Topical compositions

Abstract

Provided is the use of a composition for treating or ameliorating female sexual dysfunction in a subject, wherein the composition comprises a volatile solvent comprising a lower alcohol and water, and a non-volatile solvent comprising a polyol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

Description

Technical Field

[0001] This invention relates to compositions for treating or improving female sexual dysfunction. Background Technology

[0002] In the International Classification of Diseases and Related Health Problems, the World Health Organization (WHO) defines sexual dysfunction as an individual's inability to engage in sexual relations in the manner he or she desires, noting that sexual response is a psychosomatic process and that the causes of sexual dysfunction typically involve both psychological and physical processes.

[0003] Female sexual dysfunction is a heterogeneous group of sexual problems experienced by women, such as pain during penetration and problems related to libido or sexual interest, sexual arousal, lubrication, genital sensation, orgasm, or sexual satisfaction. It also includes, but is not limited to, mental disorders diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, which requires women to experience extreme distress and interpersonal stress for at least six months.

[0004] It is reported that the prevalence of female sexual dysfunction in women (regardless of age) is typically 40% to 50%; however, some researchers have reported a prevalence as high as 76% in women.

[0005] Interventions for female sexual dysfunction include non-pharmacological therapies such as lifestyle recommendations, relationship counseling, cognitive behavioral therapy, and pelvic floor exercises, as well as pharmacological therapies such as estrogen therapy and flubanoxetine therapy. However, evidence for the effectiveness of these therapies is limited, and there remains an unmet need for appropriate treatments for female sexual dysfunction. Summary of the Invention

[0006] In a first aspect, the present invention provides a composition for treating or improving female sexual dysfunction, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, and the non-volatile solvent comprising a polyol and a diol. Preferably, the composition is for topical application to the vulva.

[0007] The weight ratio of polyol to diol is preferably from 1.5:1 to 6.0:1. Preferably, the pH of the composition is higher than 4.5 and lower than 7.0. In some embodiments, the pH of the composition is higher than 5.0 and lower than 7.0.

[0008] It is presumed that the compositions according to the invention, through, for example, the latent heat cooling effect of the evaporation of the volatile solvent components, locally stimulate nerves and induce endogenous NO production, thereby enhancing the production of endogenous NO. The vulva, richly innervated, contains receptors responsive to a range of physical sensations, including touch, pressure, and temperature. Topical application of the compositions according to the invention can stimulate more than one such receptor, causing them to work synergistically to improve sexual function, including but not limited to sexual arousal, libido, increased lubrication, orgasm, relief of discomfort or pain, and / or overall improvement in quality of sexual life.

[0009] Female sexual dysfunction is a heterogeneous group of sexual problems experienced by women, such as painful penetration and problems related to libido or sexual interest, sexual arousal, lubrication, genital sensation, orgasm, or sexual satisfaction. It encompasses women experiencing any of these problems, with any cause and duration, with single or multiple symptoms of any severity, and occurring in a pervasive or situational context. This includes, but is not limited to, mental disorders diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, which require women to experience extreme distress and interpersonal stress for at least six months.

[0010] Treatment or improvement of female sexual dysfunction is defined as improvement in the subject's sexual function. This includes improvement in one or more symptoms associated with female sexual dysfunction. For example, this may include, but is not limited to, enhanced sensation, enhanced stimulation, enhanced pleasure, increased satisfaction, enhanced sexual arousal, enhanced libido, increased lubrication, enhanced ability to orgasm, reduction of discomfort or pain, and / or overall improvement in quality of sexual life. The subject does not need to have been diagnosed with female sexual dysfunction, although this may be the case in some cases.

[0011] In some implementations, treatment or improvement of female sexual dysfunction may be measured using the validated “gold standard” measurement tool, the Female Sexual Function Index (FSFI). The FSFI is described in Rosen R et al., “The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function”. J Sex Marital Ther. 2000 Apr-Jun; 26(2):191-208. In some implementations, use of the composition will result in an increase in FSFI when data are collected at baseline (before treatment) and at the end of the treatment period. In some implementations, the FSFI score may increase by ≥0.5, ≥1, ≥1.5, ≥2, ≥2.5, ≥3, ≥3.5, ≥4 or more. In some embodiments, the pre-treatment FSFI score of subjects using the composition may be ≤29, ≤28.5, ≤28, ≤27.5, ≤27, ≤26.55, ≤26, ≤25.5, ≤25, ≤24.5, ≤24, ≤23.5, ≤23, ≤22.5, ≤22, ≤21.5, ≤21, ≤20.5, or ≤20. In a particular embodiment, the pre-treatment FSFI score of subjects using the composition may be ≤26.55, and the FSFI score may increase by ≥2, ≥2.5, ≥3, ≥3.5, or ≥4 during treatment.

[0012] In some embodiments, the composition is GTN-free, i.e., does not contain any GTN. In some embodiments, the composition also does not contain any GTN derivatives or prodrugs.

[0013] In some embodiments, the composition does not contain phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, androgens such as testosterone, flibanserin, bremelanotide, estrogens (also known as estradiol), or ospemifene.

[0014] In some embodiments, the composition also does not contain an acetylcholinesterase inhibitor. The acetylcholinesterase inhibitor can be any acetylcholinesterase inhibitor, such as Δ9-tetrahydrocannabinol (THC), physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, rivastigmine, galantamine, caffeine, donepezil, tetrahydroaminoacridine, edrophonium, huperzine A, bis-huperzine A, bis-huperzine B, huperzine A-tacrine, or derivatives of huperzine A. A) ladostigil, ungeremine, and lactucopicrin.

[0015] In some embodiments, the composition does not contain any pharmaceutically active ingredients used to treat female sexual dysfunction, such as hormones like estrogen and testosterone, synthetic hormones like tibolone, estrogen receptor modulators like opemifene, serotonin agonists or antagonists like flubancerine or bupropion, melanocortin receptor agonists like bumenotide, PDE5 inhibitors like tadalafil and sildenafil, acetylcholinesterase inhibitors, and vasodilators like vasoactive vitamins (e.g., vitamin B3), alprostadil, and phentolamine mesylate.

[0016] In some embodiments, the composition does not contain any pharmaceutically active ingredient. A pharmaceutically active ingredient (also known as an active pharmaceutical ingredient (API) or a drug substance) is any substance intended to treat or prevent disease, or to restore, correct, or modify physiological function through pharmacological, immunological, or metabolic actions. Compositions containing pharmaceutically active ingredients require regulatory approval as pharmaceutical products and are accompanied by clinical trials (e.g., through a New Drug Application (NDA) with the FDA or at the EMA according to EU Directive 2001 / 83 / EC). Conversely, compositions that do not contain pharmaceutically active ingredients but can be used to treat patients (e.g., through a physical mechanism of action) can be approved as medical devices. Therefore, whether an ingredient is considered a pharmaceutically active ingredient depends on the ingredient and the intended use of the composition containing it. Thus, in the case of a composition according to the invention acting as a medical device and through a physical mechanism of action, excipients such as ethanol, glycerin, propylene glycol, etc., are not pharmaceutically active ingredients.

[0017] In some embodiments, the composition does not contain compounds selected from PDE-5 inhibitors, amide anesthetics, local anesthetics, natural prostaglandins, synthetic prostaglandins, testosterone, or combinations thereof. Preferably, the composition does not contain PDE-5 inhibitors or amide anesthetics.

[0018] In some embodiments, the composition does not contain menthol, menthol derivatives, borneol, camphor, or mengdiol.

[0019] In certain embodiments, the composition does not contain white petrolatum and / or paraffin.

[0020] This composition is not intended for use as a hand sanitizer. The composition may contain no more than 50% lower alcohol, optionally no more than 45%, optionally no more than 40%, and more optionally no more than 36%. In some embodiments, the composition contains no more than 50% ethanol, optionally no more than 45%, optionally no more than 40%, and more optionally no more than 36%.

[0021] Preferably, the composition is in the form of a gel, cream, or serum, but other forms, such as foams or sprays (with suitable additional excipients, such as propellant gases in the foam or spray), are also considered and within the scope of the invention. More preferably, the formulation is a gel. For formulations in gel form that are applied by hand, a viscosity in the range of 250 mPas to 6000 mPas is suitable to ensure optimal application control, determined by a pH in the range of 4.5-7.0 or 5.0-7.0. Preferably, at 25°C, the viscosity value, measured by a Brookfield viscometer, E-type rotor, at 0.3 RPM, should be in the range of 500 to 4500 mPas, more preferably 1000-3500 mPas, for example, 3000 mPas.

[0022] It has been found that pH affects not only viscosity but also stability and appearance. Regarding viscosity, when the pH is below 4.5 and the composition is a gel, the viscosity is too low, the composition is too fluid to be applied without diffusion or spontaneous dissipation from the application site. Viscosity is acceptable when the pH is above 4.5, preferably above 5.0 or 5.2, although when the pH is above about 5.8, depending on other components present in the composition, the risk of thickeners or gelling agents forming precipitates increases, making the composition unacceptable in appearance. It has been found that the tendency to flocculate, caused or exacerbated by thickeners or gelling agents, can be mitigated by pH. Specifically, viscosity is unacceptable when the pH is significantly below 4.5 (preferably 5.2), while the risk of flocculation is significant when the pH is above 5.8, potentially leading to the product being considered unacceptable by consumers.

[0023] Within a wide pH range of 4.5–7.0, preferably 5.0–7.0, more preferably 5.2–6, and even more preferably 5.25–5.75, viscosity and flocculation are acceptable at this pH range.

[0024] The pH values ​​mentioned above refer to the composition at the time of preparation, although the pH may tend to drift upwards by up to approximately 0.25 pH units in the weeks following manufacturing. Nevertheless, any increase in pH after manufacturing is acceptable because the higher viscosity is tolerable.

[0025] Since the pH tends to shift upwards after manufacturing, the preferred pH range for the composition according to the present invention should be considered as 5.25-6.0, and the upper limits of other ranges should be adjusted accordingly.

[0026] The compositions according to the invention may also contain, depending on their physical form, at least one additional ingredient selected from: agents that enhance skin feel, such as silicone oil compositions like dimethicone 200; thickeners or gelling agents, such as polyacrylate-based compositions; pH control agents, such as triethanolamine or inorganic bases; and antimicrobial preservatives, such as methylparaben and / or propylparaben. In some embodiments, the composition may also contain one or more fragrances and / or one or more colorants.

[0027] The concentration of the additional ingredient is preferably less than 5% by weight, more preferably less than 2% by weight, for example 1.0%. However, the pH control agent is added to bring the pH to the desired target range of 5.0-7.0, preferably 5.1-6.0 or more preferably 5.25-5.75, all of which are the pH at the time of preparation.

[0028] Regarding thickeners or gelling agents, compositions based on polyacrylates have been found to be desirable, which are readily dispersible in solvent blends and facilitate rapid evaporation of volatile solvents to achieve a skin penetration equilibrium rate, preferably within one minute, more preferably within thirty seconds, after application to the vulva. Suitable thickeners or gelling agents comprise high molecular weight interpolymers of crosslinked unsaturated carboxylic acid polymers (which may be homopolymers or copolymers), and copolymeric steric stabiliser having hydrophilic and hydrophobic portions. Preferably, the monomer of the unsaturated carboxylic acid polymer comprises acrylic acid or its alkyl ester derivative, and the steric stabiliser preferably comprises block copolymers and / or random copolymers, wherein the block copolymer preferably comprises a polyester such as 12-hydroxystearic acid as a hydrophobic portion and polyethylene glycol as a hydrophilic portion. Preferably, the unsaturated carboxylic acid comprises acrylic acid crosslinked with allyl sucrose. Such interpolymers, which incorporate steric stabilizers during polymerization, are rapidly wetted and readily dispersed, and will be referred to as “easily dispersible interpolymers of the type described herein” throughout the remainder of this specification (including the claims). Commercially available examples include Carbopol® Ultrez 10, 20, 21, and 30. Homopolymers such as Carbopol® 934P and 937P are not “easily dispersible interpolymers of the described type” because they do not contain steric stabilizers.

[0029] The thickener or gelling agent in the composition preferably comprises 0.5% to 2% by weight. In some embodiments, the composition contains 0.5% to 1.5% by weight of thickener or gelling agent. In other embodiments, the composition contains 0.7% to 1.5% by weight of thickener or gelling agent. In various embodiments, the composition contains 0.8% to 1.2% by weight of thickener or gelling agent. In a particular embodiment, the composition contains about 1% by weight of thickener or gelling agent.

[0030] In some embodiments, the composition may also contain aloe vera. This is a gel-like substance found in the leaves of plants of the genus Aloe. This includes species such as Aloe vera, Aloe ferox, Aloe arborescens, and Aloe perryi. Aloe vera is the most commonly used plant species for obtaining aloe vera gel. The amount of aloe vera in the composition may be 0.5% to 5% by weight. In some embodiments, the amount of aloe vera in the composition may be 0.5% to 4%, 1% to 3%, 1.5% to 2.5%, or about 2% by weight.

[0031] In some embodiments, the composition may also contain a warming agent. This can be used as a sensory agent to provide a physical warming sensation to the skin after the initial cooling sensation provided by the composition. Warming agents can be selected from vanillyl ethyl ether, vanillyl propyl ether, vanillin propylene glycol acetal, ethyl vanillin propylene glycol acetal, capsaicin, gingerol, vanillyl butyl ether, 4-(1-menthoxy-methyl)-2-phenyl-1,3-dioxolane, 12-(1-menthoxy-methyl)-2-(3,4-dihydroxyphenyl)-1,3-dioxolane, 4-(1-menthoxy-methyl)-2-(2-hydroxy-3-methoxyphenyl)-1,3-dioxolane, 13-(1-menthoxy-methyl)-2-(4-methoxyphenyl)-1,3-dioxolane, 14-(1-menthoxy-methyl)-2-(3,4-methylenedioxy-phenyl)-1,3-dioxolane, hot pepper oil, capsicum oleoresin, ginger olioresin, and nonyl vanillyl oleate. The warming agent is (acidvanillylamide), or a combination thereof. Preferably, the warming agent is vanillyl butyl ether (VBE). The amount of the warming agent in the composition may be from 0.001% to 0.05% by weight. In some embodiments, the composition does not contain a warming agent. In some embodiments, the composition does not contain VBE.

[0032] The compositions according to the invention can be considered as single-phase solutions, comprising a volatile solvent pair such as ethanol and water, and a non-volatile solvent pair such as glycerol and propylene glycol. It has been found that using a gelling agent containing readily dispersible polymers of this type and having the desired pH in such systems allows for precise application of the composition to the vulva. Furthermore, the use of readily dispersible polymers of this type, particularly Carbopol® Ultrez 10, unexpectedly results in a higher viscosity than previously thought, which is advantageously acceptable because such polymers of this type impart rheological properties to the composition such that during use and when applied to the vulva by hand, rubbing or spreading causes a temporary decrease in viscosity, allowing the volatile solvents to evaporate even more rapidly, thereby establishing equilibrium within a target time of less than one minute, preferably less than 30 seconds. Simultaneously, the increase in viscosity under non-shear conditions does not affect penetration.

[0033] Volatile solvents may have a molecular weight of 15 g / mol to 75 g / mol. Non-volatile solvents may have a molecular weight of 40 g / mol to 200 g / mol, preferably 50 g / mol to 150 g / mol, and more preferably 60 g / mol to 120 g / mol.

[0034] The weight ratio of volatile solvent to non-volatile solvent can be from 0.5:1 to 4:1. Preferably, the weight ratio of volatile solvent to non-volatile solvent is from 1:1 to 3:1. More preferably, the weight ratio of volatile solvent to non-volatile solvent is from 2:1 to 2.5:1.

[0035] The carbon-to-oxygen ratio of the polyol is preferably 2:1 to 1:1. The carbon-to-oxygen ratio of the diol is preferably 2:1 to 1:1.

[0036] The boiling point of lower alcohols is preferably below 150°C. The boiling point of polyols is preferably below 150°C. The boiling point of diols is preferably below 250°C.

[0037] The compositions according to the invention may be completely miscible with water. Volatile and non-volatile solvents may be miscible with water.

[0038] The compositions according to the present invention may be transparent and / or colorless.

[0039] Preferably, the weight ratio of the polyol to the diol is 2:1 to 6:1. More preferably, the weight ratio of the polyol to the diol is 2.5:1 to 5.5:1. Even more preferably, the weight ratio of the polyol to the diol is 3:1 to 5:1. Still more preferably, the weight ratio of the polyol to the diol is 3.5:1 to 4.5:1.

[0040] Regarding component concentration, the compositions according to the present invention may contain the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 15% to 45%, - Water: 20% to 55%, - Polyols: 22% to 26%, - Diols: 4% to 12%.

[0041] Regarding component concentration, the compositions according to the present invention may contain the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 45%, - Water: 20% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 12%.

[0042] The concentration of water is preferably 30% to 40% by weight. The 20% mentioned above is a preferred minimum value for gelling purposes. Similarly, the concentration of the lower alcohol is preferably 15% to 35% by weight, but concentrations up to 45% can be used without compromising the efficacy of the composition, depending on user tolerance. In some embodiments, the concentration of the lower alcohol is 15% to 30% by weight. In some embodiments, the concentration of the lower alcohol is 30% to 40% by weight. In some embodiments, the concentration of the lower alcohol is 30% to 35% by weight. The ratio of ethanol to water in the volatile solvent pair can be adjusted to change the evaporation rate. Ethanol is more volatile than water, up to about 1:1. The upper limit of the concentration of ethanol, as an example of a lower alcohol, is limited by local tolerance as a skin irritant.

[0043] Preferably, the total amount of polyols and diols does not exceed 35% by weight.

[0044] In this specification, the term "lower alcohol" means an aliphatic alcohol having one to five carbon atoms, such as ethanol or isopropanol; ethanol is generally preferred. The term "lower alcohol" may also include volatile ester derivatives of lower alcohols. For example, in some cases, volatile esters such as methyl acetate, ethyl acetate, etc., may be used.

[0045] "Polyols" refers to aliphatic polyols, such as glycerol, although sorbitol, erythritol, arabinitol and xylitol are examples of other water-soluble polyols that may be used in conjunction with or as a substitute for glycerol.

[0046] "Diol" refers to a primary or secondary diol or a polyol compound, such as propylene glycol (propylene-1,2-diol), butanediol (butane-1,3-diol), pentanediol (pentane-1,5-diol), or hexanediol (2-methyl-2,4-pentanediol). Preferably, the diol is a primary or secondary diol.

[0047] In some embodiments, the compositions according to the invention have the following weight percentage concentrations: - Lower alcohols: 15% to 35%, - Water: 33% to 52%, - Polyols: 22% to 26%, - Diols: 4% to 8%.

[0048] Preferably, the composition according to the invention has the following weight percentage concentration: - Lower alcohols: 30% to 35%, - Water: 33% to 37%, - Polyols: 22% to 26%, - Diols: 4% to 8%.

[0049] For example, a formulation according to the present invention has the following components by weight percentage: - Ethanol: 33%, - Water: 35%, - Glycerin: 24%, - Propylene glycol: 6%.

[0050] For example, another formulation according to the present invention has the following components by weight percentage: - Ethanol: 33%, - Water: 35%, - Glycerin: 24%, - Propylene glycol: 6%, - Carbopol® Ultrez 10: 1%.

[0051] In the above formulation, the ratio of glycerol to propylene glycol is 4:1. The above formulation may also contain an alkali to maintain a pH in the range of 4.5-7.0, preferably 5.0-7.0.

[0052] In some embodiments, a composition is provided for treating or improving sexual dysfunction in a female subject, the composition comprising a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, and the non-volatile solvent comprising a polyol and a diol. The composition contains the following components, in percentages of the total weight of the composition: - Lower alcohols: 30% to 45%, - Water: 20% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 12% The composition does not contain any active pharmaceutical ingredients used to treat female sexual dysfunction.

[0053] In some embodiments, the lower alcohol is present at 30% to 40%. In some embodiments, water is present at 30% to 40%.

[0054] On the other hand, a composition is provided for treating or improving sexual dysfunction in a female subject, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, and the non-volatile solvent comprising a polyol and a diol. The composition comprises the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 45%, - Water: 30% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 12% The composition also contains aloe vera, and The composition does not contain any active pharmaceutical ingredients used to treat female sexual dysfunction.

[0055] Further features in this regard are the same as those described above for compositions used to treat or improve sexual dysfunction in female subjects. For example, the composition may not contain any pharmaceutically active ingredient. The composition may also contain a thickener or gelling agent. The pH of the composition may be higher than 4.5 and lower than 7.0.

[0056] In some embodiments, the composition contains a warming agent, such as vanillyl butyl ether.

[0057] The compositions according to the invention can be prepared by mixing the components together. Conventional process principles can be applied, for example, dispersing Carbopol® Ultrez 10 in an aqueous phase, adding ethanol, and then adding the remaining solvent, optionally simultaneously with or before pH adjustment. While organic bases such as triethanolamine can be used for pH adjustment purposes, inorganic bases such as potassium hydroxide, sodium hydroxide, or liquid ammonia are preferred to avoid the possibility of nitrosamine formation. Such bases, preferably potassium hydroxide, are particularly advantageous in solvent-rich systems (e.g., those according to the invention) because potassium may, for example, form salts with gelling agents that may be insoluble at the concentrations used, leading to phase separation after manufacturing. Easily dispersible interpolymers of this type appear to be less prone to phase separation, which may be attributed to the increased solvent affinity of the block copolymer backbone segments. Even so, it is still considered preferable to control the pH in the range of 5.25 to 5.75 to achieve application precision, prevent Carbopol® salt phase separation (e.g., using Carbopol® Ultraz 10, 20, 21 or 30), and ensure that the gel viscosity does not impair the rate of loss of volatile solvents.

[0058] Preferably, the composition is used for topical application to the external genitalia, such as the vulva. In some embodiments, the composition is used for topical application to the labia. In some embodiments, the composition is used for topical application to the inner labia and / or clitoris. In some embodiments, the composition is used for topical application to the clitoris.

[0059] The subject can be any subject with female external genitalia. For example, the subject can be a female subject, a subject with female external genitalia, or a subject with a neovulva due to gender confirmation surgery. In some embodiments, the subject is a female subject. In some embodiments, the subject is a human subject. In some embodiments, the subject is a female human subject.

[0060] In some implementations, the subject is premenopausal.

[0061] In some implementations, the subject is in the perimenopausal, menopausal, or postmenopausal period. In some implementations, the subject is in the menopausal period.

[0062] In some implementations, the subject is postmenopausal. This refers to a female subject who has not menstruated for 12 months.

[0063] Subjects may have pre-existing medical conditions that prevent them from taking the active ingredient used to treat female sexual dysfunction.

[0064] The pre-existing medical condition can be any condition that prevents the use of the active ingredient for treating female sexual dysfunction. For example, the pre-existing medical condition could be angina, hypotension, hypertension, benign prostatic hyperplasia, or retinitis pigmentosa.

[0065] Treatment of the existing medical condition (which prevents the use of active ingredients for treating female sexual dysfunction) may involve the administration of an active ingredient selected from PDE-5 inhibitors, nitrates, and alpha-receptor blockers. For example, active ingredients for treating the existing medical condition may be selected from GTN, isosorbide mononitrate, isosorbide dinitrate, alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin.

[0066] The method may further include administering to a subject at least one active agent for treating or improving female sexual dysfunction. The at least one active agent for treating or improving female sexual dysfunction may be selected from: hormones such as estrogen and testosterone, synthetic hormones such as tibolone, estrogen receptor modulators such as opemifene, serotonin agonists or antagonists such as flubanseri or bupropion, melanocortin receptor agonists such as bumelotide, PDE5 inhibitors such as tadalafil and sildenafil, and vasodilators such as alprostadil and phentolamine mesylate. In some embodiments, the at least one active agent for treating or improving female sexual dysfunction may be selected from estrogen, testosterone, tibolone, opemifene, flubanseri, bupropion, bumelotide, PDE-5 inhibitors, alprostadil, and phentolamine mesylate. In one embodiment, the at least one active agent for treating or improving female sexual dysfunction is administered orally. In some embodiments, the at least one active agent for treating or improving female sexual dysfunction is administered topically.

[0067] Subjects may suffer from severe female sexual dysfunction. This may include one or more of the following: hyposexuality disorder (HSDD), female sexual arousal disorder (FSAD), female orgasmic disorder (FOD), dyspareunia, vaginismus, sexual aversion disorder, female sexual interest and arousal disorder (FSIAD), and genital-pelvic pain / penetration disorder (GPPPD). In some implementations, subjects may suffer from one or more of the following: hyposexuality disorder, female sexual arousal disorder, female orgasmic disorder, and dyspareunia.

[0068] According to a second aspect of the invention, a kit is provided comprising the composition (described above) and an active agent for treating or improving female sexual dysfunction.

[0069] The active agent is preferably applied separately from the composition, for example, it is not intended to be added to the topical composition (as described above). The active agent may be selected from: hormones such as estrogen and testosterone, synthetic hormones such as tibolone, estrogen receptor modulators such as opemifene, serotonin agonists or antagonists such as flubanseri or bupropion, melanocortin receptor agonists such as bumenotide, PDE5 inhibitors such as tadalafil and sildenafil, and vasodilators such as alprostadil and phentolamine mesylate. In one embodiment, the active agent for treating or improving female sexual dysfunction is administered orally, i.e., in an oral dosage form. In some embodiments, the active agent for treating or improving female sexual dysfunction is administered topically. In some embodiments, the active agent is not intended for treating or improving erectile dysfunction in male subjects.

[0070] The description of the compositions used according to the first aspect also applies to this aspect.

[0071] According to the third aspect, the use of the composition (described above) in the preparation of a medicament for treating or improving female sexual dysfunction is provided. The description of the composition for use according to the first aspect also applies to this aspect.

[0072] According to a fourth aspect, a method for treating or improving female sexual dysfunction is provided, the method comprising applying topically to the vulva of a subject in a biologically effective amount of the composition (described above). Optionally, the method may further comprise manual stimulation of the vulva. The description of the composition for use according to the first aspect also applies to this aspect.

[0073] In one related aspect, a composition for improving a subject's FSFI score is provided, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, and the non-volatile solvent comprising a polyol and a diol.

[0074] A method for improving a subject's FSFI score is also provided, comprising applying topically to the subject's vulva a biologically effective amount of the composition (described above). Optionally, the method may further comprise manual stimulation of the vulva. The description of the composition according to the first aspect also applies to this aspect.

[0075] Those skilled in the art will understand that all aspects of this invention are equally applicable to all other aspects of this invention. Specifically, aspects of the compositions for use have been described in more detail than other aspects of the invention (e.g., kits). However, those skilled in the art will understand that where more detailed information about a particular aspect of the invention has been given, that information generally applies equally to other aspects of the invention.

[0076] All patents and references cited in this specification are incorporated herein by reference in their entirety. Attached Figure Description

[0077] The invention will now be described in detail by way of example only, with reference to the accompanying drawings, in which: Figure 1 This is a graph showing the change in the average temperature (°C) of the sample gel over time (minutes) at various ambient temperatures (27°C, 32°C, 37°C).

[0078] Figure 2 This is a graph showing the percentage change in the average weight of the sample gel over time (minutes) at various ambient temperatures (27℃, 32℃, 37℃).

[0079] Figure 3 This is a graph showing the percentage change in the average weight of the sample gel as a function of temperature (°C) at various ambient temperatures (27°C, 32°C, 37°C).

[0080] Figure 4 (A) A schematic diagram of an exemplary experimental setup; and (B) A schematic diagram of an exemplary placement of a temperature probe on an ex vivo tissue surface.

[0081] Figure 5 The temperature (°C) of the tissue surface was recorded by three probe thermometers during an 11-minute experimental duration following administration of 300 mg of the composition (10-second intervals in the first minute, 15-second intervals in the second minute, and 30-second intervals in the third and fourth minutes). (A) Repeat Experiment #1. (B) Repeat Experiment #2. (C) Repeat Experiment #3.

[0082] Figure 6 The temperature (°C) of the tissue surface was recorded by three probe thermometers during an 11-minute experimental duration following administration of 800 mg of the composition (10-second intervals in the first minute, 15-second intervals in the second minute, and 30-second intervals in the third and fourth minutes). (A) Repeat Experiment #1. (B) Repeat Experiment #2. (C) Repeat Experiment #3.

[0083] Figure 7 The temperature (°C) of the untreated (control) tissue surface, recorded by three probe thermometers, is shown during the 11-minute experimental duration (10-second intervals in the first minute, 15-second intervals in the second minute, and 30-second intervals in the third and fourth minutes). (A) Repeat Experiment #1. (B) Repeat Experiment #2. (C) Repeat Experiment #3.

[0084] Figure 8 The temperature (°C) curves for the 300 mg dose, 800 mg dose, and untreated control are shown, expressed as the average of three replicates. Detailed Implementation

[0085] Example 1: Composition The composition of this invention comprises: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol® Ultrez 10: 1%. The pH is adjusted to 5.25 using potassium hydroxide solution. The ethanol used to prepare this composition is anhydrous ethanol (i.e., 100% ethanol without water), such that the final composition contains 33% pure ethanol. If a lower grade of ethanol containing impurities (e.g., 96% ethanol) is used, the amounts used must be adjusted to ensure that the final composition contains the correct amounts of each component, i.e., 33% pure ethanol and 35% water.

[0086] The availability of an effective composition (not containing GTN or any other active ingredient) for treating female sexual dysfunction means that the composition has fewer contraindications compared to other treatments, thus enabling its use, for example, in subjects taking nitrate medications. Furthermore, its high safety profile allows the composition to be used in combination with other treatments such as sildenafil, flubancerine, or bupropion. In summary, the compositions according to the invention represent a significant improvement over known treatments while providing rapid onset of action and improved sexual function (including, but not limited to, sexual arousal, libido, increased lubrication, orgasm, reduction of discomfort or pain, and / or overall improvement in quality of sexual life) and high safety, offering further treatment opportunities for patients who have been unable or contraindicated to use existing treatments to date.

[0087] Example 2: Cooling effect of the composition As described above, the compositions of the present invention are believed to enhance the production of endogenous NO through the latent heat cooling effect of the evaporation of the volatile solvent components, locally stimulating nerves and leading to the generation of endogenous NO. In the vulva, there are receptors that respond to a range of physical sensations, including touch, pressure, and temperature, and the local application of the compositions of the present invention stimulates these receptors. It is believed that the rapid cooling effect of the composition and the subsequent temperature recovery have a stimulating effect, causing a synergistic response of the receptors, resulting in improved sexual function, including but not limited to sexual arousal, libido, increased lubrication, orgasm, reduction of discomfort or pain, and / or overall improvement in sexual quality of life.

[0088] The cooling effect of the compositions used in the above examples (ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol® Ultrez 10: 1%, pH adjusted to 5.25 with potassium hydroxide solution) was tested, and a scheme to compare the cooling effects of different compositions was developed.

[0089] 1. Principle The cooling effect and recovery rate of the gel composition were measured by applying the gel to a calibrated temperature probe (weighed on an analytical balance). This allowed for simultaneous monitoring of temperature changes over time and weight loss. Different cooling / recovery "curves" were generated when the device was incubated at different ambient temperatures (i.e., 27°C, 32°C, and 37°C).

[0090] 2. Overview A suitable method has been developed for evaluating the cooling profiles of the compositions of the present invention at three different ambient temperatures: 27°C, 32°C, and 37°C. This method is formulated to describe the process used to obtain the cooling profiles.

[0091] The results of the validation study confirmed that the method is suitable for its purpose in terms of repeatability (precision), reproducibility (intermediate precision), and accuracy.

[0092] 3. Instruments and Equipment • Temperature probe (e.g., Fisherbrand Traceable Flip-Stick thermometer, P / N: 14-648-45). Total probe surface area: 11.64 cm² 2 • 15 mL plastic centrifuge tubes or equivalent • A drill or equivalent capable of drilling holes with a diameter of 5 mm. • Analytical balances (e.g., Sartorius four-decimal-place analytical balances or equivalents) Stopwatch • Tabletop ovens capable of maintaining 27℃, 32℃, and 37℃ ±1℃ • Tabletop centrifuge • Video recorder / camera.

[0093] 4. Sample The following samples were used for verification: The gel contains 33% ethanol, 35% water, 24% glycerol, 6% propylene glycol, and 1% Carbopol® Ultrez 10. The pH was adjusted to 5.25 with potassium hydroxide solution.

[0094] 5. Method Development The method was developed using three different ambient temperatures: 27°C, 32°C, and 37°C, to evaluate the cooling profiles of the sample gels. The method description is available in Section 6 (only the 32°C version is described). The temperature and weight of the gel were recorded over a 25-minute run. Six replicate preparations were performed, and the average values ​​of the data at each ambient temperature were calculated. The following cooling profiles were generated: temperature vs. time (…). Figure 1 ), percentage change in weight vs. time ( Figure 2 ) and percentage change in weight vs. temperature ( Figure 3 These cooling profiles are designed to uniquely characterize the cooling properties of sample gels.

[0095] During development, it was observed that the first replicate experiment each day at each ambient temperature deviated further from the average compared to the other five replicate experiments. This was likely due to temperature fluctuations when the oven door was first opened after overnight incubation. Therefore, it was decided to omit the first replicate experiment each day in the validation study to allow the oven to stabilize before proceeding with further replicate experiments.

[0096] The results obtained from the development work show that different cooling profiles are obtained when the analysis is performed at different ambient temperatures. These differences in cooling profiles are reflected when temperature (°C) is plotted against time (minutes). Figure 1 The temperature drop was most pronounced at 37°C. At all three ambient temperatures, the gel temperature reached its lowest point after approximately 1–1.5 minutes, then began to recover to ambient temperature. The temperature decrease appeared to increase with increasing ambient temperature, with an ambient temperature of 37°C showing a decrease of approximately 13°C, compared to approximately 8°C at 27°C. After 25 minutes, the sample gel had recovered to within approximately 3°C of its initial starting temperature (ambient temperature). The plateau period of temperature recovery occurred at approximately 15 minutes at 37°C, while at 32°C and 27°C, both tended to plateau at approximately 25 minutes.

[0097] Figure 2 The cooling curves at various ambient temperatures are shown when the percentage change in weight is plotted against time (minutes). Generally, for all three ambient temperatures, the percentage change in weight is most rapid at the beginning of the curve, then begins to plateau after approximately 5 minutes. Second decreases in the percentage change in weight are observed at approximately 15 minutes at 32°C and approximately 20 minutes at 37°C. Overall, a significant difference is seen between the curves for 27°C and 32°C / 37°C, while the curve for 32°C shows only a slight difference compared to the curve for 37°C.

[0098] The cooling curve obtained by plotting temperature (°C) against the percentage change in weight is shown below. Figure 3 Similarly, similar curve shapes were obtained at each ambient temperature. Overall, these curves exhibited a U-shaped pattern. As the ambient temperature increased, the amount of temperature drop / recovery also increased, such as... Figure 1 As observed, the maximum temperature drop was reached at approximately 24% weight change at all three ambient temperatures. Complete temperature recovery required approximately 70% weight change at 32°C and 37°C, while returning to the 27°C environment required only 60% weight change.

[0099] 6. Analysis Guidelines Perform the following steps to test the sample gel.

[0100] Note The first round of analysis each day will be ignored and treated as a simulation run to allow the oven settings to stabilize after the first round.

[0101] 1. Drill a hole approximately 5 mm in diameter in the cap of a 15 mL centrifuge tube. Weigh the empty centrifuge tube on an analytical balance. Record the weight and zero the balance.

[0102] 2. Using a syringe, transfer approximately 14 mL of sample gel into a 15 mL centrifuge tube. Seal with a standard cap and centrifuge at 1500 rpm for 30 seconds to collect the gel.

[0103] 3. Place the tube containing the sample gel, the calibrated temperature probe, and the analytical balance into a benchtop oven set to 32℃ ±1℃.

[0104] 4. Weigh the tube containing the sample gel. Record the weight of the gel (Weight Check 1).

[0105] 5. Place another calibrated temperature probe inside the balance chamber (for ambient temperature monitoring only). Incubate all equipment (including tubes containing sample gels) overnight for incubation.

[0106] 6. After incubation, weigh the tube containing the sample gel (weight check 2). Calculate the weight change and check for any significant weight loss (not exceeding 2% (NMT)).

[0107] 7. Place the cap with the 5 mm hole cut into it onto the centrifuge tube containing the sample gel. Plug the hole to prevent any evaporation until ready to collect the sample. Return to the benchtop oven.

[0108] 8. Zero the balance using a temperature probe. Ensure the probe temperature is within the range of 32℃ ±1℃.

[0109] 9. Start recording, ensuring temperature and weight are visible. (Note: Recording does not need to exceed 5 minutes. Readings after this time can be recorded manually.)

[0110] 10. Remove the temperature probe from the balance and insert it into the centrifuge tube containing the sample gel until the bottom of the probe touches the cap. Apply approximately 70 mg (±20 mg). (Note: Time-sensitive step).

[0111] 11. Remove the probe from the gel with a smooth motion, being careful not to touch the side wall of the centrifuge tube cap. Place the probe back on the balance, close the oven door, and start the stopwatch. Plug the centrifuge tube cap and centrifuge at 1500 rpm for 15 seconds to collect the gel. Seal the tube with a regular cap and return it to the oven. (Note: Time-sensitive step).

[0112] 12. Record the probe weight and temperature for 25 minutes. The reading intervals are shown in Table 1.

[0113] 13. If an ambient temperature drift is observed, the oven can be maintained at 32℃ ±1℃ by adjusting the oven control knob or by leaving a small gap for ventilation on the oven door (opposite to the balance).

[0114] 14. After 25 minutes, remove the temperature probe from the balance and clean it with a dry, lint-free paper towel. Place the temperature probe back on the balance, which is maintained at 32℃ ±1℃. Repeat steps 7-14 for the next experiment.

[0115] 15. Repeat all steps for the remaining ambient temperatures of 27℃ ±1℃ and 37℃ ±1℃.

[0116]

[0117] 7. Results Calculate the percentage change in weight for each reading interval using the following formula: Percentage change in weight = -100 + ((weight at reading interval (g) / initial weight (g)) 100) Calculate the following: Maximum temperature drop = Ambient temperature (°C) - Minimum temperature (°C) Temperature recovery (T=25 minutes) = Final temperature (°C) - Minimum temperature (°C) In a validation study conducted according to the protocol given in Section 6 at an ambient temperature of 32℃ ±1℃, the test samples yielded the following results:

[0118] Example 3: Evaluation of thermal properties on isolated tissues introduction This embodiment documents the evaluation of the thermal properties of the composition of the present invention under simulated use conditions: the study measured the spatiotemporal temperature changes on the surface of an ex vivo tissue caused by the application of the composition.

[0119] Tests were conducted using samples of the final product composition manufactured to the same specifications and at the same production scale and packaged in the same primary packaging system as intended for market release.

[0120] This study was conducted to further demonstrate the thermal properties of the composition (i.e., the rapid local cooling effect followed by a recovery heating effect).

[0121] Tests conducted Under simulated use conditions, the composition was applied to the surface of isolated porcine muscle tissue blocks, and the temperature-time history was measured by resistance thermometry.

[0122] The composition is applied to the area of ​​the tissue. Prior to application, the surface of the tissue block is maintained at a temperature relevant to the intended use of the composition by immersing the tissue block in a 37°C water bath, exposing its top surface to room air for application.

[0123] Three (3) probe thermometers were used to measure tissue surface temperature-time information; one was placed at the center of the area on the tissue surface where the composition was applied, and two were placed at opposite edges of the application area (each equidistant from the center probe) to depict the complete spatiotemporal temperature distribution on the tissue.

[0124] Test objective The aim of this study is to further demonstrate the thermal properties of the composition (i.e., the rapid cooling effect followed by the recovery heating effect) under in vitro simulated use conditions.

[0125] The purpose of this study was to evaluate in vitro temperature profiles to investigate the spatiotemporal temperature changes on the skin surface after application of the composition when a prescribed dose (300 mg) and a maximum dose (800 mg) were administered to in vitro tissues.

[0126] One dose of the composition is a pea-sized amount of gel (weighing approximately 300 mg). The primary packaging of the gel is a single-dose aluminum tube, so a portion of the gel contained in the tube shoulder cannot be expelled by squeezing the tube. These tubes are filled to a nominal weight of 800 mg to ensure delivery of at least 300 mg of gel. Considering the unlikely occurrence of a user squeezing out the entire contents of the tube, the thermal effects of both 300 mg and 800 mg doses were evaluated.

[0127] Test method description gel This study evaluated the composition. The formulation of the composition is shown in Table 2.

[0128] Table 2: Gel Formulations

[0129] Ex vivo tissue The gel was applied to the skin surface of isolated porcine muscle tissue blocks.

[0130] The surface of the block is maintained at a steady-state temperature of approximately 32-34°C. In a variant of the test method, the surface of the block can be maintained at a steady-state temperature of up to approximately 37°C.

[0131] A region measuring 3.5 cm (length) × 3.5 cm (width) for applying the composition was marked on the tissue surface.

[0132] The tissue block dimensions are 8 cm (length) × 8 cm (width) × 6 cm (depth). A continuous tissue edge of at least 2 cm is present in all three dimensions surrounding the application area of ​​the composition to ensure that boundary conditions do not affect measurements taken at the application site.

[0133] water bath The excised tissue block was immersed in a 14-liter digital water bath with internal dimensions of 353 × 325 × (height) 200 mm, and the temperature was set to 37°C (accuracy ±0.1°C). Temperature uniformity throughout the circulating water was confirmed using calibrated probes at five points (center and four corners) in the water bath.

[0134] Temperature probe thermometer Throughout the testing process, the surface temperature of the skin was measured using three (3) calibrated Class A Pt100 temperature probe thermometers with a resolution of 0.1 °C (range -199.9 °C to +199.9 °C).

[0135] The probes are positioned at the center of the application area of ​​the composition (1 probe) and at the opposite edges of the application area (2 probes).

[0136] A fourth calibrated Pt100 probe was inserted into the center of the muscle block to measure the core temperature of the tissue.

[0137] Before the study began, the temperature probe was calibrated at 0°C, 10°C, and 50°C.

[0138] The probe's response time is approximately 7.5 seconds, which was determined to be sufficient for accurately measuring temperature changes occurring on the tissue over several minutes. Independent measurements at three discrete points on the tissue surface are preferred (accurate to 0.1°C under the study conditions), as this allows for measurement of the temperature distribution with sufficient spatial and temporal resolution to characterize the thermal effects of the composition over a larger area of ​​the tissue surface.

[0139] method 1. Mark the skin surface of the pig tissue block to identify the approximately 12 cm area for gel application. 2 The area.

[0140] 2. Immerse the tissue block—exposing only the top (skin) surface to air—in a water bath maintained at 37°C.

[0141] 3. Place three temperature probes on the skin surface. One (1) at the center of the area where the composition is applied, and two (2) on the skin surface at opposite diagonal points marking the edges of the area.

[0142] 4. Allow the tissue block to equilibrate in a covered water bath for approximately 2.5 hours (initial equilibration) until the steady-state temperature, measured by temperature probes at three points on the skin surface, is between approximately 32-34°C, and the core tissue temperature reaches 37°C (measured by a fourth probe inserted into the tissue block). In some cases, the water bath may need to be closed to achieve the desired range of initial skin surface temperatures.

[0143] 5. Remove the water bath cover.

[0144] 6. Apply 300 mg of gel to the marked 12 cm area on the tissue block. 2 Apply the gel to the marked area containing the probe using your finger.

[0145] 7. Record the real-time readings displayed on the temperature probe before applying the gel and during the 11-minute experiment.

[0146] 8. After application of the composition, leave the water bath uncovered to allow the formulation to evaporate, as is the case in a clinical setting. After 6 minutes, when the evaporation effect is deemed complete, re-cover the water bath to support and maintain skin surface temperature.

[0147] 9. Remove all gel residue from the tissue block.

[0148] 10. Repeat steps 3 through 9 for two additional replicates of the 300 mg dose and three replicates of the 800 mg dose.

[0149] 11. For the experimental control of untreated tissue (n=3), repeat steps 3-5, 7 and 8 three times.

[0150] 12. Review the video recordings of all experimental runs (repeated experiments) and record data at the following time points (0.17, 0.33, 0.5, 0.67, 0.83, 1.0, 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0, 11.0 minutes).

[0151] Test Results After the composition was applied, the temperature change on the surface of the tissue block was recorded using three Grade A Pt100 probe thermometers during the 11-minute experimental duration (by which time the initial temperature of 32°C had been reached) to study the temperature profile of the effect of the formulation on the tissue.

[0152] Temperatures (°C) of the 300 mg dose composition (n=3) recorded during the full duration of the experiment (including 10-second intervals within the first minute, 15-second intervals within the second minute, and 30-second intervals within the third and fourth minutes) are shown in Tables 3, 4, and 5. Figure 5 (AC).

[0153] The temperatures (°C) for the 800 mg dosage composition (n=3) are shown in Tables 6, 7, and 8. Figure 6 (AC).

[0154] Temperatures (°C) of untreated control tissues (n=3) are shown in Tables 9, 10, and 11. Figure 7 (AC).

[0155] In addition, the following datasets are listed for comparison: The average surface temperature (°C) of tissue blocks at doses of 300 mg and 800 mg (expressed as the average of measurements taken by the three probes) during the 11-minute experimental duration is shown in Table 12.

[0156] The average surface temperature (°C) of tissue blocks from the 300 mg, 800 mg, and control runs during the 11-minute experimental duration is shown in Table 13 (expressed as the average of three replicates).

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168] Data Analysis For both dose volumes, an immediate temperature drop was observed during the cooling phase of the experiment (recorded at the 6-minute time point) (maximum temperature drop of 7.5°C (average 6.8°C)), followed by a gradual temperature increase over the duration of the experiment. The maximum temperature drop was observed when the composition was administered to tissue at a dose of 800 mg (a decrease of approximately 7.5°C from the initial starting temperature of approximately 32°C after 6 minutes). For the 300 mg dose, a decrease of approximately 7.2°C from the starting temperature was achieved after 6 minutes.

[0169] Within the first 2 minutes after application of the composition, a maximum temperature decrease of 5.9 °C was observed at the 2-minute time point when 800 mg of gel was applied to the tissue surface; the mean temperature decreases at the 2-minute time point were 5.3 °C and 5.1 °C for the 300 mg and 800 mg doses, respectively. In contrast, the control showed a mean temperature decrease of 2.2 °C during the initial 2-minute period.

[0170] During the experimental duration, the composition-induced temperature decrease plateaued after approximately 6 minutes, with a maximum temperature decrease of 7.5°C observed at the 6-minute time point when 800 mg was applied to the tissue surface. The mean temperature decreases at the 6-minute time point were 6.7°C and 6.8°C for the 300 mg and 800 mg doses, respectively. In contrast, the control showed a mean temperature decrease of 3.2°C during the initial 6-minute period.

[0171] After 6 minutes, when the temperature drop induced by the composition had plateaued, the recovery period was monitored for another 5 minutes—until the temperature returned to near the initial temperature. A slightly faster tissue temperature recovery rate was observed after administration of a 300 mg dose compared to an 800 mg dose. This is expected because the smaller mass of the gel has a smaller residual heat capacity.

[0172] Measurements from the three surface probes were consistent at any given time point, demonstrating the homogeneity of the composition effect on the tissue surface. For all replicates of both doses and the control, the RSD did not exceed 5% at any time point and was less than 3.5% in most cases.

[0173] Data from repeated experiments were highly consistent. For the 300 mg dose, the relative standard deviation (RSD) was no more than 2.1%. For the 800 mg dose, the RSD was no more than 3.3%. For the untreated tissue control, the RSD was no more than 2.4%.

[0174] Discussion / Conclusion The spatiotemporal temperature changes of the composition after administration to ex vivo tissues at two dosage intensities were successfully evaluated to further demonstrate the thermal properties of the composition, particularly its rapid cooling effect followed by a slower recovery heating effect.

[0175] The results of in vitro experiments showed that, at both of the evaluated dosage levels, the composition achieved a rapid cooling effect, followed by a gradual increase in temperature.

[0176] Immediate cooling of the tissue surface was observed after application of the composition. The cooling effect lasted for several minutes, reaching a maximum temperature drop of 7.5°C after approximately 6 minutes. Skin surface temperature was observed to recover after 6 minutes, and fully returned to the initial temperature approximately 11 minutes after application.

[0177] No significant difference in tissue thermal effects was observed between the 300 mg and 800 mg doses. It should be noted that while 300 mg represents the ideal dose, the results suggest that the 800 mg dose would also be safe and effective in the unlikely event of increased gel extraction during patient use.

[0178] A control of untreated tissue (n=3) was run to demonstrate that the study conditions—particularly the closed water bath—were not the cause of the claimed composition effect. The control results, produced under the same experimental conditions as the treated tissue, provided confidence that the temperature profiles attributable to the composition were the true composition effect.

[0179] To illustrate this, Figure 18 shows a comparison of the mean temperature curves (average of three replicates) for each dose (300 mg and 800 mg) with the control.

[0180] Example 4: Home User Study A home user study was conducted to evaluate the use of this composition and its effectiveness on symptoms of female sexual dysfunction. The composition tested contained: ethanol: 33%; water: 35%; glycerin: 24%; propylene glycol: 6%; Carbopol® Ultraz 10: 1%. The pH was adjusted to 5.5 with potassium hydroxide solution.

[0181] Within the overall framework, the study included a 1-week pre-treatment assessment period followed by a 4-week treatment period, during which subjects were instructed to use the product on at least 4 occasions, with or without a sexual partner. The analysis used 67 subjects, including premenopausal and postmenopausal women. Subjects were instructed to apply 300 mg of the product to their external genitalia (e.g., labia minora and clitoris) prior to sexual activity.

[0182] The assessment was conducted in two ways: 1. The validated “gold standard” measurement tool, the Female Sexual Function Index (FSFI), was used, with data collected at baseline (before treatment) and at the end of the 4-week treatment period (retrospective information). The FSFI is described in Rosen R et al., “The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function”. J Sex Marital Ther. 2000 Apr-Jun;26(2):191-208.

[0183] 2. Answers to multiple questions recorded in a diary shortly after the sexual event. These questions relate to the sensory characteristics of the product and related likes / dislikes, and include questions related to changes in vaginal lubrication, sensation / feeling in the genital area, sexual pleasure, and the ability to achieve orgasm.

[0184] The main findings of this study are as follows: 1. FSFI measurement: In 67 participants, overall sexual function showed positive changes after 4 weeks, with statistically significant improvement relative to baseline (P=0.004). Although the mean baseline FSFI score was high at 26.9, exceeding what is generally considered the upper limit for sexual dysfunction (26.55).

[0185] In 67 subjects, statistical significance was achieved in all areas of improved lubrication and improved orgasmic function (P = <0.05).

[0186] A subgroup analysis was conducted among participants who experienced some degree of sexual dysfunction (i.e., participants with a baseline FSFI of 26.55 or lower (26 participants; mean baseline FSFI of 22.0)), and improvements in scores were observed. Overall, there was a positive change of 3.1 from baseline (compared to 1.5 for all 67 participants).

[0187] In these 26 subjects, P < 0.05 was achieved in 5 / 6 FSFI domains: sexual arousal, lubrication, orgasm, satisfaction, and discomfort (pain). Improvements in libido occurred but did not reach statistical significance.

[0188] It is believed that recruiting subjects with multiple symptoms of sexual dysfunction in a clinical setting could further improve scores, potentially lowering baseline FSFI scores and allowing room for greater improvement. For example, the baseline lubrication and discomfort (pain) scores of the 26 subjects in this study were quite high (4.0 / 6.0 and 4.5 / 6.0), and selecting subjects with more pronounced symptoms could have improved scores overall.

[0189] 2. Diary data analysis: a) Tolerance 84% (56 / 67) of the subjects reported experiencing a “burning” or “tingling” sensation during at least one use of the product.

[0190] However, 54% (30 / 56) of these women considered the burning / tingling sensation a positive attribute.

[0191] 39% (26 / 67) of women experienced what they perceived as a negative burning or stinging sensation.

[0192] Nevertheless, 12 of the 26 women found that the gel improved their sexual experience (in at least 40% of the cases): all of these women wanted to continue using the product.

[0193] In addition, of the 14 women who experienced negative burning or tingling sensations and whose overall experience did not improve, 8 wished to continue using the product.

[0194] Six women reported negative feelings, no improvement in their sexual experience, and a desire not to continue using the product. Only one woman opted to discontinue use of the product during the study period (discontinuing after two uses). This level of discontinuation is considered acceptable, and “toning down” the burning / tingling sensation by reducing the ethanol content may negatively impact overall efficacy, as most women appeared to find it pleasurable.

[0195] b) Efficacy recognition A basic criterion was set: subjects must report improvements in sexual function in at least 30% of use cases in order to be classified as respondents.

[0196] 46% (31 / 67) of women reported that the gel increased vaginal lubrication.

[0197] 63% (42 / 67) reported increased genital sensation.

[0198] 54% (36 / 67) reported improved genital pleasure.

[0199] o 61% (41 / 67) reported improved satisfaction with their sexual experiences.

[0200] 28% (19 / 67) reported improved ability to achieve orgasm.

[0201] 3. Product use during the research period: 38 / 67 (57%) of women used more than the recommended minimum of 4 tubes (5-8 tubes), which strongly suggests that women generally like the product.

[0202] Overall Conclusion After carefully considering the FSFI and diary data, and taking into account that the study primarily involved healthy individuals rather than recruits with sexual dysfunction, the overall positive trends observed in the study are very encouraging. Statistically significant changes in FSFI relative to baseline were achieved in all participants, and in the subgroup analysis of women with a baseline score ≤26.55, 5 / 6 of the FSFI domains achieved P = <0.05. Diary data indicate that the product was well-accepted, generally liked, and well-tolerated; 57% of women used more than the recommended minimum of 4 tubes, and most women reported continuing to use the product despite some negative burning / tingling sensations.

[0203] Various modifications may be made to the above embodiments, whether by adding, deleting or replacing features, to provide further embodiments, and all such embodiments are intended to be covered by the appended claims.

Claims

1. A composition for treating or improving sexual dysfunction in a female subject, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, and the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

2. The composition for use according to claim 1, wherein the composition is free from glycerol trinitrate (GTN), acetylcholinesterase inhibitors, vasodilators, phosphodiesterase type 5 inhibitors, androgens such as testosterone, flubanoxetine, bumenotide, estrogens, and opemifene.

3. The composition according to claim 1 or 2, wherein the composition does not contain any pharmaceutically active ingredient for treating female sexual dysfunction.

4. A composition for use according to any of the preceding claims, wherein the composition does not contain any pharmaceutically active ingredient.

5. The composition for use according to any of the preceding claims, wherein the pH of the composition is higher than 4.5 and lower than 7.

0.

6. The composition for use according to any of the preceding claims, wherein it is in the form of a gel.

7. The composition for use according to claim 6, wherein the composition is in the form of a gel with a viscosity ranging from 500 mPas to 4500 mPas.

8. The composition for use according to any of the preceding claims, wherein the lower alcohol is ethanol or isopropanol.

9. The composition for use according to any of the preceding claims, wherein the polyol is selected from glycerol, sorbitol, erythritol, arabinitol, and xylitol.

10. A composition for use according to any of the preceding claims, wherein the diol is selected from propylene glycol, butanediol, pentanediol, and hexanediol.

11. The composition for use according to any of the preceding claims, wherein the weight ratio of the polyol to the diol is from 1.5:1 to 6.0:

1.

12. The composition for use according to any of the preceding claims, wherein the weight ratio of the polyol to the diol is 3:1 to 5:

1.

13. The composition for use according to any of the preceding claims further comprises a thickener or a gelling agent.

14. The composition for use according to any of the preceding claims, further comprising aloe vera.

15. The composition for use according to any of the preceding claims further comprises a warming agent, such as vanillyl butyl ether.

16. A composition for use according to any of the preceding claims, comprising the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 15% to 45%, - Water: 20% to 55%, - Polyols: 22% to 26%, - Diols: 4% to 12%.

17. The composition for use according to any of the preceding claims, wherein the water comprises 30% to 40% by weight.

18. The composition for use according to any of the preceding claims, wherein the lower alcohol ranges from 30% to 35% by weight.

19. The composition for use according to any of the preceding claims, wherein the total amount of the polyol and the diol does not exceed 35% by weight.

20. A composition for use according to any of the preceding claims, comprising the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 45%, - Water: 20% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 12% in, The composition does not contain any pharmaceutically active ingredients used to treat female sexual dysfunction.

21. The composition for the use of claim 20, wherein the composition does not contain any pharmaceutically active ingredient.

22. A composition for use according to any of the preceding claims, comprising the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 40%, - Water: 30% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 8%.

23. A composition for use according to any of the preceding claims, comprising the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 35%, - Water: 33% to 37%, - Polyols: 22% to 26%, - Diols: 4% to 8%.

24. A composition for use according to any of the preceding claims, wherein the composition is in gel form and comprises the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 35%, - Water: 33% to 37%, - Polyols: 22% to 26%, - Diols: 4% to 8%, - Thickener or gelling agent: 0.5% to 1.5%, in, The composition is prepared at a pH range of 5.25 to 5.

75.

25. A composition for use according to any of the preceding claims, comprising the following components, wherein the components are expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 40%, - Water: 30% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 8%, - Optionally, one or more of the following: thickeners or gelling agents, pH control agents, skin-feel-enhancing agents, antimicrobial preservatives, aloe vera, and warming agents. in, The composition is prepared at a pH range of 4.5 to 7.

26. A composition for use according to any of the preceding claims, comprising the following components, said components being expressed as a percentage of the total weight of the composition: - Ethanol: 33%, - Water: 35%, - Glycerin: 24%, - Propylene glycol: 6%, - Thickener or gelling agent: 1%, - Optionally, pH control agents, skin-enhancing agents, and / or antimicrobial preservatives, in, The composition is prepared at a pH range of 5.25 to 5.

75.

27. A composition for use according to any of the preceding claims, comprising the following components, said components being expressed as a percentage of the total weight of the composition: - Ethanol: 33%, - Water: 35%, - Glycerin: 24%, - Propylene glycol: 6%, - Carbopol® Ultrez 10: 1%, - Optionally, pH control agents, skin-enhancing agents, and / or antimicrobial preservatives, in, The composition is prepared at a pH range of 5.25 to 5.

75.

28. A composition for use according to any of the preceding claims, comprising the following components, wherein the components are expressed as a percentage of the total weight of the composition: - Ethanol: 33%, - Water: 35%, - Glycerin: 24%, - Propylene glycol: 6%, - Thickener or gelling agent: 1%, - Optionally, pH control agents, skin-enhancing agents, and / or antimicrobial preservatives, in, The composition is prepared at a pH range of 5.25 to 5.

75.

29. A composition for use according to any of the preceding claims, wherein the composition is for topical application to the vulva.

30. A composition for use according to any of the preceding claims, wherein the composition is for topical application to the labia and / or clitoris.

31. The composition for use according to any of the preceding claims, wherein the female sexual dysfunction includes one or more of the following: hyposexuality disorder (HSDD), female sexual arousal disorder (FSAD), female orgasmic disorder (FOD), dyspareunia, vaginismus, sexual aversion disorder, female sexual interest and arousal disorder (FSIAD), and genital-pelvic pain / penetration disorder (GPPPD).

32. The composition for use according to any of the preceding claims, wherein using the composition increases the subject's total FSFI score by at least 2 points.

33. The composition for use according to any of the preceding claims, wherein the baseline FSFI total score of the subject using the composition is 26.55 or lower.

34. The composition for use according to any of the preceding claims, wherein the subject is premenopausal.

35. The composition for use according to any one of claims 1 to 33, wherein the subject is postmenopausal.

36. A composition for improving a subject's FSFI score, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, wherein the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

37. Use of a composition in the preparation of a medicament for treating or improving sexual dysfunction in a female subject, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, and the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

38. A method for treating or improving female sexual dysfunction, the method comprising applying a biologically effective amount of a composition topically to the vulva of a subject, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, wherein the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

39. A method for improving a subject's FSFI score, the method comprising applying a biologically effective amount of a composition topically to the subject's vulva, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, wherein the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

40. The composition for use according to any one of claims 1 to 36, or the use according to claim 37, or the method according to claim 38 or 39, wherein the subject suffers from a pre-existing medical condition, the presence or treatment of which prevents the administration of the active ingredient for treating female sexual dysfunction, optionally, wherein the pre-existing medical condition is selected from angina pectoris, hypotension, hypertension, benign prostatic hyperplasia, and retinitis pigmentosa.

41. The composition, use, or method of claim 40, wherein treating the existing medical condition involves administering an active ingredient selected from PDE-5 inhibitors, nitrates, and alpha-receptor blockers.

42. The composition, use, or method of claim 40, wherein the active ingredient for treating the pre-existing medical condition is selected from GTN, isosorbide mononitrate, isosorbide dinitrate, alfuzosin, doxazosin, indopramine, prazosin, tamsulosin, and terazosin.

43. The composition, use, or method according to any of the preceding claims further comprising the administration of at least one active agent for treating or improving female sexual dysfunction.

44. The composition, use, or method according to claim 43, wherein, The at least one active agent for treating or improving female sexual dysfunction is selected from: hormones such as estrogen and testosterone, synthetic hormones such as tibolone, estrogen receptor modulators such as opemifene, serotonin agonists or antagonists such as flubanseri or bupropion, melanocortin receptor agonists such as bumenotide, PDE-5 inhibitors, alprostadil, and phentolamine mesylate.

45. A composition, use, or method according to any of the preceding claims, wherein the subject suffers from severe female sexual dysfunction.

46. ​​A kit comprising a composition and an active agent for treating or improving female sexual dysfunction, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, the non-volatile solvent comprising a polyol and a diol, and wherein the composition is free of trinitroglycerin (GTN), acetylcholinesterase inhibitors, vasodilators, and estrogens.

47. The kit according to claim 46, wherein the active agent is selected from: hormones such as estrogen and testosterone, synthetic hormones such as tibolone, estrogen receptor modulators such as opemifene, serotonin agonists or antagonists such as flubancerine or bupropion, melanocortin receptor agonists such as bumenotide, PDE-5 inhibitors, alprostadil, and phentolamine mesylate.

48. The kit according to claim 46 or claim 47, wherein the active agent is not intended to treat or improve erectile dysfunction in a male subject.

49. A composition for treating or improving sexual dysfunction in a female subject, wherein the composition comprises a volatile solvent and a non-volatile solvent, the volatile solvent comprising a lower alcohol and water, and the non-volatile solvent comprising a polyol and a diol. in, The composition comprises the following components, the range of which is expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 45%, - Water: 30% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 12% The composition further comprises aloe vera, and The composition does not contain any pharmaceutically active ingredients used to treat female sexual dysfunction.

50. The composition according to claim 49, wherein the composition does not contain any pharmaceutically active ingredient.

51. The composition according to claim 49 or 50, comprising the following components, said components being expressed as a percentage of the total weight of the composition: - Lower alcohols: 30% to 40%, - Water: 30% to 40%, - Polyols: 22% to 26%, - Diols: 4% to 8%, - Aloe vera: 0.5% to 5%, - Optionally, one or more of the following: thickeners or gelling agents, pH control agents, skin-feel-enhancing agents, antimicrobial preservatives, and warming agents. in, The composition is prepared at a pH range of 4.5 to 7.

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