extract, jasmine extract, cananga odorata extract, quince extract, olive tree extract, vaccinium oxycoccus extract, vaccinium macrocarpon extract, prickly pear extract, gymnema sylvestre extract, Portulaca oleracea extract, Rosa penduline extract, Ceratonia siliqua extract, Prunus amygdalus extract, Prunus dulcis extractdulcis extract, prunus armeniaca extract, ginkgo biloba extract, avocado extract, persea americana extract, camellia sinensis extract, eucalyptus extract, linum usitatissimum extract, cyamopsis tetragonoloba extract, sea buckthorn extract, helianthus annuus extract, simmondsia chinensis extract, limnanthes alba extract, sesamum indicum extract, azadirachta indica extract, moringa oleifera extract, cedrus atlantica extract atlantica extract, calophyllum extract, calophyllum inophyllum extract, calophyllum tacamahaca extract, daucus carota extract, daucus carota sativa extract, euphorbia cerifera extract, candelilla extract, carnauba palm extract, echinacea purpurea extract, zea mays extract, quercus infectoria extract, arrowroot extract, eurocoma longifolia extract, trigonella foenum-graecum extract foenum-graecum extract, salvia extract, rosemary extract, sage extract, clary sage extract, oryza sativa extract, zingiber officinale extractand at least one botanical extract selected from: (a) behenyl alcohol (behenyl alcohol) extract, (b) glycerin (behenyl alcohol) extract, (c) behenyl alcohol (behenyl alcohol) extract, (d) behenyl alcohol ...

[0007] The present disclosure also provides a method of treating at least one symptom of menopause in a subject suffering from at least one symptom of menopause, comprising administering to the subject an effective amount of at least one TRPV1 antagonist and at least one hydroxypropyl stearate, alanine, laurel wort extract ... Sesame seed extract, turmeric extract, coriander extract, watercress extract, sweet orange extract, lavender extract, English lavender extract, bay laurel extract, sweet basil extract, basil extract, basil extract, basil extract, mint extract, peppermint extract, green peppermint extract, Taiwan peppermint extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, cymbopogon citratus extract, lemon eucalyptus extract, prunus mandjurica extract, apple leaf extract, cinnamon bark extract, strawberry extract Extracts, Angelica acai extract, Acai oil extract, Mango extract, Mango extract, Rumex extract, Guaiac wood extract, Sophora japonica extract, Sophora japonica extract, Lemongrass extract, Citrus oil extract, Bergamot extract, Vanilla planifolia extract, Vanilla tahitensis extract, Vanilla pompona extract, Theobroma cacao extract, Pomegranate extract, Myrciaria dubia extract, Houtsuiniia cordata extract, Ulva extract, Enteromorpha platyphylla extract, Agatha mabetulina extract, Mentha arvensis extract, Eclipta prostrata extract, Calendula officinalis extract Prunus persica extract, Silybum marianum extract, Cydonia oblonga extract, Oenothera biennis extract, Lepidium meyenii extract, Ulmus rubra extract, Olea europaea extract, Acmella oleracea extract, Humulus lupulus extract, Nicotiana sylvestris extract, Jasmine extract, Cananga odorata extract, Quince extract, Olive tree extract, Cranberry extract, Cranberry extract, Prickly pear extract, Vitis vinifera extract, Portulaca oleracea extract, Rosa penduline extract, Ceratonia siliqua extract, Prunus amygdalus extract,Prunus dulcis extract, Prunus armeniaca extract, Ginkgo biloba extract, Avocado extract, Persea americana extract, Camellia sinensis extract, Eucalyptus extract, Limnaus tatisimum extract, Cluster bean extract, Sea buckthorn extract, Helianthus annuus extract, Simmondsia chinensis extract, Limnanthes alba extract, Sesamum indicum extract, Azadirachta indica extract, Moringa oleifera extract, Cedrus atlantica extract, Calophyllum extract, Calophyllum inophyllum extract, Calophyllum tacamahaca extract, Daucus carota extract, Daucus carota sativa extract, Euphorbia cerifera extract, Candelilla extract, Carnauba palm extract, Echinacea purpurea extract, Corn extract, and at least one plant extract selected from Quercus infectoria extract, Arrowroot extract, Eurycoma longifolia extract, Trigonella foenum-graecum extract, Salvia extract, Rosemary extract, Sage extract, Clary sage extract, Oryza sativa extract, Zingiber officinale extract, Licorice extract, Matricaria recutita extract, Oil palm extract, Tapioca extract, Vitis vinifera extract, Hazelnut tree extract, Turnella diffusa extract, Viola extract, Podocarpus totara extract, Raspberry extract, Rubus idaeus extract, Rubus strigosus extract, Blossom extract, Safflower extract, and Apple extract.

[0008] The present disclosure still further relates to the use of any of the aqueous topical formulations disclosed herein to help treat and / or ameliorate at least one symptom of menopause.

[0009] Additional objects and advantages will be set forth in part in the description which follows and in part will be understood from the description or may be learned by practice. The objects and advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims.

[0010] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory but are not restrictive of the scope of the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Reference will now be made in detail to certain embodiments. While the present disclosure provides illustrated embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the present disclosure as defined by the appended claims.

[0012] Any section headings used herein are for organizational purposes only and should not be construed as limiting the desired subject matter in any way. In the event that any document incorporated by reference conflicts with any term defined herein, the present specification shall control. Although the present teachings are described in conjunction with various embodiments, it is not intended that the present teachings be limited to such embodiments. On the contrary, the present teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those skilled in the art.

[0013] A subject can experience a reduction in normal estrogen levels for a variety of reasons, including due to natural physiological circumstances, such as going through pre-menopause, peri-menopause, menopause, post-menopause, or lactation; due to an induced medical or surgical intervention, such as chemotherapy, radiation therapy, oophorectomy or oophorectomy, hysterectomy, or by taking a selective estrogen receptor modulator, selective estrogen receptor degrader, or antigonadotropin, or due to another condition, such as hypothalamic dysfunction, failed pregnancy, anorexia, or polycystic ovarian syndrome.

[0014] The compositions and methods described herein may be applied to treat, alleviate, and / or regulate at least one symptom in a subject experiencing reduced estrogen levels for at least one of the reasons described above. In at least one embodiment, the reduced estrogen levels are a result of the subject experiencing perimenopause or menopause. In at least one embodiment, the reduced estrogen levels are a result of the subject experiencing menopause. In at least one embodiment, the reduced estrogen levels are a result of the subject undergoing chemotherapy and / or radiation. In at least one embodiment, the reduced estrogen levels are a result of the subject undergoing oophorectomy or oophorectomy. In at least one embodiment, the reduced estrogen levels are a result of the subject undergoing hysterectomy. In at least one embodiment, the reduced estrogen levels are a result of the subject undergoing antigonadotropin therapy. In at least one embodiment, the reduced estrogen levels are a result of the subject undergoing selective estrogen receptor modulator therapy.

[0015] As used herein, the term estrogen refers to hormonally active estrogens, including estrone, estradiol, and estriol. In at least one embodiment, the term estrogen refers to estradiol. In at least one embodiment, the term estrogen refers to at least one of estrone, estradiol, and estriol. In at least one embodiment, the term estrogen refers to at least one of estrone, estradiol, and estriol. In at least one embodiment, the term estrogen includes at least one of estrone, estradiol, and estriol. In at least one embodiment, the term estrogen includes estradiol.

[0016] Normal blood estrogen levels range from about 30 to about 400 pg / mL in premenopausal women and from about 0 to about 30 pg / mL in postmenopausal women. In studies of postmenopausal subjects not using hormone therapy and experiencing chronic vulvodynia, for example, serum hormone levels of estradiol ranged from 12.0 to 27.2 pg / mL, with a mean of 19.8 pg / mL. Mitro et al.,Women's Midlife Health,2:4,(2016).

[0017] In at least one embodiment, a subject experiencing reduced or lower than normal levels of estrogen has a blood estrogen level in the range of about 0 to about 300 pg / mL, e.g., about 0 to about 200 pg / mL, about 5 to about 100 pg / mL, about 10 to about 50 pg / mL, or about 10 pg / mL, about 15 pg / mL, about 20 pg / mL, about 25 pg / mL, about 30 pg / mL, or about 50 pg / mL. In at least one embodiment, a subject experiencing reduced levels of estrogen has a blood estrogen level of about 5 pg / mL or less, about 10 pg / mL or less, about 15 pg / mL or less, about 20 pg / mL or less, about 30 pg / mL or less, or about 50 pg / mL or less. In at least one embodiment, a subject experiencing reduced levels of estrogen has a blood estrogen level that is not measurable or is about 0.

[0018] A subject experiencing reduced levels of estrogen may have a level of estrogen that is in the range of about 10% to about 99% of normal levels, e.g., about 50% to about 99% of normal levels, about 60% to about 95% of normal levels, or about 75% to about 90% of normal levels. In at least one embodiment, a subject experiencing reduced levels of estrogen may have a level of estrogen that is about 50% or less of normal levels, about 75% or less of normal levels, or about 95% or less of normal levels. In at least one embodiment, a subject experiencing reduced levels of estrogen may have a level of estrogen that is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 50%, about 60%, or about 75% of normal levels. In at least one embodiment, a subject experiencing reduced levels of estrogen may have a level of estrogen that is about 20% of normal, about 30% of normal, about 40% of normal, about 50% of normal, about 60% of normal, about 70% of normal, about 80% of normal, about 90% of normal, or about 95% of normal.

[0019] The compositions and methods described herein can be applied to treat, alleviate, and / or regulate at least one symptom of reduced estrogen levels.Subjects with reduced levels of estrogen, also referred to as hypoestrogenic, can experience at least one symptom, including experiencing multiple symptoms.Symptoms of low estrogen conditions include vaginal and / or vulvar dryness, irritation, burning sensation, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, incontinence, dysuria, urinary tract infection (UTI), difficulty in sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of vaginal wall, reduced lubrication, impaired skin barrier function, pain in the area of ​​the vulvar vestibule, allodynia, and hyperalgesia.

[0020] The subject may experience symptoms that may be related to reduced estrogen levels due to natural conditions, such as premenopause, perimenopause, menopause, postmenopause, or lactation. Menopause-related symptoms include, for example, hot flashes, night sweats, dry skin associated with menopausal transition, menstrual irregularities, mood changes, difficulty sleeping, and osteoporosis. The subject may experience symptoms that may be related to reduced estrogen levels due to medical or surgical interventions, such as chemotherapy, radiation, oophorectomy, oophorectomy, hysterectomy, or by taking selective estrogen receptor modulators, selective estrogen receptor degraders, or antigonadotropins. The subject may experience symptoms that may be related to reduced estrogen levels due to disease or disorder, such as hypothalamic dysfunction, pregnancy failure, anorexia, polycystic ovarian syndrome, VVD, VVA, GSM, atrophic vaginitis, or vestibulodynia. A subject may experience symptoms that may be associated with reduced estrogen levels due to at least one condition, or from multiple conditions, including any combination of the conditions described herein.

[0021] The compositions and methods described herein may be applied to treat, alleviate, and / or regulate at least one menopause-related symptom. Menopause-related symptoms may be due to estrogen levels that are temporarily or permanently reduced in a subject. Temporarily reduced estrogen levels may result from subjects who are, for example, breastfeeding or undergoing chemotherapy, while permanently reduced estrogen levels may result from, for example, after hysterectomy or during late menopause. Menopause-related symptoms include vaginal and / or vulvar dryness, irritation, burning sensation, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), sexual arousal difficulties, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal wall, reduced lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0022] A low estrogen state can manifest as an imbalance in the vulvovaginal microflora resulting in an altered pH. A component of the vaginal microflora is the lactobacillus bacteria, which produce lactic acid and maintain an optimal low pH of the vaginal fluid. Naumova et al., Int. J. of Women's Health, 10, 387-395 (2018). Low pH protects against infections of the urogenital tract, and under conditions of estrogen deficiency, the balance of the microflora is disrupted and the vagina can develop a less acidic pH, such as 5.5 to 6.8. Id. A shift in the normal microflora can result in a decrease in Lactobacillus ssp., which can lead to an overgrowth of skin and rectal pathogens, such as the pathogenic yeast Candida albicans. Flores, et al., StatPearls (2020), StatPearls Publishing: https: / / www.ncbi.nlm.nih.gov / books / NBK564341 / ;retrieved August 31, 2021; De Andres, et al., Pain Practice, 16:2, 204-236 (2016).

[0023] At least one TRPV1 antagonist and a combination of Chamomilla recutita flower extract, Sapindus trifolatus fruit extract, Aloe barbadensis leaf juice, Cucumber extract, Hydrolyzed quinoa, Witch hazel leaf extract, Oat kernel extract, Oat kernel flour, Coconut extract, Rosa damask flower extract, Microalgae extract, Akebia japonica extract, Rhodosolus marinus extract, Phaeodactylum tricornutum extract, Coniferous tree extract, Euonymus edulis extract, Turmeric extract, Coriander extract, Ensui extract, Sweet orange extract, Lavender extract, English Lavender extract, bay laurel extract, sweet basil extract, basil extract, basil extract, mint extract, peppermint extract, green peppermint extract, Taiwan peppermint extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, cymbopogon citratus extract, lemon eucalyptus extract, prunus mandjurica extract, apple leaf extract, cinnamon bark extract, strawberry extract, angelica extract, acai oil extract, mango extract, rambutan extract, guaiac wood extract, yuso Poria Coix Extract, Bahamas Common Grass Extract, Lemongrass Extract, Citrus Oil Extract, Bergamot Extract, Vanilla Planifolia Extract, Vanilla Tahitensis Extract, Vanilla Pompona Extract, Theobroma Cacao Extract, Pomegranate Extract, Myrciaria Dubia Extract, Houtsuini Cordata Extract, Ulva Extract, Enteromorpha Ova Extract, Agathus Mabetulina Extract, Mentha Tuberosa Extract, Eclipta Prostrata Extract, Calendula Extract, Silybum Milk Thistle Extract, Cydonia Oblonga Extract, Oenothera Biennis Extract, Lepidium Meyenii Extract, Ulmus Rubi Extract Extract of La, Olea europaea Extract, Acmella oleracea Extract, Humulus lupulus Extract, Nicotiana sylvestris Extract, Jasmine Extract, Cananga odorata Extract, Quince Extract, Olive Tree Extract, Cranberry Extract, Cranberry Extract, Prickly Pear Extract, Venus Vine Extract, Portulaca oleracea Extract, Rosa penduline Extract, Ceratonia siliqua Extract, Prunus amygdalus Extract, Prunus dulcis Extract, Prunus armeniaca Extract, Ginkgo Biloba Extract, Avocado Extract, Persea americana Extract,Camellia sinensis extract, Eucalyptus extract, Limnanthes tachissimum extract, Cluster bean extract, Sea buckthorn extract, Helianthus annuus extract, Simmondsia chinensis extract, Limnanthes alba extract, Sesamum indicum extract, Azadirachta indica extract, Moringa oleifera extract, Cedrus atlantica extract, Calophyllum extract, Calophyllum inophyllum extract, Calophyllum tacamahaca extract, Daucus carota extract, Daucus carota sativa extract, Euphorbia cerifera extract, Candelilla extract, Carnauba palm extract, Echinacea purpurea extract, Zea mays extract, Quercus infectoria extract, Arrowroot extract and at least one plant extract selected from: Eurycoma longifolia extract, Trigonella foenum-graecum extract, Salvia officinalis extract, Rosemary extract, Sage extract, Clary sage extract, Oryza sativa extract, Zingiber officinale extract, Licorice extract, Matricaria recutita extract, Oil palm extract, Tapioca extract, Vitis vinifera extract, Hazelnut tree extract, Turnella diffusa extract, Viola extract, Podocarpus totara extract, Raspberry extract, Rubus idaeus extract, Rubus strigosus extract, Buzzard plant extract, Safflower extract, and Apple extract.

[0024] In some embodiments, the at least one TRPV1 antagonist is present in an amount ranging from 0.0001% w / w to 7% w / w, e.g., from 0.001% w / w to 5% w / w, from 0.01% w / w to 3.5% w / w, and from 0.1% w / w to 3.0% w / w. In some embodiments, the total amount of the plant extract is present in an amount ranging from 0.00001% w / w to 4.0% w / w, e.g., from 0.0001% w / w to 3.5% w / w, from 0.001% w / w to 2.5% w / w, from 0.01% w / w to 1.5%, and from 0.1% to 1% w / w. In at least one embodiment, the at least one TRPV1 antagonist is present in an amount ranging from 0.001% w / w to 4% w / w, and the total amount of plant extract is present in an amount ranging from 0.001% w / w to 4% w / w.

[0025] The aqueous topical formulations disclosed herein can further include sodium hyaluronate and / or other hyaluronic acid salts and / or derivatives. In some embodiments, sodium hyaluronate is present in an amount ranging from 0.0001% w / w to 5% w / w, such as from 0.001% w / w to 4% w / w, from 0.01% w / w to 2.5% w / w, and from 0.1% w / w to 1% w / w. In at least one embodiment, the aqueous topical formulation includes sodium hyaluronate in an amount ranging from 0.001% w / w to 1% w / w.

[0026] The aqueous topical formulations disclosed herein can further include at least one form of vitamin E. In some embodiments, vitamin E is present in an amount ranging from 0.0000001% w / w to 2.0% w / w, such as from 0.000001% w / w to 1% w / w, and from 0.00001% w / w to 0.1% w / w. In at least one embodiment, the aqueous topical formulation includes vitamin E in an amount ranging from 0.0000001% w / w to 1% w / w.

[0027] The aqueous topical formulations disclosed herein can further comprise coconut oil. In some embodiments, the coconut oil is present in an amount ranging from 0.0000001% w / w to 1.0% w / w, such as from 0.000001% w / w to 0.5% w / w, from 0.00001% w / w to 0.2%, and from 0.0001% to 0.1% w / w. In at least one embodiment, the aqueous topical formulation comprises an amount of coconut oil ranging from 0.0001% w / w to 1% w / w.

[0028] The aqueous topical formulations disclosed herein can further include betaine. In some embodiments, betaine is present in an amount ranging from 0.00001% w / w to 3.0% w / w, such as 0.0001% w / w to 2.0%, 0.001% w / w to 1.0% w / w, and 0.01% w / w to 0.5% w / w. In at least one embodiment, the aqueous topical formulation includes betaine in an amount ranging from 0.001% w / w to 1% w / w.

[0029] The aqueous topical formulations disclosed herein can further include arginine. In some embodiments, arginine is present in an amount ranging from 0.00001% w / w to 3.0% w / w, such as 0.0001% w / w to 2.0%, 0.001% w / w to 1.0% w / w, and 0.01% w / w to 0.5% w / w. In at least one embodiment, the aqueous topical formulation includes an amount of arginine ranging from 0.01% w / w to 1% w / w.

[0030] The aqueous topical formulation disclosed herein can further comprise niacinamide. In some embodiments, niacinamide is present in an amount of less than 3.0% w / w, for example, less than 2.0% w / w, less than 1.0% w / w, less than 0.5% w / w, less than 0.1% w / w, less than 0.01% w / w, or less than 0.0001% w / w. In at least one embodiment, the aqueous topical formulation does not comprise niacinamide. In at least one embodiment, the aqueous topical formulation is substantially free of niacinamide.

[0031] The aqueous topical formulation disclosed herein can be made without or without certain ingredients.For example, ingredients that are hormonally active and / or disrupt the endocrine system, such as parabens, phthalates, or xenoestrogens, may not be desirable for use in formulations suitable for low-estrogen subjects.Similarly, ingredients that cause cancer or are suspected to be carcinogenic, such as formaldehyde, may not be desirable, as may ingredients that cause allergic reactions, such as gluten, soybeans, nuts, mineral oil, or fragrances.In at least one embodiment, the aqueous topical formulation does not contain at least one of niacinamide, estrogen, progesterone, parabens, phthalates, sulfates, gluten, fragrances, soybeans, nuts, mineral oils, and formaldehyde. In at least one embodiment, the aqueous topical formulation is substantially free of at least one of niacinamide, estrogen, progesterone, parabens, phthalates, sulfates, gluten, fragrances, soy, nuts, mineral oil, and formaldehyde.

[0032] Similarly, the aqueous topical formulation disclosed herein can be made without or without ingredients that can irritate the vulvovaginal environment.Irritating ingredients that can shift the pH or osmolality of the formulation to values ​​outside of normal, such as citric acid at a concentration that makes the formulation very acidic (i.e., less than a pH of about 3.5), may be undesirable.In at least one embodiment, the aqueous topical formulation does not include citric acid.

[0033] As used herein, the term "substantially free" of an ingredient refers to containing less than about 1% by weight, e.g., less than about 0.5% by weight, e.g., less than about 0.25% by weight, e.g., less than about 0.1% by weight of such ingredient. In at least one embodiment, "substantially free" means completely free of such ingredient.

[0034] The aqueous topical formulations disclosed herein may further comprise at least one pH adjusting agent. In at least one embodiment, the aqueous topical formulation comprises a pH adjusting agent. In at least one embodiment, the pH adjusting agent comprises lactic acid.

[0035] The aqueous topical formulations disclosed herein can further comprise at least one TRPV1 antagonist.

[0036] Non-limiting examples of TRPV1 antagonists include those selected from Table A. [Table 1-1] [Table 1-2] [Table 1-3]

[0037] In some embodiments, the aqueous topical formulations disclosed herein comprise at least one TRPV1 antagonist selected from Table A.

[0038] Certain marine natural products, including those derived from sea anemones or microalgae, exhibit TRPV1 activity. For example, sea anemones produce a small protein (56 amino acids) called APHC1 that inhibits TRPV1, and a smaller pentapeptide (RRRFV) that retains TRPV1 activity has been designed based on APHC1 for improved formulation and sustainability. SensAmone P5, a commercially available product from Mibelle AG Biochemistry, contains this small pentapeptide encapsulated in a lipid-based carrier system. The carrier system protects the pentapeptide from degradation, improves skin penetration, and can release the pentapeptide when pressure is applied during application or pumped from the packaging. The INCI description for SensAmone P5 is Pentapeptide-59 (and) Hydrogenated Lecithin (and) Butyrospermum Parkii (Shea) Butter (and) Phenethyl Alcohol (and) Ethylhexylglycerin (and) Maltodextrin (and) Water (Aqua / Water). Other commercially available products that may affect the production of TRPV1 and / or inhibit TRPV1 are Mariliance™ and Sensityl™ from Givaudan, both of which contain extracts derived from microalgae: Mariliance contains an extract of the red microalgae, Rhodosorus Marinus, and Sensityl contains an extract of the diatom, Phaeodactylum tricornutum.

[0039] Certain plant extracts have been found to exhibit TRPV1 activity. For example, extracts of plant materials from Mangifera indica, Fumaria officinalis, and Rumex japonicus exhibit TRPV1 antagonistic activity. EP 2700431A1. In addition, extracts of guaiac wood from Zygophyllaceae plants, such as extracts of vermilion and vermilion show TRPV1 antagonistic activity. US2013 / 0315843. Terpenes, modified terpenes, and terpene derivatives produced by plants, including conifers, including borneol, bornyl acetate, and isobornyl isobutyrate, can be isolated from plants of the Heterotheca, Artemisia, Callicarpa, and Dipterocarpaceae families, Blumea balsamifera, and Kaempferia galanga, and also exhibit TRPV1 antagonistic activity. Id. Piperitone is a monoterpene ketone that can be isolated from plants of the Cymbopogon, Andropogon, and Mentha families and exhibits TRPV1 antagonistic activity. Id. Hydroxy-citronellal can be isolated from the seeds of Cymbopogon and plants that produce citronella oil and also exhibit TRPV1 antagonistic activity. Id. Extracts from citrus plants, such as Citrus sinesis and Citrus bergamia, can contain jasminone (2-(trans-2-pentenyl)cyclopentanone) and dihydrojasmone (3-methyl-2-pentylcyclopent-2-en-1-one), which exhibit TRPV1 antagonistic activity. Id. Extracts from vanilla beans, produced by orchids of the Vanilla family, including Vanilla planifolia, Vanilla tahitensis, and Vanilla pompona, contain vanillin. The vanillin derivative, vanillin propylene glycol acetate, exhibits TRPV1 antagonistic activity. Id.

[0040] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist selected from the following: JYL-1421 [N-(4-tert-butylbenzyl)-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea]; KJM429 [N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea]; A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]; BCTC [N-(4-tert-butyl)benzyl-3-(4-trifluoromethyl-benzyl)-urea]; n-(2-bromophenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide];JNJ-17203212[4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide];SB-705498[N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea];SB-366791[4'-chloro-3-methoxycinnamanilide];AMG-9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide];AMG-2674[3-amino-5-[[2-[(2-methoxyethyl)amino]-6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2(1H)-quinoxalinone];Capsazepine;MK-2295[6-((R)-4-(6-(4-fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazine-1 -yl)-5-methylnicotinic acid];Ruthenium red;RRRRWW-NH2;Methoctramine;AG-489;AG-505;DD-161515[N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide];DD-191515[[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide];A-784168 [1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide]; A-795614 [N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea]; AMG-0347 [(E)-N-(7-hydroxy-5,6,7 ,8-Tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide];AMG-517[N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I];Pentapeptide-59;Mariliance;Sensityl;Resiniferatoxin, SYMSITIVE 1609 [4-Tertiary butylcyclohexane], Apritone [2-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]cyclopentanone];(-)-Bornyl acetate;Hydroxycitronellal [(7-hydroxy-3,7-dimethyloctanal];Methyl N,N-dimethylanthranilate;2-Ethoxy-3-ethylpyrazine;L-Piperitone;Isobornyl isobutyrate;4-Acetoxy-2,5-dimethyl-3(2H)-furanone;Tripropylamine;Dihydrojasmone [3-methyl-2- Pentylcyclopent-2-en-1-one];1-methyl-2-pyrrolecarboxaldehyde;3-octyl acetate;2-methylbutyl isovalerate;Jasminone [2-(trans-2-pentenyl)cyclopentanone];Piperonyl isobutyrate;Phenoxyethyl propionate;Propylene glycol vanillin acetate;Octenylcyclopentanone;Butyl isobutyrate;Guaiac wood oil;Tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2H-pyran;and 4-tert-butylcyclohexanol.

[0041] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist that is pentapeptide 59 / SensAmone P5. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist that is a structural derivative or analog of APHC1. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 modulating agent that is pentapeptide 59 / SensAmone P5. In at least one embodiment, the TRPV1 antagonist comprises pentapeptide 59 / SensAmone P5. In at least one embodiment, the TRPV1 modulating agent comprises pentapeptide 59 / SensAmone P5. In at least one embodiment, the aqueous topical formulation comprises at least one of pentapeptide 59 / SensAmone P5, Mariliance™, and Sensityl™. In at least one embodiment, the aqueous topical formulation comprises a marine natural product derived from sea anemones or microalgae. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising a microalgae extract. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising a red microalgae extract. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising a diatom extract. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising an extract of Rhodosorus Marinus. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising an extract of Phaeodactylum tricornutum. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist and a microalgae extract. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist comprising a marine natural product. In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist derived from a sea anemone.

[0042] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising mango extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising ramsey extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising Rumex extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising at least one of guaiac wood extract, euonymus pratense extract, and euonymus pratense extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising guaiac wood extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising euonymus pratense extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising turmeric extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a lemongrass extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a citrus extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a citrus oil extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a citrus oil extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a citrus sinesis extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a bergamot extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a vanilla planifolia extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a vanilla tahitensis extract.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising a vanilla pompona extract.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist comprising vanilla extract.

[0043] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a mango extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a ramsey extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a Rumex extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one of a guaiac wood extract, a scutellaria extract, and a scutellaria extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a guaiac wood extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a daisy extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a turmeric extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a lemongrass extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a citrus extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a citronella oil extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a citrus oil extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a Citrus sinesis extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a bergamot extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a vanilla planifolia extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a vanilla tahitensis extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and vanilla pom pona extract.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and vanilla extract.

[0044] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist that is a plant extract selected from the following: mango extract, mango extract, Rumex extract, guaiac wood extract, oleander extract, oleander extract, daisy extract, turmeric extract, lemongrass extract, citronella oil extract, citrus oil extract, citrus sinesis extract, bergamot extract, vanilla planifolia extract, vanilla tahitensis extract, and vanilla pompona extract. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one botanical extract selected from the following: mango extract, mango extract, Rumex extract, guaiac wood extract, oleander extract, oleander extract, daisy extract, turmeric extract, lemongrass extract, citronella oil extract, citrus oil extract, citrus sinesis extract, bergamot extract, vanilla planifolia extract, vanilla tahitensis extract, and vanilla pompona extract.

[0045] In some embodiments, a transient receptor potential ankyrin (TRPA) antagonist may be included in the aqueous topical formulations described herein. Mammals have only one member of the TRPA ion channel, TRPA1, which is expressed in sensory neurons, epithelial cells, and hair cells. Talavera et al, Physiol Rev 100,725-803(2020).

[0046] Non-exemplary examples of TRPA antagonists are the terpene derivatives, isobornyl isobutyrate; phloretin, which can be isolated from Prunus mandulica and apple tree leaves; 3,3,5-trimethylcyclohexanol; cinnamon oil, which can be isolated from the seeds of trees of the Cinnamomum family; gamma-dodecalactone, which can be isolated from strawberry; vanillic acid, which can be isolated from Angelica sinesis and acai oil and is the oxidized form of vanillin; gamma-methyldecalactone; trans,trans-2,4-nonadienal; 4-allyl-2,6-dimethoxyphenol; o-methoxycinnamalaldehyde; 4-methyl-2-phenyl-2-pentenal (mixed cis and trans); 2-methoxy-4-propyl-phenol; methyl 2-methoxy-benzoate; delta-tetradecalactone; 1-methyl-2-pyrrolecarboxaldehyde; 3,3,5-trimethylcyclohexanol; The aqueous topical formulations include: hexanol; N-(2-hydroxyethyl) lactamide; 2-(3-phenylpropyl) tetrahydrofuran; anisyl butyrate; methyl-4-phenyl butyrate; 3-heptyldihydro-5-methyl-2(3H)-furanone; 3-acetylsulfanylhexyl acetate; 3-methyl-5-propyl-2-cyclohexen-1-one; bornyl valerate; citronellyl acetate, which can be obtained from citronella oil; (2S,5S,6S)-6-) hydroxy-dihydrotheaspirane; and trans-2-hexanal. In at least one embodiment, the aqueous topical formulation includes a TRVP1 antagonist and a TRPA antagonist. In at least one embodiment, the aqueous topical formulation comprises at least one TRPA antagonist selected from terpene derivatives, Prunus manjuliaceus extract, apple leaf extract, cinnamon bark extract, strawberry extract, angelica sinesis extract, citronella oil extract, and acai oil extract.In at least one embodiment, the aqueous topical formulation comprises a TRVP1 antagonist that is also a TRPA antagonist.In at least one embodiment, the aqueous topical formulation comprises a TRPA antagonist instead of a TRPV1 antagonist.In at least one embodiment, the aqueous topical formulation comprises a TRPA antagonist in addition to a TRPV1 antagonist.

[0047] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist encapsulated in a lipid-based carrier system. For example, the lipid-based carrier system may comprise glycols, such as pentylene glycol, propane-1,3-diol, or propylene glycol (also known as propane-1,2-diol); glycerin or glyceryl derivatives, such as glyceryl laurate or ethylhexylglycerin; or polyethylene glycols having a molecular weight of less than about 50,000. The lipid-based carrier system may comprise lipids or other oil-based components that can function as a matrix in addition to an encapsulating component or shell. The matrix may comprise coconut oil, sunflower oil, safflower oil, or lecithin. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist encapsulated in a lipid-based carrier system. In at least one embodiment, the lipid-based carrier system comprises shea butter. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and shea butter. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and shea butter extracted or derived from Butyrospermum parkii. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and shea butter extracted or derived from Vitellaria paradoxa. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist, shea butter, hydrogenated lecithin, phenethyl alcohol, ethylhexylglycerin, and maltrodextrin.

[0048] The aqueous topical formulation disclosed herein can further comprise at least one cooling agent, such as menthol, menthoxypropanediol, and isopulegol, which can induce a cooling sensation when in contact with skin.Menthol is a TRPM8 agonist and can provide a cooling response due to the activation of TRPM8 receptor.Other TRPM8 agonists include borneol, linalool, geraniol, hydroxy-citronellal, icilin, WS-12, and p-menthane-3,8-diol (PMD).Borneol, linalool, geraniol, hydroxy-citronellal, and PMD are terpenes, modified terpenes, or terpene derivatives.Terpenes are produced by plants, including conifers. For example, borneol can be isolated from plants of the Heterotheca, Artemisia, Callicarpa, and Dipterocarpaceae families, Blumea balsamifera, and Kaempferia galanga; linalool can be isolated from plants of the coriander family, including Coriandrum sativum, citrus fruits, including Citrus sinensis, the Lavandula family, including Lavandula angustifolia, the Bay Laurel family, the Basil family, including Sweet Basil and Holy Basil (Ocimum tenuiflorum), and Mentha piperita (peppermint), Mentha spicata (spearmint), and Mentha haplocalyx (Bohe); geraniol can be isolated from citronella, rose, and palmarosa oils, as well as Geranium species; hydroxy-citronellal can be isolated from the seeds of lemongrass (Cymbopogon), a plant that produces citronella oil; and PMD can be isolated from Corymbia citriodora.

[0049] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and menthoxypropanediol. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and menthoxypropanediol. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and menthol. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and isopulegol. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one of menthol, menthoxypropanediol, and isopulegol. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one TRPM8 agonist. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one of a terpene, a modified terpene, or a terpene derivative. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one TRPM8 agonist selected from borneol, linalool, geraniol, hydroxy-citronellal, icilin, WS-12, and PMD. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one plant extract selected from coniferous extracts, extracts from plants of the Heterotheca family, extracts from plants of the Artemisia family, extracts from plants of the Callicarpa family, extracts from plants of the Dipterocarpaceae family, Blumea balsamifera extract, Kaempferia galanga extract, coriander extract, Coriandrum sativum extract, extracts from plants of the Citrus family, Citrus sinensis extract, lavender extract, bay laurel extract, basil extract, mint extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, extract from Cymbopogon, and Corymbia citriodora extract.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one botanical extract selected from coniferous extract, Blumea balsamifera extract, Kaempferia galanga extract, coriander extract, Coriandrum sativum extract, Citrus sinensis extract, lavender extract, bay laurel extract, basil extract, mint extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, Cymbopogon citratus extract, and Corymbia citriodora extract.

[0050] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a coniferous tree extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a daisy extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a turmeric extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a coriander extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a staghorn extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a citrus sinensis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a lavender extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an English lavender extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a bay laurel. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a basil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a basil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a sweet basil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a basil extract.

[0051] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a peppermint extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a mint extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a mint extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a mint extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a citronella oil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a rose oil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a palmerosa oil extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a geranium extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Cymbopogon citratus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a lemon eucalyptus extract.

[0052] The aqueous topical formulations disclosed herein may further comprise at least one humectant and / or moisturizer, such as betaine; aloe; glycol or glycol derivatives, such as polyethylene glycol, pentylene glycol, propane-1,3-diol, or propylene glycol (also known as propane-1,2-diol); glycerin or glyceryl derivatives, such as glyceryl laurate or ethylhexylglycerin; sorbitol or sorbitol derivatives, such as sorbitan oleate decyl glucoside polymer; at least one fatty acid, such as coconut oil; lecithin; or honey. The lecithin may be hydrogenated.

[0053] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one of betaine, aloe, pentylene glycol, propylene glycol, glyceryl laurate, ethylhexylglycerin, glycerin, sorbitan oleate decyl glucoside polymer, lecithin, and coconut oil. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist, betaine, pentylene glycol, ethylhexylglycerin, glycerin, sorbitan oleate decyl glucoside polymer, lecithin, and coconut oil. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist, ethylhexylglycerin, glycerin, hydrogenated lecithin, propylene glycol, and coconut oil. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, ethylhexylglycerin, pentylene glycol, hydrogenated lecithin, and glycerin. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist, pentylene glycol, ethylhexylglycerin, glycerin, sorbitan oleate decyl glucoside polymer, hydrogenated lecithin, propylene glycol, and aloe.

[0054] The aqueous topical formulation disclosed herein may further comprise a skin repair component, such as sodium hyaluronate or other salts or derivatives of hyaluronic acid. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and sodium hyaluronate. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and a hyaluronic acid salt. In at least one embodiment, the aqueous topical formulation comprises sodium hyaluronate. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and sodium hyaluronate.

[0055] The aqueous topical formulation disclosed herein can further include other components that are beneficial to the skin. For example, the formulation can include at least one collagen promoter, such as palmitoyl-lysyl-valyl-lysine acetate salt, available in the commercial product Syn-Coll®. In at least one embodiment, the aqueous topical formulation includes at least one TRPV1 antagonist and palmitoyl-lysyl-valyl-lysine bistrifluoroacetate salt.

[0056] The aqueous topical formulation disclosed herein can further comprise other components that are beneficial to the skin.For example, the formulation can comprise at least one amino acid, such as arginine or its salt.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least arginine and arginine salt.In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and arginine.

[0057] The aqueous topical formulations disclosed herein can further include at least one vitamin or a salt thereof, such as vitamin E, vitamin B, or any form of vitamin E or B. For example, B vitamins include thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), pantothenic acid (vitamin B5), vitamin B6, biotin (vitamin B7), folic acid (vitamin B9), and cobalamin (vitamin B12), and vitamin E includes the four tocopherols, including tocopheryl acetate and tocopheryl, and the four tocotrienols.

[0058] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one form of vitamin E or vitamin B. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one form of vitamin E. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one form of vitamin B. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one form of each of vitamin E and vitamin B. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one of tocopherol and tocopheryl acetate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and tocopheryl acetate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and tocopherol.

[0059] The aqueous topical formulation disclosed herein can further comprise at least one component that is beneficial to the skin and is based on or includes a seed or plant extract. For example, extracts with anti-inflammatory or anti-irritant activity can be included, such as aloe vera juice, Chamomilla recutita flower extract, witch hazel leaf extract, or oat kernel extract including oat kernel flour. Witch hazel is a genus of flowering plants in the Hamamelidaceae family, including Witch Hazel. Plants that contain phenolic alkaloids called avenanthramides include oats, such as Avena sativa, and avenanthramides have anti-inflammatory and antioxidant activity. Oxalic acid-containing seeds or plants, or their extracts, can be used as antioxidants, such as quinoa or other plants of the Oxalis, Chenopodium, or Amaranthaceae family. Seed or plant extracts can be solubilized in oil or other solvents, such as glycerin. Fruit extracts with mild cleansing properties, such as Sapindus trifolatus fruit extract, may be included. Punica granatum (pomegranate) and Myrciaria dubia (camu camu fruit) contain large amounts of vitamin C and may be included in their extracts. Houttuynia cordata (Houttuynia cordata) extracts, including those of leaves or flowers, may be included. Edible seaweed extracts, including Ulva (sea lettuce) family, such as Ulva compressa (formerly known as Enteromorpha compressa), may be included.

[0060] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one extract of aloe, chamomile, witch hazel, oats, quinoa, Sapindus trifolatus fruit, pomegranate, Myrciaria dubia, Houtsuiniia cordata, or Enterophora japonica. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one extract of aloe, chamomile, witch hazel extract, oat kernel extract, oat kernel flour, hydrolyzed quinoa, or Sapindus trifolatus fruit extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and aloe or an aloe extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and Aloe barbadensis leaf juice. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a chamomile flower extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a witch hazel extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an oat kernel extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and avena sativa flour. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and hydrolyzed quinoa. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a sapindus trifolatus fruit extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a witch hazel leaf extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a pomegranate extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Myrciaria dubia extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Houtsuiniia cordata extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Enteromorpha platyphylla extract.In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, Chamomilla recutita extract, Avena sativa extract, and Sapindus trifolatus fruit extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, aloe barbadensis leaf juice, and hydrolyzed quinoa.

[0061] The aqueous topical formulations disclosed herein may further comprise components with a pleasant or beneficial scent. These components may be based on or comprise seed or plant extracts. For example, they may comprise chocolate scented extracts, such as extracts from Akebia quinate or Theobroma cacao, melon scented extracts, such as cucumber extract, including Cucumis sativus fruit extract, coconut scented extracts, such as coconut extracts, such as Cocos nucifera, including coconut, coconut oil, coconut germ, coconut juice, or coconut water, or floral scented extracts and / or components, such as Rosa damascena flower, Jasminum officianale (jasmine) flower, Cananga odorata (ylang-ylang) flower, or phenethyl alcohol. Similarly, plant extracts having herbal aromas may be included, including those from plants of the Agathosma plant family, such as Agathosma betulina (buf leaf), those from plants of the Mentha (mint) family, such as Mentha canadensis, those from plants of the Asteraceae family, such as Eclipta prostrate (hawkweed), Calendula (marigold), and Silybum marianum (milk thistle), those from Cydonia oblonga (quince tree), Oenothera biennis (evening primrose), Lepidium meyenii (maca), Ulmus rubra (slippery elm), Olea europaea (olive), Acmella oleracea, Humulus lupulus (hops), and Nicotiana sylvestris (alcohol).

[0062] from Vaccinium oxycoccus (cranberry family) such as Vaccinium macrocarpon, from Opuntia (prickly pear) family, from Gymnema sylvestre (grumpy plant), from Portulaca (purslane) family, from Rosa (rose) family such as Rosa penduline (rhododendron), from Ceratonia siliqua (carob), from Prunus amygdalus (almond tree), Prunus dulcis (sweet almond), and Prunus armeniaca (apricot) family, from Ginkgo biloba, from avocado plants such as Persea americana, from Camellia Sinensis (tea plant), from Melaleuca (myrtle) such as Eucalyptus, from Linum usitatissimum (linseed), from Cyamopsis from Tetragonoloba (Guar), from the Hippophae (Sea Buckthorn) family, from Helianthus annuus (Sunflower), from Simmondsia chinensis (Jojoba), from Limnanthes alba (White Meadowfoam), from the Sesamum (Pesamum) family such as Sesamum Indicum, from Azadirachta indica (Indian Lilac), from Moringa oleifera (Moringa), from Cedrus atlantica (Atlas Cedar), from the Calophyllum family such as Calophyllum inophyllum and Calophyllum tacamahaca, from the Carrot family such as Daucus Carota Sativa, from Euphorbia Cerifera (also known as Euphorbia antisyphilitica) (Candelilla), from Copernicia prunifera (Carnauba Palm), from Echinacea purpurea (cornflower), Zea mays (corn), Quercus infectoria (manjacnica), Arrowroot and other Pueraria family extracts, Eurocoma longifolia (longjack), Trigonellafrom foenum-graecum (fenugreek), from the Salvia family, such as Salvia rosmarinus (rosemary), Salva officinalis (common sage), and Salvia sclarea (clary sage), from Oryza sativa (Asian rice), from Zingiber officinale (ginger), from Glycyrriza glabra (licorice), from Matricaria recutita (German chamomile), from the Elaeis family, from Manihot esculenta (tapioca), from Vitis vinifera (grape), from the Corylaceae family, such as Corylus avellana (hazelnut), from Turnera diffusa (damiana), from Viola sororia (common violet), from the Podocarpus family, such as Podocarpus totara, Rubus idaeus and Rubus Extracts derived from plants, including flowers, seeds, fruits, petals, and / or stems commonly associated with various traditional medicines, including from the Rubus (Raspberry) family, such as strigosus, from the Baptisia (Purple Rose) family, such as Baptisia australis, from Carthamus tinctorius (Safflower), and from the Malus (Apple) family, may be included in the aqueous topical formulations disclosed herein.

[0063] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a component (a) of the invention, comprising phenylethyl alcohol, Akebia quinate extract, Theobroma cacao extract, Cucumber extract, Coconut extract, Damask rose extract, Jasmine extract, Cananga odorata extract, Agathus mabetulina extract, Mentha arvensis extract, Eclipta prostrata extract, Calendula extract, Silybum marianum extract, Quince extract, Oenothera biennis extract, Lepidium meyenii extract, Ulmus rubra extract, Olive tree extract, Acmella oleracea extract, Humulus Lupulus extract, Nicotiana sylvestris extract, Cranberry extract, Cranberry extract, Prickly pear extract, Blue vine extract, Portulaca oleracea extract, Rosa penduline extract, Ceratonia siliqua extract, Prunus amygdalus extract, Prunus dulcis extract, Prunus armeniaca extract, Ginkgo biloba extract, Avocado extract, Persea americana extract, Camellia sinensis extract, Eucalyptus extract, Linum usitatissimum extract, Cluster bean extract, Sea buckthorn extract, Helianthus annuus extract , Simmondsia Chinensis Extract, Limnanthes Alba Extract, Sesamum Indicum Extract, Azadirachta Indica Extract, Moringa Oleifera Extract, Cedrus Atlantica Extract, Calophyllum Extract, Calophyllum Inophyllum Extract, Calophyllum Takamahaka Extract, Daucus Carota Extract, Daucus Carota Sativa Extract, Euphorbia Cerifera Extract, Candelilla Extract, Carnauba Extract, Echinacea Purpurea Extract, Zea Mays Extract, Quercus Infectoria Extract, Arrowroot Extract, Eurycomarone Gypholia Extract, Trigonella foenum-graecum Extract, Salvia Extract, Rosemary Extract, Sage Extract, Clary Sage Extract, Oryza Sativa Extract, Zingiber Officinale Extract, Licorice Extract, Matricaria Recutita Extract, Oil Palm Extract, Tapioca Extract, Vitis Vinifera Extract, Hazelnut Tree Extract, Turnella Diffusa Extract, Viola Extract, Podocarpus Totara Extract, Raspberry Extract, Rubus Idaeus Extract, Rubus Strigosus Extract, Blossom Extract, Safflower Extract,or apple extract.

[0064] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and Akebia. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and phenethyl alcohol. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and Theobroma Cacao extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and cucumber extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and Cucumis sativus fruit extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and coconut. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and coconut extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and coconut liquid endosperm. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and coconut water. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and coconut juice.In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Damask rose extract.

[0065] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a jasmine extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a cananga oderata extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an agathus mabetulina extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a menthol extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an eclipta prostate extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a calendula extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a milk thistle extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a quince extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Oenothera biennis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Lepedium meyenii extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Ulmus rubra extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Olive Tree extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Acmella oleracea extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Humulus lupulus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Nicotiana sylvestris extract.

[0066] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a cranberry extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a bilberry extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a prickly pear extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a venus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a portulaca extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a rose extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a rosa penduline extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a ceratonia siliqua extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Prunus amygdalus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Prunus dulcis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Prunus armeniaca extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Ginkgo extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Avocado extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Persea americana extract.

[0067] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Camellia sinensis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a myrtle extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a eucalyptus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Linum usitatissimum extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a guar nut extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a sea buckthorn extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Helianthus annuus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Simmondsia chinensis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Limnanthes alba extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Sesame extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Sesamum indicum extract.

[0068] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Azadirachta indica extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Moringa oleifera extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Cedrus atlantica extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Calophyllum extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Calophyllum inophyllum extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Calophyllum tacamahaca extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a ginseng extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Daucus carota sativa extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Euphorbia cerifera extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Candelilla extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Carnauba palm extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Echinacea purpurea extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a corn extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Quercus infectoria extract.

[0069] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Pueraria extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Arrowroot extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Eurycoma Longifolia extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Fenugreek extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Salvia extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Rosemary extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Sage extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Clary Sage extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an Oryza Sativa extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Zingiber officinale extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a ginger root extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a licorice extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Matricaria recutita extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an oil palm extract.

[0070] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a tapioca extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Vitis vinifera extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a grape extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Corylus avellana extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Hazelnut extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Tournella diffusa extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Viola oleracea extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Viola oleracea extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Podocarpus totara extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a raspberry extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Rubus idaeus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Rubus strigosus extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Purple Thorn extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Baptisia australis extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Safflower extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Safflower extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an apple tree extract.In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an apple extract.

[0071] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Prunus mandulica extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an apple leaf extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a cinnamon bark extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a strawberry extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and a Chinese angelica extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and an acai oil extract.

[0072] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, phenylethyl alcohol, and an extract of Akebia japonica. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, phenylethyl alcohol, coconut liquid endosperm, coconut water, coconut juice, and a Damask rose extract. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, phenylethyl alcohol, and a fruit extract of Cucumis sativus.

[0073] The aqueous topical formulation disclosed herein may further comprise a stabilizer, emulsifier, additive, and / or preservative, such as sodium benzoate, potassium sorbate, xanthan gum, lecithin or modified lecithin, such as hydrogenated lecithin, gluconolactone, hydroxypropyl starch or modified starch, such as hydroxypropyl starch phosphate, styrene / acrylate copolymer, phytic acid or its salts, sodium lauryl sulfoacetate, or maltodextrin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and sodium benzoate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and sodium sorbate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and xanthan gum. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and lecithin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and hydrogenated lecithin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and gluconolactone. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and hydroxypropyl starch. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and styrene / acrylate copolymer. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and sodium phytate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and phytic acid or a salt thereof. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and hydroxypropyl starch phosphate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and maltodextrin.

[0074] In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist and at least one of sodium benzoate, potassium sorbate, xanthan gum, lecithin, hydrogenated lecithin, gluconolactone, hydroxypropyl starch, hydroxypropyl starch phosphate, styrene / acrylate copolymer, phytic acid or a salt thereof, sodium laurel sulfoacetate, or maltodextrin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, sodium benzoate, potassium sorbate, xanthan gum, hydrogenated lecithin, and maltodextrin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, sodium benzoate, hydrogenated lecithin, gluconolactone, hydroxypropyl starch phosphate, styrene / acrylate copolymer, sodium phytate, sodium laurel sulfoacetate, and maltodextrin. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, hydrogenated lecithin, and maltodextrin.

[0075] The total amount of plant extract in the aqueous topical formulations described herein may be present in the formulation in an amount lower than the amount of TRVP1 antagonist (w / w), may be present in the formulation in an amount greater than the amount of TRVP1 antagonist (w / w), or may be present in the formulation in an amount approximately the same as the amount of TRVP1 antagonist (w / w).

[0076] In at least one embodiment, the aqueous topical formulation comprises water, pentapeptide-59, hydrogenated lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, propylene glycol, xanthan gum, glycerin, witch hazel leaf extract, akebia japonica extract, sodium benzoate, potassium sorbate, sodium hyaluronate, coconut oil, tocopheryl acetate, and lactic acid. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, water, propylene glycol, xanthan gum, glycerin, witch hazel leaf extract, akebia japonica extract, sodium benzoate, potassium sorbate, sodium hyaluronate, coconut oil, tocopheryl acetate, and lactic acid.

[0077] In at least one embodiment, the aqueous topical formulation includes water, sodium lauryl sulfoacetate, hydroxypropyl starch phosphate, pentylene glycol, glycerin, gluconolactone, sodium benzoate, styrene / acrylates copolymer, arginine, sodium phytate, chamomilla recutita flower extract, coconut liquid endosperm, coconut water, coconut juice, rosa damascene flower extract, pentapeptide-59, hydrogenated lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, Avena sativa oat kernel flour, tocopherol, and sapindus trifolatus fruit extract. In at least one embodiment, the aqueous topical formulation comprises a TVRP1 antagonist, water, sodium lauryl sulfoacetate, hydroxypropyl starch phosphate, pentylene glycol, glycerin, gluconolactone, sodium benzoate, styrene / acrylates copolymer, arginine, sodium phytate, chamomilla recutita flower extract, coconut extract, rosa damascena flower extract, Avena sativa oat kernel flour, tocopherol, and sapindus trifolatus fruit extract.

[0078] In at least one embodiment, the aqueous topical formulation comprises water, pentylene glycol, palmitoyl-lysyl-valyl-lysine acetate salt, glycerin, sorbitan oleate decyl glucoside crosspolymer, Aloe barbadensis leaf juice, pentapeptide-59, hydrogenated lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, propylene glycol, menthoxypropanediol, betaine, hydrolyzed quinoa, Cucumis sativus fruit extract, and sodium hyaluronate. In at least one embodiment, the aqueous topical formulation comprises a TRPV1 antagonist, water, pentylene glycol, palmitoyl-lysyl-valyl-lysine acetate salt, glycerin, sorbitan oleate decyl glucoside crosspolymer, Aloe barbadensis leaf juice, propylene glycol, menthoxypropanediol, betaine, hydrolyzed quinoa, Cucumis sativus fruit extract, and sodium hyaluronate.

[0079] The aqueous topical formulations disclosed herein may include at least one pH adjusting component to adjust and / or maintain the formulation at a suitable pH. For example, lactic acid may be used to adjust the pH. As described above, a healthy vulvovaginal environment is acidic, with a pH ranging from about 3.5 to about 5.5, for example, a pH of about 3.5 to about 4.5. A relatively high pH, ​​such as a pH above 4.5, may result in or be caused by changes in the vaginal flora, such as Candida (yeast) infection and / or reduced levels of estrogen.

[0080] In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and at least one pH adjusting component. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and lactic acid. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 3.0 to about 7.5. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 3.5 to about 5.5. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 3.5 to about 4.5. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 4. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 5. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 6. In at least one embodiment, the aqueous topical formulation comprises at least one TRPV1 antagonist and has a pH that is about 7.

[0081] The aqueous topical formulations disclosed herein may have an osmolality that is appropriate for feminine intimate products. That is, the product may have an osmolality similar to, or isotonic with, that of normal vaginal secretions, including in the range of about 260 to about 295 mOsm / kg. Products with relatively high osmolality may draw water from the vulvovaginal environment. In at least one embodiment, the aqueous topical formulation has an osmolality in the range of about 150 to about 400 mOsm / kg. In at least one embodiment, the aqueous topical formulation has an osmolality in the range of about 200 to about 400 mOsm / kg. In at least one embodiment, the aqueous topical formulation has an osmolality in the range of about 250 to about 350 mOsm / kg. In at least one embodiment, the aqueous topical formulation has an osmolality in the range of about 260 to about 280 mOsm / kg. In at least one embodiment, the aqueous topical formulation has an osmolality that is about 400 mOsm / kg or less, about 380 mOsm / kg or less, about 375 mOsm / kg or less, or about 350 mOsm / kg or less. In at least one embodiment, the aqueous topical formulation has an osmolality that is about 150 mOsm / kg or more, about 200 mOsm / kg or more, about 300 mOsm / kg or more, about 350 mOsm / kg or more, about 380 mOsm / kg or more, or about 400 mOsm / kg or more.

[0082] The aqueous topical formulations disclosed herein may be in any form that allows for topical exposure to a subject with a low estrogen state and / or menopausal symptoms, such as an emulsion, gel, foam, serum, or lotion for female intimate areas; bath milk; bath soak; body mist; body lotion; or serum. In at least one embodiment, the aqueous topical formulations disclosed herein are in the form of a bath milk or bath soak. In at least one embodiment, the aqueous topical formulations disclosed herein are in a form suitable for female intimate areas, such as an emulsion, gel, foam, serum, or lotion. In at least one embodiment, the aqueous topical formulations disclosed herein are in the form of a body mist. In at least one embodiment, the aqueous topical formulations disclosed herein are in the form of a lotion. In at least one embodiment, the aqueous topical formulations disclosed herein are in the form of a serum. In at least one embodiment, the aqueous topical formulations disclosed herein are in the form of at least one of a lotion, serum, bath milk, bath soak, or body mist.

[0083] The present disclosure also relates to a method of treating at least one symptom of menopause in a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of any of the aqueous topical formulations disclosed herein.

[0084] In some embodiments, at least one symptom is associated with vulvodynia. In some embodiments, at least one symptom is associated with vulvovaginal atrophy. In some embodiments, at least one symptom is associated with hot flashes. In some embodiments, at least one symptom is associated with night sweats. In some embodiments, at least one symptom is associated with dry skin associated with the menopausal transition. In at least one embodiment, at least one symptom is associated with vulvodynia and / or vulvovaginal atrophy.

[0085] The present disclosure still further relates to the use of any of the aqueous topical formulations disclosed herein to help treat and / or ameliorate at least one symptom of menopause.

[0086] In at least one embodiment, the at least one symptom is selected from vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty in sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, soreness, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0087] The present disclosure still further relates to the use of any of the aqueous topical formulations disclosed herein to help treat and / or ameliorate at least one symptom of reduced estrogen levels.

[0088] In at least one embodiment, the at least one symptom of reduced estrogen levels is associated with at least one of premenopause, perimenopause, menopause, postmenopause, lactation, chemotherapy, radiation, oophorectomy, oophorectomy, hysterectomy, administration of a selective estrogen receptor modulator, administration of a selective estrogen receptor degrader, administration of an antigonadotropin, hypothalamic dysfunction, pregnancy failure, anorexia, polycystic ovary syndrome, VVD, VVA, GSM, atrophic vaginitis, and vestibulodynia.

[0089] However, the following formulation examples illustrate formulations according to the present disclosure without limiting its scope.

[0090] Formulation examples In the formulations described herein, the proportions of the various components are expressed as percentages by weight relative to the total weight of the composition.

[0091] Example 1A. Delicate Serum Formulation A serum or lotion formulation suitable for topical application to the vulvovaginal area may contain the range of components listed below: [Table 2]

[0092] A delicate serum was prepared with the following formulation: [Table 3]

[0093] Example 1B. User feedback on delicate serum A total of 31 women experiencing menopause were offered the Delicate Serum formulation with Formulation 1A. Of these women, a total of 27 participants used the Delicate Serum over the full 4-week trial period. Participants were surveyed at the following intervals: pre-trial (27 participants surveyed), 3 days (24), 1 week (24), 2 weeks (26), 3 weeks (28), and post-trial / 4 weeks (27).

[0094] When asked if the product provided "instant hydration and moisturization" after the trial period, 17 of 27 (63%) strongly agreed, 7 of 27 (26%) agreed, 2 of 27 (7%) neither agreed nor disagreed, and 1 of 27 (4%) disagreed. When asked if the product "feel soothing after application" after the trial period, 18 of 27 (67%) strongly agreed, 8 of 27 (30%) agreed, 0 neither agreed nor disagreed, and 1 of 27 (4%) disagreed. When asked if the subject "felt a significant improvement in vaginal dryness" after the trial period, 17 of 27 (63%) strongly agreed, 8 of 27 (30%) agreed, 2 of 27 (7%) neither agreed nor disagreed, and 0 disagreed.

[0095] When asked how they rated the severity of their vaginal dryness before the study began, on average, 5 / 27 (19%) rated their dryness as severe, 16 / 27 (60%) rated their dryness as moderate, 6 / 27 (22%) rated their dryness as mild, and no participants considered themselves to have no vaginal dryness. Thus, 21 / 27 (78%) participants rated their dryness as severe or moderate before the study period began. After 1 week of use, of the 24 participants who completed the survey, 18 / 24 (75%) participants rated the severity of their vaginal dryness as mild, 2 / 24 (8%) rated it as severe, 1 / 24 (4%) rated it as moderate, and 3 / 24 (13%) rated it as not having dryness. After 4 weeks of use, of the 27 participants who completed the survey, 9 / 27 (33%) participants rated the severity of their vaginal dryness as mild, 0 / 27 (11%) rated it as severe, 3 / 27 (11%) rated it as moderate, and 15 / 27 (56%) rated it as not having dryness.

[0096] Before the study began, the majority of women (24 of 27, or 67%) reported that vaginal dryness affected their ability to enjoy sexual relations. After four weeks of use, 19 of 27 (70%) participants rated their ability to fully enjoy sexual relations as marked or good, 1 of 27 (7%) rated it as "some" improvement, and 5 of 27 (19%) participants reported that the question was not applicable.

[0097] Example 2A. Bath Milk Formulation A bath milk or bath soak formulation suitable for topical application to the vulvovaginal area via a subject bathing or immersion in a bathtub may contain the range of components listed below: [Table 4]

[0098] A soothing bath milk was prepared having the following formulation: [Table 5]

[0099] Example 2B. User feedback on bath milk A total of 22 women experiencing menopause were offered the bath milk formulation according to formulation 2B. Of these women, a total of 15 participants used the bath milk over a 7-day trial period. Participants were surveyed at the following intervals: pre-trial (15 participants surveyed) and post-trial / 7 days (15).

[0100] When asked if the product "does not irritate intimate areas" after the trial period, 10 / 15 (67%) strongly agreed, 4 / 15 (27%) agreed, 0 neither agreed nor disagreed, and 1 / 15 (7%) strongly disagreed. When asked if the product was "quick and easy to use" after the trial period, 9 / 15 (60%) strongly agreed, 5 / 15 (33%) agreed, 0 neither agreed nor disagreed, and 1 / 15 (7%) strongly disagreed. When asked if the product was "easy to incorporate into a daily wellness routine" after the trial period, 10 / 15 (67%) strongly agreed, 2 / 15 (13%) agreed, 2 / 15 (13%) neither agreed nor disagreed, and 1 / 15 (7%) strongly disagreed. When asked if the product "left them feeling calm and relaxed" after the trial period, 6 in 15 (40%) strongly agreed, 7 in 15 (47%) agreed, 2 in 15 (13%) neither agreed nor disagreed, and 0 disagreed.

[0101] When asked how they rated the severity of their vaginal dryness before the study began, on average, 2 of 15 (13%) rated their dryness as severe, 7 of 15 (47%) rated their dryness as moderate, 3 of 15 (20%) rated their dryness as mild, and 3 of 15 (20%) participants considered themselves to have no vaginal dryness. Thus, 9 of 15 (60%) participants rated their dryness as severe or moderate before the study period began. After 1 week of use, 0 participants rated their dryness as severe, 3 of 15 (20%) rated their vaginal dryness as moderate, 5 of 15 (33%) rated their vaginal dryness as mild, and 7 of 15 (47%) rated their dryness as nonexistent.

[0102] Before the study began, 7 of 15 (47%) participants rated the severity of their vaginal discomfort or irritation as severe (3 of 15, 20%) or moderate (4 of 15, 27%). After 7 days of use, 7 of 15 (47%) participants reported no vaginal discomfort.

[0103] Example 3A. Cooling mist formulation A formulation of a cooling mist suitable for topical application may contain a range of components as listed below: [Table 6]

[0104] Cooling mists were prepared according to the following formulations: [Table 7]

[0105] Example 3B. User feedback regarding Cooling Mist A total of 33 women experiencing menopause were offered the cooling mist formulation with formulation 3A. A total of 30 participants used the body mist over a 7-day trial period. Participants were surveyed at the following intervals: pre-trial (30 participants surveyed) and post-trial / 7 days (30).

[0106] When asked if the product "feels soothing after application" after the trial period, 17 / 30 (57%) strongly agreed, 11 / 30 (37%) agreed, 1 / 30 (3%) neither agreed nor disagreed, and 1 / 30 (3%) disagreed. When asked if the product "left a cooling sensation on the skin" after the trial period, 18 / 30 (60%) strongly agreed, 10 / 30 (33%) agreed, 1 / 30 (3%) neither agreed nor disagreed, and 1 / 30 (3%) disagreed. When asked if the product "promoted sleep" after the trial period, 12 / 30 (40%) strongly agreed, 11 / 30 (37%) agreed, 6 / 30 (20%) neither agreed nor disagreed, and 1 / 30 (3%) disagreed. When asked if the product "relieved hot flashes" after the trial period, 12 / 30 (40%) strongly agreed, 14 / 30 (47%) agreed, 3 / 30 (10%) neither agreed nor disagreed, and 1 / 30 (3%) disagreed. When asked if the product "relieved night sweats" after the trial period, 13 / 30 (43%) strongly agreed, 12 / 30 (40%) agreed, 2 / 30 (7%) neither agreed nor disagreed, and 2 / 30 (7%) disagreed.

[0107] When asked how they rated the severity of their hot flashes before the study began, on average, 3 / 30 (10%) participants rated their hot flashes as severe, 23 / 30 (77%) participants rated their hot flashes as moderate, 2 / 30 (7%) participants rated their hot flashes as mild, and 2 / 30 (7%) participants reported no hot flashes. Thus, 26 / 30 (87%) participants rated their hot flashes as severe or moderate before the study period began. After 1 week of use, 0 participants rated their hot flashes as severe, 14 / 30 (47%) participants rated their hot flashes as moderate, 13 / 30 (43%) participants rated their hot flashes as mild, and 3 / 30 (10%) participants reported no hot flashes.

[0108] When asked how they rated the severity of their night sweats before the study began, on average, 8 of 30 (27%) participants rated their night sweats as severe, 15 of 30 (50%) participants rated their night sweats as moderate, 6 of 30 (20%) participants rated their night sweats as mild, and 1 of 30 (3%) participants reported no night sweats. Thus, 23 of 30 (77%) participants rated their night sweats as severe or moderate before the study period began. After 1 week of use, 0 participants rated their night sweats as severe, 12 of 30 (40%) participants rated their night sweats as moderate, 14 of 30 (47%) participants rated their night sweats as mild, and 4 of 30 (13%) participants reported no night sweats. Thus, 18 of 30 (60%) participants rated their night sweats as mild or did not report night sweats after the study period had ended.

[0109] Exemplary embodiments Embodiment 1. A method for treating a rheumatoid arthritis with at least one TRPV1 antagonist, comprising administering to the patient an effective amount of at least one of the following: chamomilla recutita flower extract, sapindus trifolatus fruit extract, aloe leaf juice, cucumber extract, hydrolyzed quinoa, witch hazel leaf extract, oat kernel extract, oat kernel flour, coconut extract, damask rose extract, microalgae extract, akebia quinate extract, rhodosolus marinus extract, phaeodactylum tricornutum extract, coniferous tree extract, takasagodai extract, turmeric extract, coriander extract, sui extract, sweet orange extract, lavender extract, English Lavender Extract, Bay Laurel Extract, Sweet Basil Extract, Basil Extract, Holy Basil Extract, Mint Extract, Peppermint Extract, Green Peppermint Extract, Taiwanese Peppermint Extract, Citronella Oil Extract, Rose Oil Extract, Palmarosa Oil Extract, Geranium Extract, Cymbopogon Citratus Extract, Lemon Eucalyptus Extract, Prunus Mandjurica Extract, Apple Leaf Extract, Cinnamon Bark Extract, Strawberry Extract, Angelica Extract, Acai Oil Extract, Mango Extract, Caramel Extract, Rumex Extract, Guaiac Wood Extract Exudation, Solanum gracilis extract, Bahama Solanum extract, Lemongrass extract, Citrus oil extract, Bergamot extract, Vanilla planifolia extract, Vanilla tahitensis extract, Vanilla pompona extract, Theobroma cacao extract, Pomegranate extract, Myrciaria dubia extract, Houtsuiniia cordata extract, Ulva extract, Enteromorpha platyphylla extract, Agathus mabetulina extract, Mentha arvensis extract, Eclipta prostrata extract, Calendula extract, Silybum marianum extract, Cydonia oblonga extract, Oenothera biennis extract, Lepidium meyenii extract, Ulmus Rubra Extract, Olea Europaea Extract, Acmella Oleracea Extract, Humulus Lupulus Extract, Nicotiana Sylvestris Extract, Jasmine Extract, Cananga Odorata Extract, Quince Extract, Olive Tree Extract, Cranberry Extract, Cranberry Extract, Prickly Pear Extract, Venus Vine Extract, Portulaca Oleracea Extract, Rosa Penduline Extract, Ceratonia Siliqua Extract, Prunus Amygdalus Extract, Prunus Dulcis Extract, Prunus Armeniaca Extract, Ginkgo Biloba Extract, Avocado Extract, Persea Americana Extract,Camellia sinensis extract, Eucalyptus extract, Limnaea gracilis extract, Cluster bean extract, Sea buckthorn extract, Helianthus annuus extract, Simmondsia chinensis extract, Limnanthes alba extract, Sesamum indicum extract, Azadirachta indica extract, Moringa oleifera extract, Cedrus atlantica extract, Calophyllum extract, Calophyllum inophyllum extract, Calophyllum tacamahaca extract, Daucus carota extract, Daucus carota sativa extract, Euphorbia cerifera extract, Candelilla extract, Carnauba palm extract, Echinacea purpurea extract, Corn extract, Quercus infectoria extract, Quercus serrata extract, and at least one plant extract selected from: turmeric extract, Eurycoma longifolia extract, Trigonella foenum-graecum extract, salvia extract, rosemary extract, sage extract, clary sage extract, Oryza sativa extract, Zingiber officinale extract, licorice extract, Matricaria recutita extract, oil palm extract, tapioca extract, Vitis vinifera extract, Hazelnut tree extract, Turnella diffusa extract, Viola extract, Podocarpus totara extract, Raspberry extract, Rubus idaeus extract, Rubus strigosus extract, Blossom extract, Safflower extract, and Apple extract.

[0110] Embodiment 2. The aqueous topical formulation of embodiment 1, wherein the at least one TRPV1 antagonist is present in an amount ranging from 0.0001% w / w to 7% w / w, such as from 0.001% w / w to 4% w / w, from 0.01% w / w to 3.5% w / w, and from 0.1% w / w to 3.0% w / w.

[0111] Embodiment 3. The aqueous topical formulation of embodiment 1 or 2, wherein the total amount of the plant extract is present in an amount ranging from 0.00001% w / w to 4.0% w / w, such as from 0.0001% w / w to 3.5% w / w, from 0.001% w / w to 2.5% w / w, from 0.01% w / w to 1.5%, and from 0.1% to 1% w / w.

[0112] Embodiment 4. The aqueous topical formulation of any one of the preceding embodiments, further comprising sodium hyaluronate.

[0113] Embodiment 5. The aqueous topical formulation of embodiment 4, wherein the sodium hyaluronate is present in an amount ranging from 0.0001% w / w to 5% w / w, such as from 0.001% w / w to 4% w / w, from 0.01% w / w to 2.5% w / w, and from 0.1% w / w to 1% w / w.

[0114] Embodiment 6. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises Vitamin E.

[0115] Embodiment 7. The aqueous topical formulation of embodiment 6, wherein Vitamin E is present in an amount ranging from 0.0000001% w / w to 2.0% w / w, such as from 0.000001% w / w to 1% w / w, and from 0.00001% w / w to 0.1% w / w.

[0116] Embodiment 8. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises coconut oil.

[0117] Embodiment 9. The aqueous topical formulation of embodiment 8, wherein the coconut oil is present in an amount ranging from 0.0000001% w / w to 1.0% w / w, such as from 0.000001% w / w to 0.5% w / w, from 0.00001% w / w to 0.2%, and from 0.0001% to 0.1% w / w.

[0118] Embodiment 10. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises betaine.

[0119] Embodiment 11. The aqueous topical formulation of embodiment 10, wherein the betaine is present in an amount ranging from 0.00001% w / w to 3.0% w / w, such as from 0.0001% w / w to 2.0%, from 0.001% w / w to 1.0% w / w, and from 0.01% w / w to 0.5% w / w.

[0120] Embodiment 12. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises arginine.

[0121] Embodiment 13. The aqueous topical formulation of embodiment 12, wherein the arginine is present in an amount ranging from 0.00001% w / w to 3.0% w / w, such as from 0.0001% w / w to 2.0%, from 0.001% w / w to 1.0% w / w, and from 0.01% w / w to 0.5% w / w.

[0122] Embodiment 14. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises niacinamide.

[0123] Embodiment 15. The aqueous topical formulation of embodiment 14, wherein niacinamide is present in an amount of less than 3.0% w / w, such as less than 2.0% w / w, less than 1.0% w / w, less than 0.5% w / w, less than 0.1% w / w, less than 0.01% w / w, or less than 0.0001% w / w.

[0124] Embodiment 16. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation is free of at least one of niacinamide, estrogen, progesterone, parabens, phthalates, sulfates, gluten, fragrances, soy, nuts, mineral oil, and formaldehyde, and preferably free of niacinamide.

[0125] Embodiment 17. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation further comprises at least one pH adjusting agent.

[0126] Embodiment 18. The aqueous topical formulation of embodiment 17, wherein the at least one pH adjusting agent comprises lactic acid.

[0127] Embodiment 19. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation has a pH in the range of about 3.0 to about 7.5.

[0128] Embodiment 20. The aqueous topical formulation of embodiment 19, wherein the topical formulation has a pH in the range of about 3.5 to about 5.5.

[0129] Embodiment 21. The aqueous topical formulation of embodiment 20, wherein the topical formulation has a pH in the range of about 3.5 to about 4.5.

[0130] Embodiment 22. The aqueous topical formulation of any one of the preceding embodiments, wherein the topical formulation has an osmolality in the range of about 150 mOsm / kg to about 400 mOsm / kg.

[0131] Embodiment 23. The aqueous topical formulation of embodiment 22, wherein the topical formulation has an osmolality in the range of about 200 mOsm / kg to about 400 mOsm / kg.

[0132] Embodiment 24. The aqueous topical formulation of embodiment 23, wherein the topical formulation has an osmolality in the range of about 250 mOsm / kg to about 350 mOsm / kg.

[0133] Embodiment 25. The aqueous topical formulation of embodiment 24, wherein the topical formulation has an osmolality in the range of about 260 mOsm / kg to about 280 mOsm / kg.

[0134] Embodiment 26. The aqueous topical formulation of embodiment 22, wherein the topical formulation has an osmolality of about 400 mOsm / kg or less.

[0135] Embodiment 27. The aqueous topical formulation of embodiment 26, wherein the topical formulation has an osmolality of about 380 mOsm / kg or less.

[0136] Embodiment 28. The aqueous topical formulation of embodiment 26, wherein the topical formulation has an osmolality of about 350 mOsm / kg or less.

[0137] Embodiment 29. At least one TRPV1 antagonist is selected from the group consisting of JYL-1421 [N-(4-tert-butylbenzyl)-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea]; KJM429 [N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea]; A-425619 [1-isoquinolin-5-yl-3-(4-trifluorophenyl)phenyl]thiourea]; Fluoromethyl-benzyl)-urea];BCTC[N-(4-tertiary butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide];JNJ-17203212[4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide];SB-705498[N-(2-bromophenyl )-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea];SB-366791[4'-chloro-3-methoxycinnamanilide];AMG-9810[(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide];AMG-2674[3-amino-5-[[2-[(2-methoxy ethyl)amino]-6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2(1H)-quinoxalinone];Capsazepine;MK-2295[6-((R)-4-(6-(4-fluorophenyl)-2-((R)-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid];Ruthenium red;RRRRWW-NH 2;Methoctramine;AG-489;AG-505;DD-161515[N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide];DD-191515[[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide];A-784168[1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide];A -795614 [N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea];AMG-0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide];AMG-517 [N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I];Pentapeptide-59;Mariliance;Sensityl;Resiniferatoxin, SYMSITIVE 1609 [4-Tertiary butylcyclohexane], Apritone [2-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]cyclopentanone];(-)-Bornyl acetate;Hydroxycitronellal [(7-hydroxy-3,7-dimethyloctanal];Methyl N,N-dimethylanthranilate;2-Ethoxy-3-ethylpyrazine;L-Piperitone;Isobornyl isobutyrate;4-Acetoxy-2,5-dimethyl-3(2H )-Furanone;Tripropylamine;Dihydrojasmone [3-methyl-2-pentylcyclopent-2-en-1-one];1-Methyl-2-pyrrolecarboxaldehyde;3-Octyl acetate;2-Methylbutyl isovalerate;Jasminone [2-(trans-2-pentenyl)cyclopentanone];Piperonyl isobutyrate;Phenoxyethyl propionate;Vanillin acetate;Propylene glycol;Octenylcyclopentanone;Butyl isobutyrate;The aqueous topical formulation of any one of the preceding embodiments, wherein the active ingredient is selected from: guaiac wood oil; tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2H-pyran; and 4-tert-butylcyclohexanol.

[0138] Embodiment 30. The aqueous topical formulation of any one of the preceding embodiments, wherein the at least one TRPV1 antagonist is pentapeptide-59.

[0139] Embodiment 31. The aqueous topical formulation of embodiment 30, wherein the pentapeptide-59 comprises a lipid-based carrier system.

[0140] Embodiment 32. The aqueous topical formulation of embodiment 31, wherein the lipid-based carrier system comprises at least one of lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, and maltodextrin.

[0141] Embodiment 33. The aqueous topical formulation of embodiment 32, wherein the lipid-based carrier system comprises shea butter.

[0142] Embodiment 34. The aqueous topical formulation of embodiment 32, wherein the lipid-based carrier system comprises hydrogenated lecithin.

[0143] Embodiment 35. The aqueous topical formulation of any one of the preceding embodiments, wherein the formulation is in a form selected from an emulsion, gel, foam, serum, or lotion for the feminine intimate area; a bath milk; a bath soak; a body mist; or an emulsion, foam, serum, or lotion for the body.

[0144] Embodiment 36. The aqueous topical formulation of embodiment 35, wherein the formulation is a serum.

[0145] Embodiment 37. An aqueous topical formulation according to embodiment 36, wherein the formulation is a serum suitable for application to feminine intimate areas.

[0146] Embodiment 38. The aqueous topical formulation of embodiment 35, wherein the formulation is a bath milk.

[0147] Embodiment 39. The aqueous topical formulation of embodiment 35, wherein the formulation is a bath soak.

[0148] Embodiment 40. The aqueous topical formulation of embodiment 35, wherein the formulation is a body mist.

[0149] Embodiment 41. An aqueous topical formulation according to embodiment 40, wherein the formulation is a body mist applied to the subject via a pump spray bottle.

[0150] Embodiment 42. A method of treating at least one symptom of menopause in a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of a formulation of any one of the preceding embodiments.

[0151] Embodiment 43. The method of embodiment 42, wherein at least one symptom is associated with vulvodynia.

[0152] Embodiment 44. The method of embodiment 42, wherein the at least one symptom is associated with vulvovaginal atrophy.

[0153] Embodiment 45 The method of embodiment 42, wherein at least one symptom is associated with a hot flash.

[0154] Embodiment 46 The method of embodiment 42, wherein the at least one symptom is associated with night sweats.

[0155] Embodiment 47. The method of embodiment 42, wherein the at least one symptom is associated with dry skin associated with the menopausal transition.

[0156] Embodiment 48. The method of embodiment 42, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty in sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0157] Embodiment 49. A method of treating at least one symptom of reduced estrogen levels in a subject suffering from at least one symptom of reduced estrogen levels, comprising topically administering to the subject an effective amount of a formulation of any one of embodiments 1 to 41.

[0158] Embodiment 50. The method of embodiment 49, wherein the at least one symptom is associated with at least one of premenopause, perimenopause, menopause, postmenopause, lactation, chemotherapy, radiation, oophorectomy, oophorectomy, hysterectomy, administration of a selective estrogen receptor modulator, administration of a selective estrogen receptor degrader, administration of an antigonadotropin, hypothalamic dysfunction, pregnancy failure, anorexia, polycystic ovary syndrome, VVD, VVA, GSM, atrophic vaginitis, and vestibulodynia.

[0159] Embodiment 51. The method of embodiment 49, wherein at least one symptom is associated with vulvodynia.

[0160] Embodiment 52. The method of embodiment 49, wherein the at least one symptom is associated with vulvovaginal atrophy.

[0161] Embodiment 53 The method of embodiment 49, wherein at least one symptom is associated with a hot flash.

[0162] Embodiment 54. The method of embodiment 49, wherein the at least one symptom is associated with night sweats.

[0163] Embodiment 55. The method of embodiment 49, wherein the at least one symptom is associated with dry skin associated with the menopausal transition.

[0164] Embodiment 56. The method of embodiment 49, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, soreness, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0165] Embodiment 57. A method for improving at least one symptom of menopause in a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of a formulation described in any one of embodiments 1 to 41.

[0166] Embodiment 58. The method of embodiment 57, wherein at least one symptom is associated with vulvodynia.

[0167] Embodiment 59. The method of embodiment 57, wherein the at least one symptom is associated with vulvovaginal atrophy.

[0168] Embodiment 60. The method of embodiment 57, wherein at least one symptom is associated with a hot flash.

[0169] Embodiment 61. The method of embodiment 57, wherein at least one symptom is associated with night sweats.

[0170] Embodiment 62. The method of embodiment 57, wherein at least one symptom is associated with dry skin associated with the menopausal transition.

[0171] Embodiment 63. The method of embodiment 57, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0172] Embodiment 64. A method for improving at least one symptom of reduced estrogen levels in a subject suffering from at least one symptom of reduced estrogen levels, comprising topically administering to the subject an effective amount of a formulation described in any one of embodiments 1 to 41.

[0173] Embodiment 65. The method of embodiment 64, wherein the at least one symptom is associated with at least one of premenopause, perimenopause, menopause, postmenopause, lactation, chemotherapy, radiation, oophorectomy, oophorectomy, hysterectomy, administration of a selective estrogen receptor modulator, administration of a selective estrogen receptor degrader, administration of an antigonadotropin, hypothalamic dysfunction, pregnancy failure, anorexia, polycystic ovary syndrome, VVD, VVA, GSM, atrophic vaginitis, and vestibulodynia.

[0174] Embodiment 66. The method of embodiment 64, wherein at least one symptom is associated with vulvodynia.

[0175] Embodiment 67. The method of embodiment 64, wherein the at least one symptom is associated with vulvovaginal atrophy.

[0176] Embodiment 68. The method of embodiment 64, wherein at least one symptom is associated with a hot flash.

[0177] Embodiment 69. The method of embodiment 64, wherein at least one symptom is associated with night sweats.

[0178] Embodiment 70. The method of embodiment 64, wherein the at least one symptom is associated with dry skin associated with the menopausal transition.

[0179] Embodiment 71. The method of embodiment 64, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0180] Embodiment 72. An aqueous topical serum comprising water, pentapeptide-59, lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, propylene glycol, xanthan gum, glycerin, witch hazel leaf extract, akebia japonica extract, sodium benzoate, potassium sorbate, sodium hyaluronate, coconut oil, tocopheryl acetate, and lactic acid.

[0181] Embodiment 73. An aqueous topical serum comprising at least one TRPV1 antagonist, water, propylene glycol, xanthan gum, glycerin, witch hazel leaf extract, akebia japonica extract, sodium benzoate, potassium sorbate, sodium hyaluronate, coconut oil, tocopheryl acetate, and lactic acid.

[0182] Embodiment 74. An aqueous topical serum comprising at least one TRPV1 antagonist, water, and at least one of witch hazel leaf extract, Akebia japonica extract, and coconut oil.

[0183] Embodiment 75. An aqueous topical serum according to any one of embodiments 72 to 74, wherein the topical formulation has a pH in the range of about 3.5 to about 5.5.

[0184] Embodiment 76. The aqueous topical serum of embodiment 75, wherein the topical formulation has a pH in the range of about 3.5 to about 4.5.

[0185] Embodiment 77. An aqueous topical serum according to any one of embodiments 72 to 76, wherein the topical formulation has an osmolality in the range of about 200 mOsm / kg to about 400 mOsm / kg.

[0186] Embodiment 78. The aqueous topical serum of embodiment 77, wherein the topical formulation has an osmolality in the range of about 250 mOsm / kg to about 350 mOsm / kg.

[0187] Embodiment 79. The aqueous topical serum of embodiment 78, wherein the topical formulation has an osmolality ranging from about 260 mOsm / kg to about 280 mOsm / kg.

[0188] Embodiment 80. The aqueous topical serum of embodiment 77, wherein the topical formulation has an osmolality of about 250 mOsm / kg or more.

[0189] Embodiment 81. The aqueous topical serum of embodiment 77, wherein the topical formulation has an osmolality of about 380 mOsm / kg or more.

[0190] Embodiment 82. The aqueous topical serum of embodiment 77, wherein the topical formulation has an osmolality of about 400 mOsm / kg or more.

[0191] Embodiment 83. A method for treating a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of an aqueous topical serum described in any one of embodiments 72 to 82.

[0192] Embodiment 84. A method for treating a subject suffering from at least one symptom of reduced estrogen levels, comprising topically administering to the subject an effective amount of an aqueous topical serum of any one of embodiments 72-82.

[0193] Embodiment 85. The method of embodiment 83 or 84, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0194] Embodiment 86. The method of embodiment 83 or 84, wherein at least one symptom is associated with vulvodynia.

[0195] Embodiment 87. The method of embodiment 83 or 84, wherein at least one symptom is associated with vulvovaginal atrophy.

[0196] Embodiment 88. The method of embodiment 83 or 84, wherein at least one symptom is associated with dyspareunia.

[0197] Embodiment 89. The method of embodiment 83 or 84, wherein at least one symptom is associated with vaginal and / or vulvar dryness.

[0198] Embodiment 90. The method of embodiment 83 or 84, wherein at least one symptom is associated with dry skin associated with the menopausal transition.

[0199] Embodiment 91. An aqueous topical bath milk or bath soak comprising water, sodium lauryl sulfoacetate, hydroxypropyl starch phosphate, pentylene glycol, glycerin, gluconolactone, sodium benzoate, styrene / acrylates copolymer, arginine, sodium phytate, chamomilla recutita flower extract, coconut liquid endosperm, coconut water, coconut juice, rosa damascena flower extract, pentapeptide-59, hydrogenated lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, Avena sativa oat kernel flour, tocopherol, and sapindus trifolatus fruit extract.

[0200] Embodiment 92. An aqueous topical bath milk or bath soak comprising at least one TRPV1 antagonist, water, sodium lauryl sulfoacetate, hydroxypropyl starch phosphate, pentylene glycol, glycerin, gluconolactone, sodium benzoate, styrene / acrylates copolymer, arginine, sodium phytate, Chamomilla recutita flower extract, coconut extract, Rosa damascena flower extract, Avena sativa oat kernel flour, tocopherol, and Sapindus trifolatus fruit extract.

[0201] Embodiment 93. An aqueous topical serum comprising at least one TRPV1 antagonist, water, and at least one of Chamomilla recutita flower extract, coconut extract, Rosa damascena flower extract, Avena sativa oat kernel flour, and Sapindus trifolatus fruit extract.

[0202] Embodiment 94. A method of treating a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of an aqueous topical milk bath or bath soak as described in any one of embodiments 91 to 93.

[0203] Embodiment 95. A method of treating a subject suffering from at least one symptom of reduced estrogen levels, comprising topically administering to the subject an effective amount of an aqueous topical milk bath or bath soak as described in any one of embodiments 91 to 93.

[0204] Embodiment 96. The method of embodiment 95 or 95, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0205] Embodiment 97. The method of embodiment 94 or 95, wherein at least one symptom is associated with vulvodynia.

[0206] Embodiment 98. The method of embodiment 94 or 95, wherein at least one symptom is associated with vulvovaginal atrophy.

[0207] Embodiment 99. The method of embodiment 94 or 95, wherein at least one symptom is associated with vaginal and / or vulvar dryness.

[0208] Embodiment 100. The method of embodiment 94 or 95, wherein at least one symptom is associated with vaginal and / or vulvar inflammation or vaginal and / or vulvar irritation.

[0209] Embodiment 101. The method of embodiment 94 or 95, wherein at least one symptom is associated with dry skin associated with the menopausal transition.

[0210] Embodiment 102. An aqueous topical body mist comprising water, pentylene glycol, palmitoyl-lysyl-valyl-lysine acetate salt, glycerin, sorbitan oleate decylglucoside crosspolymer, Aloe barbadensis leaf juice, pentapeptide-59, hydrogenated lecithin, shea butter, phenethyl alcohol, ethylhexylglycerin, maltodextrin, propylene glycol, menthoxypropanediol, betaine, hydrolyzed quinoa, Cucumis sativus fruit extract, and sodium hyaluronate.

[0211] Embodiment 103. An aqueous topical body mist comprising at least one TRPV1 antagonist, water, water, pentylene glycol, palmitoyl-lysyl-valyl-lysine acetate salt, glycerin, sorbitan oleate decylglucoside crosspolymer, Aloe barbadensis leaf juice, propylene glycol, menthoxypropanediol, betaine, hydrolyzed quinoa, Cucumis sativus fruit extract, and sodium hyaluronate.

[0212] Embodiment 104. An aqueous topical body mist comprising at least one TRPV1 antagonist, water, and at least one of Aloe barbadensis leaf juice, hydrolyzed quinoa, and Cucumis sativus fruit extract.

[0213] Embodiment 105. A method for treating a subject suffering from at least one symptom of menopause, comprising topically administering to the subject an effective amount of an aqueous topical body mist described in any one of embodiments 102 to 104.

[0214] Embodiment 106. A method for treating a subject suffering from at least one symptom of reduced estrogen levels, comprising topically administering to the subject an effective amount of an aqueous topical body mist described in any one of embodiments 102-104.

[0215] Embodiment 107. The method of embodiment 105 or 106, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dry labia, thinning and / or inflammation of the vaginal walls, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, and hyperalgesia in the area of ​​the vulvar vestibule.

[0216] Embodiment 108. The method of embodiment 105 or 106, wherein at least one symptom is associated with vulvodynia.

[0217] Embodiment 109. The method of embodiment 105 or 106, wherein at least one symptom is associated with vulvovaginal atrophy.

[0218] Embodiment 110. The method of embodiment 105 or 106, wherein at least one symptom is associated with a hot flash.

[0219] Embodiment 111. The method of embodiment 105 or 106, wherein at least one symptom is associated with night sweats.

[0220] Equivalent The foregoing written specification is believed to be sufficient to enable one skilled in the art to practice the embodiments. The foregoing description and examples detail certain embodiments and set forth the best mode contemplated by the inventors. However, no matter how detailed the foregoing may appear in text, it will be understood that the embodiments can be practiced in many ways and should be construed in accordance with the appended claims and any equivalents thereof.

[0221] As used herein, the term about refers to numerical values, including, for example, integers, fractions, and percentages, whether or not explicitly stated. The term about generally refers to a range of numerical values ​​(e.g., + / - 5 to 10% of the recited range) that one of ordinary skill in the art would consider equal to (e.g., having the same function or result) the recited value. When terms such as at least and about precede a list of numerical values ​​or ranges, the term modifies all of the values ​​or ranges provided in the list. In some instances, the term about may include numerical values ​​that are rounded to the nearest significant figure.

Claims

1. 1. An aqueous topical formulation comprising: at least one TRPV1 antagonist; and Chamomilla recutita flower extract, sapindus trifoliatus fruit extract, aloe leaf juice, cucumber extract, hydrolyzed quinoa, witch hazel (hamamelis virginiana) leaf extract, oat grain extract, oat grain flour, coconut extract, damask rose (rosa damascena) extract, microalgae extract, akebia quinate extract, rhodosorus marinus extract, phaeodactylum tricornutum extract, coniferous tree extract, blumea balsamifera extract, turmeric (kaempferia galanga) extract, coriander extract, coriander (coriandrum sativum) extract, sweet orange (citrus sinensis) extract, lavender extract, English lavender (lavandula angustifolia) extract, bay laurel extract, sweet basil extract, basil (ocimum basilicum) extract, basil (ocimum tenuiflorum) extract, mint extract, peppermint (mentha piperita) extract, green peppermint (mentha spicata) extract, Taiwan peppermint (mentha haplocalyx extract, citronella oil extract, rose oil extract, palmarosa oil extract, geranium extract, cymbopogon citratus extract, lemon eucalyptus (corymbia citriodora) extract, prunus mandshurica extract, apple leaf extract, cinnamon bark extract, strawberry extract, angelica sinensis extract, acai oil extract, mango (mangifera indica) extract, fumaria officinalis extract, rumex japonicus extract, guaiac wood extract, guaiaicum officinale extract, Guaiacumsanctum extract, lemongrass extract, citrus oil extract, bergamot (citrus bergamia) extract, vanilla planifolia extract, vanilla tahitensis extract, vanilla pompona extract, theobroma cacao extract, pomegranate extract, myrciaria dubia extract, houttuynia cordata extract, sea lettuce extract, Ulva compressa extract, Agathosma betulina betulina extract, Mentha canadensis extract, Eclipta prostrata extract, Calendula extract, Milk thistle (Silybum marianum) extract, Cydonia oblonga extract, Evening primrose (Oenothera biennis) extract, Lepidium meyenii extract, Ulmus rubra extract, Olea europaea extract, Acmella oleracea extract, Humulus lupulus extract lupulus extract, Nicotiana sylvestris extract, Jasmine extract, Cananga odorata extract, Quince extract, Olive tree extract, Cranberry (Vaccinium oxycoccus) extract, Vaccinium macrocarpon extract, Prickly pear extract, Gymnema sylvestre extract, Portulaca oleracea extract, Rosa penduline extract, Ceratonia siliqua extract, Prunus amygdalus extract amygdalus extract, prunus dulcis extract, prunus armeniaca extract, ginkgobiloba extract, avocado extract, persea americana extract, camellia sinensis extract, eucalyptus extract, linum usitatissimum extract, guar bean extract, cyamopsis tetragonoloba extract, sea buckthorn extract, helianthus annuus extract, simmondsia chinensis extract, limnanthes alba extract, sesamum indicum extract, azadirachta indica extract indica extract, Moringa oleifera extract, Cedrus atlantica extract, Calophyllum extract, Calophyllum inophyllum extract, Calophyllum tacamahaca extract, Daucus carota extract, Daucus carota sativa extract, Euphorbia cerifera extract, Candelilla extract, Carnauba palm extract palm extract, echinacea purpurea extract, zea mays extract, quercus infectoria extract, arrowroot extract, eurocoma longifolia extract, trigonella foenum-graecum extract, salvia extract, rosemary extract, sage extract, clary sage extract, oryza sativa extract, zingiber officinale extract, licorice extract, matricaria recutita extract recutita extract, oil palm extract, tapioca extract, vitis vinifera (vitisand at least one plant extract selected from: hazelnut tree extract, turnera diffusa extract, violet extract, podocarpus totara extract, raspberry extract, rubus idaeus extract, rubus strigosus extract, baptisteryx extract, safflower extract, and apple extract.

2. 10. The aqueous topical formulation of claim 1, wherein the at least one TRPV1 antagonist is present in an amount ranging from 0.0001% w / w to 7.0% w / w and the at least one plant extract is present in an amount ranging from 0.00001% w / w to 4.0% w / w.

3. (a) sodium hyaluronate present in an amount ranging from 0.0001% w / w to 5% w / w; (b) Vitamin E, present in an amount ranging from 0.0000001% w / w to 1.0% w / w; (c) coconut oil present in an amount ranging from 0.0000001% w / w to 1.0% w / w; (d) betaine, present in an amount ranging from 0.00001% w / w to 3.0% w / w; (e) arginine, present in an amount ranging from 0.00001% w / w to 3.0% w / w; and (f) niacinamide, present in an amount less than 3.0% w / w.

10. The aqueous topical formulation of claim 1, further comprising at least one of:

4. 10. The aqueous topical formulation of claim 1, wherein the topical formulation is free of at least one of niacinamide, estrogen, progesterone, parabens, phthalates, sulfates, gluten, fragrances, soy, nuts, mineral oil, and formaldehyde.

5. 10. The aqueous topical formulation of claim 1, further comprising at least one pH adjusting agent and having a pH in the range of about 3.0 to about 7.

5.

6. 10. The aqueous topical formulation of claim 1, wherein the topical formulation has an osmolality ranging from about 150 mOsm / kg to about 400 mOsm / kg.

7. the at least one TRPV1 antagonist JYL-1421 [N-(4-tert-butylbenzyl)-N'-[3-fluoro-4-(methylsulfonylamino)benzyl]thiourea], KJM429 [N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea], A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], BCTC [N-(4-tertiary butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide], JNJ-17203212 [4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide], SB-705498 [N-(2-bromophenyl)-N'-[(I-1-(5-trifluoromethyl-2-pyridyl) 68 ylidin-68 ne-3-yl)] urea], SB-366791 [4'-chloro-3-methoxycinnamanilide], AMG-9810 [I-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide], AMG-2674 [3-amino-5-[[2-[(2-methoxyethyl)amino]-6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2(1H)-quinoxalinone], Capsazepine, MK-2295 [6-(I-4-(6-(4-fluorophenyl)-2-(I-2-methylpyrrolidin-1-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)-5-methylnicotinic acid], Ruthenium Red, RRRRWW-NH2, methoctramine, AG-489, AG-505, DD-161515 [N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide], DD-191515 [[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide], A-784168 [1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine-4-carboxamide], A-795614 [N-1H-indazol-4-yl-N'-[(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-yl]urea], AMG-0347 [I-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl) 69-ylidin-3-yl)acrylamide], AMG-517 [N-(4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl)-acetamide I], Pentapeptide-59, Mariliance, Sensityl, Resiniferatoxin, SYMSITIVE 1609 [4-tert-butylcyclohexane], Apritone [2-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]cyclopentanone, (-)-Bornyl acetate, Hydroxycitronellal [(7-hydroxy-3,7-dimethyloctanal], Methyl N,N-dimethylanthranilate, 2-ethoxy-3-ethylpyrazine, L-piperitone, isobornyl isobutyrate, 4-acetoxy-2,5-dimethyl-3(2H)-furanone, tripropylamine, Dihydrojasmone [3-methyl-2-pentylcyclopent-2-en-1-one], 1-methyl-2-pyrrolecarboxaldehyde, 3-octyl acetate, 2-methylbutyl isovalerate, Jasminone (2-(trans-2-pentenyl)cyclopentanone), Piperonyl isobutyrate, Phenoxyethyl propionate, Vanillin acetate propylene glycol, octenylcyclopentanone, butyl isobutyrate, Guaiac Wood Oil, tetrahydro-4-methyl-2-(2-methyl-1-propenyl)-2H-pyran, and 4-tert-butylcyclohexanol, 2. The aqueous topical formulation of claim 1, wherein the aqueous topical formulation is selected from the group consisting of:

8. 10. The aqueous topical formulation of claim 1, wherein the at least one TRPV1 antagonist is pentapeptide-59.

9. 10. The aqueous topical formulation of claim 1, wherein the formulation is in a form selected from emulsions, gels, foams, serums, or lotions for female intimate areas; bath milks; bath soaks; body mists; and emulsions, foams, serums, or lotions for the body.

10. 10. The aqueous topical formulation of any one of claims 1 to 9 for use in a method for treating or ameliorating at least one symptom of menopause or reduced estrogen levels in a subject suffering from at least one symptom of menopause or reduced estrogen levels, the method comprising topically administering to the subject an effective amount of the formulation.

11. 11. The aqueous topical formulation of claim 10, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dryness of the labia, thinning and / or inflammation of the vaginal wall, decreased lubrication, impaired skin barrier function, rawness in the area of ​​the vulvar vestibule, spotting, allodynia, hyperalgesia, symptoms associated with vulvodynia, symptoms associated with vulvovaginal atrophy, symptoms associated with hot flashes, symptoms associated with night sweats, and symptoms associated with dry skin associated with the menopausal transition.

12. 11. The aqueous topical formulation of claim 10, wherein the at least one symptom is associated with at least one of premenopause, perimenopause, menopause, postmenopause, lactation, chemotherapy, radiation, oophorectomy, oophorectomy, hysterectomy, administration of a selective estrogen receptor modulator, administration of a selective estrogen receptor degrader, administration of an antigonadotropin, hypothalamic dysfunction, pregnancy failure, anorexia, polycystic ovary syndrome, VVD, VVA, GSM, atrophic vaginitis, vestibulodynia, vulvodynia, vulvovaginal atrophy, hot flashes, night sweats, dry skin associated with the menopausal transition.

13. An aqueous topical serum comprising at least one TRPV1 antagonist, water, and at least one of witch hazel leaf extract, Akebia extract, and coconut oil.

14. 14. The aqueous topical serum of claim 13, wherein the topical formulation has a pH ranging from about 3.5 to about 5.

5.

15. 15. The aqueous topical serum of claim 13 or 14, wherein the topical formulation has an osmolality ranging from about 200 mOsm / kg to about 400 mOsm / kg.

16. 15. An aqueous topical serum according to claim 13 or 14 for use in a method of treating a subject suffering from at least one symptom of menopause or reduced estrogen levels, said method comprising topically administering to said subject an effective amount of said aqueous topical serum.

17. 17. The aqueous topical serum of claim 16, wherein the at least one symptom is selected from the following: vaginal and / or vulvar dryness, irritation, burning, dyspareunia, pain, palpitations, itching, stinging; frequent yeast infections, pressure, yellow, foul-smelling vaginal discharge, tenderness, frequent urination, urinary incontinence, and urgency, urinary tract infections (UTIs), difficulty with sexual arousal, vaginal bleeding from fragile atrophic skin, dryness of the labia, thinning and / or inflammation of the vaginal wall, decreased lubrication, impaired skin barrier function, pain, spotting, allodynia, hyperalgesia in the area of ​​the vulvar vestibule, symptoms associated with vulvodynia, symptoms associated with vulvovaginal atrophy, symptoms associated with dyspareunia, symptoms associated with vaginal and / or vulvar dryness, symptoms associated with dry skin associated with the menopausal transition.