Topical composition

Abstract

There is provided the use of a composition for the treatment or amelioration of female sexual dysfunction in a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

Description

[0001] Topical Composition

[0002] Field of the Invention

[0003] This invention relates to compositions for use in the treatment or amelioration of female sexual dysfunction.

[0004] Background to the Invention

[0005] In the International Classification of Diseases and Related Health Problems, The World Health Organization (WHO), defines sexual dysfunction as an individual’s inability to participate in a sexual relationship as he or she would wish, noting that sexual response is a psychosomatic process and both psychological and somatic processes are usually involved in the causation of sexual dysfunction.

[0006] Female sexual dysfunction is a heterogeneous group of sexual problems experienced by women, such as penetrative pain and problems related to sexual desire or interest, arousal, lubrication, genital sensation, orgasm or sexual satisfaction. It also includes, but is not limited to, psychiatric disorders diagnosed under the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, which require a woman to feel extreme distress and interpersonal strain for a minimum duration of six months.

[0007] The prevalence of female sexual dysfunction among women, regardless of their age, is commonly reported to be 40-50%; however, some researchers have reported prevalence in up to 76% of women.

[0008] Interventions for female sexual dysfunction include non-pharmacological approaches, such as lifestyle advice, relationship counselling, cognitive behavioural therapy and pelvic floor exercises, as well as pharmacological approaches, such as oestrogen therapy and flibanserin therapy. However, there is limited evidence of the efficacy of these approaches and there remains an unmet need of a suitable therapy for treating female sexual dysfunction. Summary of the Invention

[0009] In a first aspect, the present invention provides a composition for use in the treatment or amelioration of female sexual dysfunction, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol. Preferably, the composition is for topical application to the vulva.

[0010] The poly hydric alcohol and glycol preferably have a ratio by weight of from 1.5:1 to 6.0:1. Preferably, the pH of the composition is above 4.5 and lower than 7.0. In some embodiments, the pH of the composition is above 5.0 and lower than 7.0.

[0011] Speculatively, compositions according to the invention enhance production of endogenous NO by virtue, for example, of the latent heat of cooling as the volatile solvent component evaporates, stimulating the nerves locally and resulting in generation of endogenous NO. On the vulva, which is very highly innervated, there are sensors which are reactive to a range of physical sensations, such as and including touch, pressure and temperature, and topical application of compositions according to invention may stimulate more than one such sensor so that they react synergistically and, results in improved sexual function including but not limited to arousal, desire, increased lubrication, orgasm, reduced discomfort or pain, and / or overall improved sex life.

[0012] Female sexual dysfunction is a heterogeneous group of sexual problems experienced by women, such as penetrative pain and problems related to sexual desire or interest, arousal, lubrication, genital sensation, orgasm or sexual satisfaction. It encompasses women experiencing any of these problems, of any aetiology and for any duration, with single or multiple symptoms of any severity and in generalised or situational contexts. This includes, but is not limited to, psychiatric disorders diagnosed under the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, which require a woman to feel extreme distress and interpersonal strain for a minimum duration of six months. The treatment or amelioration of female sexual dysfunction is defined as the improvement of sexual function in a subject. This includes the improvement of one or more symptoms associated with female sexual dysfunction. For example, this can include, but is not limited to, increased sensation, stimulation, pleasure, satisfaction, arousal, desire, lubrication, ability to orgasm, reduced discomfort or pain, and / or overall improved sex life. The subject does not need to have been diagnosed with female sexual dysfunction, although in some instances, this may be the case.

[0013] In some embodiments, the treatment or amelioration of female sexual dysfunction can be measured using the validated “gold standard” measuring instrument FSFI (female sexual function index). 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 embodiments, the use of the composition will result in an increase in FSFI where data is gathered at baseline (pre-treatment) and at the end of the treatment period. In some embodiments, the FSFI score may increase by >0.5, >1, >1.5, >2, >2.5, >3, >3.5, >4 or more. In some embodiments, the subjects using the composition may have a pre-treatment FSFI score of <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 particular embodiments, the subjects using the composition may have a pre-treatment FSFI score of <26.55 and the FSFI score may increase by >2, >2.5, >3, >3.5 or >4 over the course of treatment.

[0014] In some embodiments, the composition is free of GTN, i.e. it does not contain any GTN. In some embodiments, the composition further does not contain any derivatives or prodrugs of GTN.

[0015] In some embodiments, the composition is free of phosphodiesterase type 5 inhibitors (PDE5 inhibitors) such as sildenafil, androgens such as testosterone, flibanserin, bremelanotide, oestrogen (also known as estrodiol), and ospemifene.

[0016] In some embodiments, the composition is also free of an acetylcholinesterase inhibitor. The acetylcholinesterase inhibitor may be any acetylcholinesterase inhibitor such as A9- tetrahydrocannabinol (THC), physostigmine, neostigmine, pyridostigmine, ambenonium, demarcarium, rivastigmine, galantamine, caffeine, donepezil, tetrahydroaminoacridine, edrophonium, huperzine A, bis-huperzine A, bis-huperzine B, huperzine A-tacrine, derivatives of huperzine A, ladostigil, ungeremine, and lactucopicrin.

[0017] In some embodiments, the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction, for example, hormones such as oestrogen and testosterone, synthetic hormones such as tibolone, oestrogen receptor modulators such as ospemifene, serotonin agonists or antagonists such as flibanserin or bupropion, melanocortin receptor agonists such as bremelanotide, PDE5 inhibitors such as tadalafil and sildenafil, acetylcholinesterase inhibitors, and vasodilators such as vasoactive vitamins (e.g. vitamin B3), alprostadil and phentolamine mesilate.

[0018] In some embodiments, the composition does not contain any pharmaceutically active ingredients. A pharmaceutical active ingredient (also known as an active pharmaceutical ingredient (API) or a drug) is any substance that is intended to treat or prevent a disease, or to restore, correct or modify physiological functions by exerting a pharmacological, immunological or metabolic action. Compositions containing a pharmaceutical active ingredient are required to go through the regulatory approval process as a medicinal product with accompanying clinical trials (e.g. via a New Drug Application (ND A) at the FDA or at the EMA in accordance with EU Directive 2001 / 83 / EC). In contrast, compositions not containing a pharmaceutical active ingredient, but which can be used to treat a patient, for example, through a physical mechanism of action, can be approved as a medical device. Therefore, whether or not an ingredient is considered to be a pharmaceutical active ingredient is determined by the intended use of the ingredient and the composition in which it is contained. As a result, in the context of the present composition which is a medical device and works through a physical mechanism of action, excipients such as ethanol, glycerol, propylene glycol and the like are not pharmaceutical active ingredients.

[0019] In some embodiments, the composition is free of compounds selected from PDE-5 inhibitors, amide anaesthetics, local anaesthetics, natural prostaglandins, synthetic prostaglandins, testosterone or combinations thereof. Preferably, the composition is free of PDE-5 inhibitors and amide anaesthetics.

[0020] In some embodiments, the composition does not comprise menthol, menthol derivatives, borneol, Camphor or Mengdiol.

[0021] In particular embodiments, the composition does not comprise white petroleum jelly and / or paraffin.

[0022] The composition is not intended for use as a hand sanitizer. The composition may have a lower alcohol content of not more than 50%, optionally not more than 45%, optionally not more than 40%, further optionally not more than 36%. In some embodiments, the composition has an ethanol content of not more than 50%, optionally not more than 45%, optionally not more than 40%, further optionally not more than 36%.

[0023] Preferably the composition is in gel, cream or serum form although other forms, such as foams or sprays, may be contemplated and are within the scope of the invention with appropriate additive excipients, for example a propellant gas in the case of a foam or spray. More preferably, the formulation is a gel. In formulation types where the composition has the form of a gel and is applied by hand, viscosities in the range of 250- 6,000 mPas are appropriate to ensure optimum control of application, as governed by the pH being in the range 4.5-7.0 or 5.0-7.0. Preferably, the viscosity should have a value in the range 500 to 4,500 mPas, more preferably 1,000-3,500 mPas, for example 3,000 mPas when measured by Brookfield Viscometer, Spindle E, 0.3 RPM, at a temperature of 25 °C.

[0024] It has been found that the pH affects not only viscosity but also stability and appearance. Regarding viscosity, at a pH of below 4.5 and where the composition is a gel, the viscosity is too low and the composition is too fluid to be applied without being spread or spontaneously dissipating away from the site of application. At pH values greater than 4.5, preferably greater than 5.0 or 5.2, viscosity is acceptable although, at a pH above about 5.8, there is an increasing risk, depending on other ingredients present in the composition, that the thickening or gelling agent will form a precipitate, thus rendering the composition visually unacceptable. It has been found that the tendency towards flocculation, arising from or exacerbated by the thickening or gelling agent, is mitigated by the pH. In particular, viscosity is unacceptable at a pH significantly below 4.5 (preferably 5.2) whereas, at a pH greater than 5.8, there is a significant risk of flocculation occurring, resulting in a product which may be regarded by consumers as unacceptable.

[0025] Within the broad pH range of 4.5-7.0, a preferred range is 5.0-7.0, a more preferred range is 5.2-6 and an even more preferred range is 5.25-5.75. At a pH within this range, viscosity and flocculation are acceptable.

[0026] The above pH values refer to the composition as manufactured, although there may be a tendency for the pH to drift upwards by up to approximately 0.25 of a pH unit within a few weeks of manufacture. Nevertheless, since higher viscosities can be tolerated, any increase in pH after manufacture is also acceptable.

[0027] Because of the tendency for upward drift of pH following manufacture, the more preferred pH range for compositions according to the invention should be regarded as 5.25-6.0 and the upper values of the other ranges should be adjusted accordingly.

[0028] Compositions according to the invention may also include, depending on their physical form, at least one additional ingredient selected from: agents for enhancing skin feel, for example a silicone oil composition such as Dimethicone 200; a thickening or gelling agent such as a polyacrylate-based composition; a pH control agent such as triethanolamine or an inorganic base; and an antimicrobial preservative such as methylparaben and / or propylparaben. In some embodiments, the compositions may also include one or more fragrances and / or one or more colourants.

[0029] Concentrations of the additional ingredients are preferably less than 5% by weight, preferably less than 2% by weight, for example 1.0%. However, the pH control agent is added until the pH is within the desired target range of 5.0-7.0, preferably 5.1-6.0 or more preferably 5.25-5.75, all as manufactured. Regarding the thickening or gelling agent, it has been found desirable to use a polyacrylate-based composition which is readily dispersible in the solvent blend and which facilitates rapid evaporation of the volatile solvents so as to achieve the equilibrium rate for skin permeation preferably within one minute or more preferably within thirty seconds of application to the vulva. Suitable thickening or gelling agents comprise high molecular weight interpolymers of a crosslinked unsaturated carboxylic acid polymer, which may be a homopolymer or a copolymer, and a copolymeric steric stabiliser having hydrophilic and hydrophobic moieties. Preferably, the monomer of the unsaturated carboxylic acid polymer comprises acrylic acid or an alkyl ester derivate thereof, and the steric stabiliser preferably comprises either a block copolymer and / or a random copolymer, the block copolymer preferably comprising a polyester such as 12- hydroxy stearic acid as the hydrophobic moiety and polyethylene glycol as the hydrophilic moiety. Preferably, the unsaturated carboxylic acid comprises acrylic acid crosslinked with allyl sucrose. Such interpolymers which include a steric stabiliser in the polymerisation process are rapidly wetted and easy to disperse and, throughout the remainder of this specification, including the claims, will be referred to as “easy to disperse interpolymers of the type described”. Commercially-available representative examples include Carbopol® Ultrez 10, 20, 21 and 30. Homopolymers such as Carbopol® 934P and 937P are not “easy to disperse interpolymers of the type described”, since they do not include the steric stabiliser.

[0030] The thickening or gelling agent is preferably present in the composition at 0.5% to 2% by weight. In some embodiments, the composition comprises a thickening or gelling agent at 0.5% to 1.5% by weight. In other embodiments, the composition comprises a thickening or gelling agent at 0.7% to 1.5% by weight. In various embodiments, the composition comprises a thickening or gelling agent at 0.8% to 1.2% by weight. In particular embodiments, the composition comprises a thickening or gelling agent at about 1% by weight.

[0031] In some embodiments, the composition may further include aloe. This is the gel-like substance that can be found in the leaves of plants in the genus aloe. This includes species such as aloe vera, aloe ferox, aloe arborescens, aloe perryi, and the like. Aloe vera is the most commonly used plant species to obtain aloe gel. The amount of aloe in the composition may be 0.5% to 5% by weight. In some embodiments, the amount of aloe in the composition may be 0.5% to 4%, 1% to 3%, 1.5% to 2.5% or about 2% by weight.

[0032] In some embodiments, the composition may further include a warming agent. This can be used as a sensory agent to provide a physical warming sensation to the skin following the initial cooling sensation provided by the composition. The warming agent may be selected from vanillyl ethyl ether, vanillyl propyl ether, vanillin propylene glycol acetal, ethyl vanillin propylene glycol acetal, capsaicin, gingerol, vanillyl butyl ether, 4-(l- menthoxy-methyl)-2-phenyl-l,3-dioxolane, 12-(l-menthoxy-methyl)-2-(3,4-dihydroxy- phenyl) 1,3 -dioxolane, 4-(l-menthoxy-methyl)-2-(2-hy droxy-3-methoxy -phenyl)- 1,3- dioxolane, 13 -( 1 -menthoxy-methyl)-2-(4-methoxyphenyl)- 1 ,3 -dioxolane, 14 - ( 1 - menthoxy-methyl)2-(34-methylenedioxy-phenyl)-l,3-dioxolane, hot pepper oil, capsicum oleoresin, ginger olioresin, nonyl acid vanillylamide, or combinations thereof. Preferably, the warming agent is vanillyl butyl ether (VBE). The amount of warming agent in the composition may be 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.

[0033] Compositions according to the invention may be considered as a single-phase solution comprising the volatile solvent pair of, for example, ethanol and water and the nonvolatile solvent pair of, for example, glycerol and propylene glycol. The use in such systems of a gelling agent comprising an easy to disperse interpolymer of the type described and having the required pH has been found to permit precise application of the composition to the vulva. Additionally, the use of easy to disperse interpolymers of the type described, especially Carbopol® Ultrez 10, surprisingly results in higher viscosities than previously imagined being advantageously acceptable, since such interpolymers of the type described result in the compositions having rheological properties such that, in use and on being applied to the vulva by hand, the rubbing or smearing action results in a temporary reduction in viscosity such that evaporation of volatile solvent is rendered even more rapid, whereby equilibrium is established in the target time of less than one minute, preferably less than 30 seconds. At the same time, permeation is unaffected by the increased viscosity under non-shear conditions.

[0034] The volatile solvents may have a molecular weight of 15 to 75 g / mol. The non-volatile solvents may have a molecular weight of 40 to 200 g / mol, preferably 50 to 150 g / mol, and more preferably 60 to 120 g / mol.

[0035] The volatile solvents to non-volatile solvents may have a ratio by weight of from 0.5:1 to 4:1. Preferably, the volatile solvent to non-volatile solvent ratio by weight is from 1:1 to 3:1. More preferably, the volatile solvent to non-volatile solvent ratio by weight is from 2:1 to 2.5:1.

[0036] The polyhydric alcohol preferably has a carbon to oxygen atom ratio of from 2:1 to 1:1. The glycol preferably has a carbon to oxygen atom ratio of from 2:1 to 1:1.

[0037] The lower alcohol preferably has a boiling point below 150 °C. The poly hydric alcohol preferably has a boiling point below 150°C. The glycol preferably has a boiling point below 250°C.

[0038] Compositions according to the invention may be fully water miscible. The volatile and non-volatile solvents may be water miscible.

[0039] Compositions according to the invention may be clear and / or colourless.

[0040] Preferably, the polyhydric alcohol and the glycol have a ratio by weight of from 2: 1 to 6:1. More preferably, the polyhydric alcohol to glycol ratio by weight is from 2.5:1 to 5.5:1. Even more preferably, the polyhydric alcohol to glycol ratio by weight is from 3:1 to 5:1. More preferably still, the polyhydric alcohol to glycol ratio by weight is from 3.5:1 to 4.5:1. In terms of concentration of ingredients, compositions according to the invention may comprise the following, the ranges being expressed in percentages by weight of the overall composition:

[0041] - lower alcohol: 15-45%

[0042] - water: 20-55%

[0043] - polyhydric alcohol: 22-26%

[0044] - glycol: 4-12%

[0045] In terms of concentration of ingredients, compositions according to the invention may comprise the following, the ranges being expressed in percentages by weight of the overall composition:

[0046] - lower alcohol: 30-45%

[0047] - water: 20-40%

[0048] - polyhydric alcohol: 22-26%

[0049] - glycol: 4-12%

[0050] The concentration of water is preferably in the range 30-40% by weight. The 20% referred to above is the minimum which is preferred for gelling purposes. Likewise, the lower alcohol concentration is preferably in the range 15-35% by weight but, subject to user tolerance, concentrations up to 45% may be accommodated without compromising the efficacy of the composition. In some embodiments, the lower alcohol concentration is in the range 15-30% by weight. In some embodiments, the lower alcohol concentration is in the range 30-40% by weight. In some embodiments, the lower alcohol concentration is in the range 30-35% by weight. The ratio of ethanol to water in the volatile solvent pair may be adjusted to alter the rate of evaporation, ethanol being more volatile than water, up to approximately 1:1, the limiting concentration of ethanol as an example of the lower alcohol being governed by local intolerance as a skin irritant.

[0051] Preferably, the combined amount of the polyhydric alcohol and the glycol is not more than 35% by weight. In the present specification, the term “lower alcohol” means an aliphatic alcohol having from one to five carbon atoms, for example, ethanol or isopropanol; ethanol is generally preferred. The term “lower alcohol” can also include volatile ester derivatives of the lower alcohol. For example, in some instances, volatile esters such as methyl acetate, ethyl acetate, and the like, can be used.

[0052] By “polyhydric alcohol” is meant an aliphatic polyol such as glycerol, although sorbitol, erythrotol, arabitol and xylitol are examples of other water-soluble polyols which may optionally be used together with or instead of glycerol.

[0053] By “glycol” is meant a primary or secondary diol or polyol compound, such as propylene glycol (propene- 1,2-diol), butyline glycol (butane- 1,3 -diol), pentylene glycol (pentane- 1,5-diol) or hexyline glycol (2-methyl-2,4-pentane diol). Preferably, the glycol is a primary or secondary diol.

[0054] In some embodiments, compositions according to the invention have the following concentrations in percentages by weight:

[0055] - lower alcohol: 15-35%

[0056] - water: 33-52%

[0057] - polyhydric alcohol: 22-26%

[0058] - glycol: 4-8%

[0059] Preferably, compositions according to the invention have the following concentrations in percentages by weight:

[0060] - lower alcohol: 30-35%

[0061] - water: 33-37%

[0062] - polyhydric alcohol: 22-26%

[0063] - glycol: 4-8%

[0064] By way of example, one formulation according to the invention has the following ingredients in percentages by weight:

[0065] - ethanol: 33% - water: 35%

[0066] - glycerol: 24%

[0067] - propylene glycol: 6%

[0068] By way of example, another formulation according to the invention has the following ingredients in percentages by weight:

[0069] - ethanol: 33%

[0070] - water: 35%

[0071] - glycerol: 24%

[0072] - propylene glycol: 6%

[0073] - Carbopol® Ultrez 10: 1%

[0074] In the above formulations, the ratio of glycerol to propylene glycol is 4:1. The above formulations may also contain a base to bring the pH within the range of 4.5-7.0, preferably 5.0-7.0.

[0075] In some embodiments, there is provided a composition for use in treating or ameliorating female sexual dysfunction in a subject, the composition comprising volatile and nonvolatile solvents, the volatile solvents comprising a lower alcohol and water and the nonvolatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition comprises the following amount of ingredients, the ranges being expressed in percentages by weight of the overall composition:

[0076] - lower alcohol: 30-45%

[0077] - water: 20-40%

[0078] - polyhydric alcohol: 22-26%

[0079] - glycol: 4-12%, wherein the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction.

[0080] In some embodiments, the lower alcohol is present at 30%-40%. In some embodiments, the water is present at 30%-40%. In another aspect, there is provided a composition for treating or ameliorating female sexual dysfunction in a subject, wherein the composition comprises volatile and nonvolatile solvents, the volatile solvents comprising a lower alcohol and water and the nonvolatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition comprises the following ingredients, the ranges being expressed in percentages by weight of the overall composition:

[0081] - lower alcohol: 30-45%

[0082] - water: 30-40%

[0083] - polyhydric alcohol: 22-26%

[0084] - glycol: 4-12%, wherein the composition further comprises aloe, and wherein the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction.

[0085] Further features of this aspect are the same as those described above for the composition for use in the treatment or amelioration of female sexual dysfunction in a subject. For example, the composition may not contain any pharmaceutically active ingredients. The composition may further comprise a thickening or gelling agent. The composition may have a pH above 4.5 and lower than 7.0.

[0086] In some embodiments, the composition comprises a warming agent such as vanillyl butyl ether.

[0087] Compositions according to the invention may be made by mixing the ingredients together. Conventional process principles may be applied, for example that the Carbopol® Ultrez 10 is dispersed in the water phase, the ethanol added and the remaining solvents then added optionally with or before pH adjustment. While an organic base, such as triethanolamine, may be used for the purpose of pH adjustment, it is preferred to use an inorganic base such as potassium hydroxide, sodium hydroxide or liquid ammonia, to avoid a possibility of nitrosamine formation. Such bases, preferably potassium hydroxide, are especially beneficial in solvent-rich systems such as those according to the present invention, since the potassium, for example, has the potential to form a salt with the gelling agent, the salt possibly being insoluble at the concentrations used, leading to phase separation after manufacture. Easy to disperse interpolymers of the type described appear to be less susceptible to phase separation, due possibly to the increased solvent affinity of the block copolymer backbone segments. Even so, it is considered preferable to control pH to within a range of 5.25 to 5.75 such that precision of application is achieved, Carbopol® salt phase separation (e.g. using Carbopol® Ultrez 10, 20, 21 or 30) does not occur and gel viscosity does not compromise rate of loss of volatile solvents.

[0088] Preferably, the composition is for topical application to the external genitalia, for example, the vulva. In some embodiments, the composition is for topical application to the labia. In some embodiments, the composition is for topical application to the inner labia and / or clitoris. In some embodiments, the composition is for topical application to the clitoris.

[0089] The subject may be any subject with external female genitalia. For example, the subject may be a female subject, an inter sex subject with external female genitalia or a subject with a neovulva as a result of gender- affirming 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.

[0090] In some embodiments, the subject is pre-menopausal.

[0091] In some embodiments, the subject is in perimenopause, menopause or post-menopause. In some embodiments, the subject is in menopause.

[0092] In some embodiments, the subject is in post-menopause. This is a female subject who has not experienced menstruation for 12 months.

[0093] The subject may have an existing medical condition, wherein the existence of the condition precludes the taking of an active ingredient for treating female sexual dysfunction. The subject may have an existing medical condition, wherein the treatment of the condition precludes the taking of an active ingredient for treating female sexual dysfunction.

[0094] The existing medical condition may be any condition that precludes the taking of an active ingredient for treating female sexual dysfunction. For example, the existing medical condition may be angina, low blood pressure, high blood pressure, benign prostatic hyperplasia, or retinitis pigmentosa.

[0095] Treatment of the existing medical condition which precludes the taking of an active ingredient for treating female sexual dysfunction may involve the administration of an active ingredient selected from PDE-5 inhibitors, nitrates and alpha blockers. For example, the active ingredient for treating the existing medical condition may be selected from GTN, isosorbide mononitrate, isosorbide dinitrate, alfuzosin, doxazosin, indoramin, prazosin, tamsulosin, and terazosin.

[0096] The method may further comprise administering at least one active agent for treating or ameliorating female sexual dysfunction to the subject. The at least one active agent for treating or ameliorating female sexual dysfunction may be selected from hormones such as oestrogen and testosterone, synthetic hormones such as tibolone, oestrogen receptor modulators such as ospemifene, serotonin agonists or antagonists such as flibanserin or bupropion, melanocortin receptor agonists such as bremelanotide, PDE5 inhibitors such as tadalafil and sildenafil, and vasodilators such as alprostadil and phentolamine mesilate. In some embodiments, the at least one active agent for treating or ameliorating female sexual dysfunction may be selected from oestrogen, testosterone, tibolone, ospemifene, flibanserin, bupropion, bremelanotide, PDE-5 inhibitors, alprostadil and phentolamine mesilate. In one embodiment, the at least one active agent for treating or ameliorating female sexual dysfunction is administered orally. In some embodiments, the at least one active agent for treating or ameliorating female sexual dysfunction is administered topically.

[0097] The subject may have severe female sexual dysfunction. This may include one or more of Hypoactive Sexual Desire Disorder (HSDD), Female Sexual Arousal Disorder (FSAD), Female Orgasmic Disorder (FOD), Dyspareunia, Vaginismus, Sexual Aversion Disorder, Female Sexual Interest and Arousal Disorder (FSIAD), and Genito Pelvic Pain Penetration Disorder (GPPPD). In some embodiments, the subject has one or more of: hypoactive sexual desire disorder, female sexual arousal disorder, female orgasmic disorder and sexual pain disorder.

[0098] According to a second aspect of the invention, there is provided a kit comprising the composition (as herein before described) and an active agent for treating or ameliorating female sexual dysfunction.

[0099] The active agent is preferably administered separately from the composition, e.g. it is not intended to be added to the topical composition (as herein before described). The active agent may be selected from hormones such as oestrogen and testosterone, synthetic hormones such as tibolone, oestrogen receptor modulators such as ospemifene, serotonin agonists or antagonists such as flibanserin or bupropion, melanocortin receptor agonists such as bremelanotide, PDE5 inhibitors such as tadalafil and sildenafil, and vasodilators such as alprostadil and phentolamine mesilate. In one embodiment, the active agent for treating or ameliorating female sexual dysfunction is for oral administration, i.e. it is in an oral dosage form. In some embodiments, the active agent for treating or ameliorating female sexual dysfunction is for topical administration. In some embodiments, the active agent is not for treating or ameliorating erectile dysfunction in male subjects.

[0100] The description of the composition for use according to the first aspect is equally applicable to this aspect.

[0101] According to a third aspect, there is provided the use of the composition (as herein before described) in the manufacture of a medicament for treating or ameliorating female sexual dysfunction. The description of the composition for use according to the first aspect is equally applicable to this aspect.

[0102] According to a fourth aspect, there is provided is a method of treating or ameliorating female sexual dysfunction, the method comprising topical application of a biologically effective amount of the composition (as herein before described) to the vulva of a subject. Optionally, the method may further comprise manual stimulation of the vulva. The description of the composition for use according to the first aspect is equally applicable to this aspect.

[0103] In a related aspect, there is provided a composition for use in increasing the FSFI score of a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol.

[0104] There is also provided is a method of increasing the FSFI score of a subject, the method comprising topical application of a biologically effective amount of the composition (as herein before described) to the vulva of a subject. Optionally, the method may further comprise manual stimulation of the vulva. The description of the composition for use according to the first aspect is equally applicable to this aspect.

[0105] A skilled person will appreciate that all aspects of the invention are equally applicable to all other aspects of the invention. In particular, aspects of the composition for use have been described in greater detail than in other aspects of the invention, for example, the kit. However, the skilled person will appreciate where more detailed information has been given for a particular aspect of the invention, this information is generally equally applicable to other aspects of the invention.

[0106] All patent and literature references cited in the present specification are hereby ference in their entirety. of the

[0107] The invention will now be described in detail by way of example only with reference to the figures in which:

[0108] Figure 1 is a graph showing the average temperature (°C) of the sample gel over time (min) at each ambient temperature (27°C, 32°C, 37°C). Figure 2 is a graph showing the average % weight change of the sample gel over time (min) at each ambient temperature (27°C, 32°C, 37°C).

[0109] Figure 3 is a graph showing the average % weight change of the sample gel over temperature (°C) at each ambient temperature (27°C, 32°C, 37°C).

[0110] Figure 4 shows (A) a schematic representation of an exemplary experimental setup; and (B) a schematic representation of an exemplary positioning of temperature probes on the ex vivo tissue surface.

[0111] Figure 5 shows the temperature (°C) at the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute, and 30s second intervals in the third and fourth minutes) after application of 300 mg of the composition. (A) Replicate #1. (B) Replicate #2. (C) Replicate #3.

[0112] Figure 6 shows the temperature (°C) at the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute, and 30s second intervals in the third and fourth minutes) after application of 800 mg of the composition. (A) Replicate #1. (B) Replicate #2. (C) Replicate #3.

[0113] Figure 7 shows the temperature (°C) at the untreated (control) tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute, and 30s second intervals in the third and fourth minutes). (A) Replicate #1. (B) Replicate #2. (C) Replicate #3.

[0114] Figure 8 shows the comparative temperature (°C) profile expressed as the mean average of 3 replicates, for 300 mg dose, 800 mg dose and untreated control. the Invention

[0115] The composition of the invention contained: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol® Ultrez 10: 1%. pH was adjusted to 5.25 with potassium hydroxide solution. The ethanol used in the manufacture of the composition was absolute ethanol (i.e. 100% ethanol free from water) such that the final composition contained 33% of pure ethanol. If a lower grade of ethanol was used which contained impurity amounts of water (e.g. 96% ethanol), then the amount used would have to be adjusted to ensure the final composition contained the correct amount of the components, i.e. 33% pure ethanol and 35% water.

[0116] The availability of an efficacious composition for treatment of female sexual dysfunction, without the inclusion of GTN or any other active ingredient, means that the composition has reduced contraindications compared with other treatments, thus for example enabling the composition to be used by subjects taking nitrate medication. Furthermore, the high safety profile enables the compositions to be used in conjunction with other treatments such as sildenafil, flibanserin or bupropion. In summary, compositions according to the invention, in providing fast onset time and improved sexual function including but not limited to arousal, desire, increased lubrication, orgasm, reduced discomfort or pain, and / or overall improved sex life, together with a high safety profile, represent a significant improvement to known treatments and offer further treatment opportunities to patients who hitherto have been unable to or are contra-indicated to use currently-available treatments.

[0117] Example 2: Cooling Effect of Composition

[0118] As indicated above, the compositions of the invention are believed to enhance production of endogenous NO by virtue of the latent heat of cooling as the volatile solvent component evaporates, stimulating the nerves locally and resulting in generation of endogenous NO. In the vulva, there are sensors which are reactive to a range of physical sensations, such as and including touch, pressure and temperature, and topical application of compositions of the invention stimulate such sensors. It is thought that the rapid cooling brought about by the composition followed by the recovery in temperature acts as a stimulant so that the sensors react synergistically and result in improved sexual function including but not limited to arousal, desire, increased lubrication, orgasm, reduced discomfort or pain, and / or overall improved sex life.

[0119] The cooling effect of the composition used in the example above (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 protocol developed to enable the comparison of the cooling effect of different compositions.

[0120] 1. PRINCIPLE

[0121] The cooling effect and rate of recovery of the gel composition is measured by applying the gel to a calibrated temperature probe that is weighed on an analytical balance. This allows the temperature change to be monitored simultaneously with weight loss over time. Different cooling / recovery ‘profiles’ can be generated when incubating the setup at different ambient temperatures (i.e. 27°C, 32°C and 37°C).

[0122] 2. Summary

[0123] A suitable method to assess the cooling profiles of the composition of the invention was developed at three different ambient temperatures: 27°C, 32°C and 37°C. The method was issued to describe the process used to obtain the cooling profiles.

[0124] The results of the validation studies confirm that the method is fit for purpose regarding the repeatability (precision), reproducibility (intermediate precision) and accuracy.

[0125] 3. Instruments & Apparatus

[0126] • Temperature probe (e.g. Fisherbrand Traceable Flip-Stick Thermometer, P / N: 14-648-45). Total probe surface area: 11.64 cm2

[0127] 15 mL plastic centrifuge tubes or equivalent

[0128] Power drill capable of drilling a 5 mm diameter hole or equivalent • Analytical balance (e.g. Sartorius 4 decimal place Analytical Balance or equivalent)

[0129] • Stopwatch

[0130] • Bench top oven capable of maintaining 27°C, 32°C and 37°C ±1°C

[0131] • Bench top centrifuge

[0132] • Video recorder / Camera

[0133] The following sample was used for the validation:

[0134] Gel comprising ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%;

[0135] Carbopol® Ultrez 10: 1%. pH adjusted to 5.25 with potassium hydroxide solution.

[0136] 5. Method development

[0137] Development of the method utilised three different ambient temperatures: 27°C, 32°C and 37°C, to assess the cooling profile of the sample gel. A description of the method can be found in section 6 (32°C described only). The temperature and weight of the gel was recorded over a run time of 25 minutes. Six replicate preparations were performed and the average of the data calculated at each ambient temperature. The following cooling profiles were generated: Temperature vs Time (Figure 1), % Weight Change vs Time (Figure 2) and % Weight Change vs Temperature (Figure 3). It is intended that these cooling profiles can be used to uniquely characterise the cooling properties of the sample gel.

[0138] During development, it was observed that the first replicate on each day at each ambient temperature was further from the mean result when compared to the other five replicates of data. This could be caused by fluctuations in oven temperature when opening the oven door for the first time after overnight incubation. For this reason, it was decided for the validation studies to disregard the first replicate on each day in order to allow the oven to stabilise before further replicates were performed.

[0139] The results obtained for the development work show that a different cooling profile is achieved when analysing at different ambient temperatures. This difference in the cooling profile is most apparent when plotting Temperature (°C) against Time (minutes) (Figure 1). At all three ambient temperatures, the temperature of the gel reached the lowest point after -1-1.5 minutes and then began to recover back to the ambient temperature. The temperature drop appeared to increase as the ambient temperature increased with an ambient temperature of 37°C showing a temperature drop of ~13°C compared to ~8°C at an ambient temperature of 27°C. After 25 minutes, the sample gel had recovered to within -3 °C of the initial starting temperature (ambient). The plateau of the temperature recovery occurred at -15 minutes for 37°C ambient and at 32°C and 27°C, both levelled off at -25 minutes.

[0140] Figure 2 shows the cooling profiles at each ambient temperature when plotting % Weight Change against Time (minutes). In general, the % weight change is most rapid at the beginning of the curve for all three ambient temperatures where after -5 minutes the % weight change begins to level off. A second % weight change drop was observed at -15 minutes for 32°C and at -20 minutes for the 37°C ambient temperature. Overall, a clear difference between the 27°C and 32°C / 37°C profiles can be seen with the 32°C profile only showing subtle differences when compared to the 37°C profile.

[0141] The cooling profiles obtained by plotting Temperature (°C) against % Weight Change are shown in Figure 3. Again, a similar profile shape was obtained at each of the ambient temperatures. Overall, the shape of these profiles represent a ‘U’ shape. As the ambient temperature increases, the amount of temperature drop / recovery is also increased as seen in Figure 1. At -24% weight change the maximum temperature drop is achieved for all three ambient temperatures. Full temperature recovery requires -70% weight change for 32°C and 37°C, whereas only 60% weight change is needed to return to 27°C ambient.

[0142] 6. Analytical Guidance

[0143] The following steps were carried out to test the sample gel.

[0144] Note: the first run on each day of analysis is to be disregarded and treated as a mock run to allow the oven setup to stabilise after the first run. Drill a hole ~5 mm in diameter into a 15 mL centrifuge tube lid. Weigh the empty centrifuge tube on an analytical balance. Record the weight and tare the balance. Place ~14 mL of sample gel into the 15 mL centrifuge tube using a syringe. Seal with a normal lid and centrifuge at 1500 rpm for 30 seconds to collect the gel. Place the tube containing sample gel, a calibrated temperature probe and an analytical balance into a bench top oven set at 32°C ±1°C. Weigh the tube containing the sample gel. Record the weight of the gel (Weight Check 1). Place another calibrated temperature probe inside the balance chamber (for ambient temperature monitoring only). Leave all apparatus including the tube containing sample gel overnight to incubate. After incubation, weigh the tube containing the sample gel. (Weight Check 2). Calculate the weight change and check there is no significant weight loss (NMT 2%). Place the lid with the 5 mm hole cut out onto the centrifuge tube containing sample gel. Stopper the hole to prevent any evaporation until it is ready to be sampled. Place back into the benchtop oven. Tare the balance with the temperature probe. Ensure the temperature of the probe is within 32°C ±1°C. Begin video recording ensuring the temperature and weight are visible. (NB: it is not required to video record beyond 5 minutes. Readings after this time may be manually recorded). 10. Remove the temperature probe from the balance and insert it into centrifuge tube containing sample gel until the base of the probe makes contact with the tube lid. Approximately 70 mg is applied (± 20 mg). (NB: Time sensitive step).

[0145] 11. In one smooth motion, withdraw the probe from the gel taking care not to make contact with the sides of the centrifuge cap. Place the probe back onto the balance, close the oven door and start the stopwatch. Stopper the centrifuge tube lid and centrifuge the tube for 15 seconds at 1500 rpm to collect the gel. Seal the tube with a regular lid and place back into the oven. (NB: Time sensitive step).

[0146] 12. Record the weight and temperature of the probe for 25 minutes. See Table 1 for reading intervals.

[0147] 13. If ambient temperature drift is observed, the oven may be maintained at 32°C ±1°C by adjusting the oven control dial or by venting with a small gap in the oven door on the opposite side of the balance.

[0148] 14. After 25 minutes, remove the temperature probe from the balance and clean with a dry lint-free tissue. Place the temperature probe back onto the balance maintained at 32°C ±1°C. Repeat steps 7 - 14 for the next replicate.

[0149] 15. Repeat all steps for the remaining ambient temperatures of 27°C ±1°C and 37°C ±1°C.

[0150] Table 1: Reading Intervals 7. Results

[0151] Calculate %weight change at each reading interval using the following equation: %weight change = -100 + ((Reading Interval Weight (g) / Initial Weight (g)) *100)

[0152] Calculate the following:

[0153] Maximum Temperature Reduction = Ambient Temperature (°C) - Lowest Temperature (°C) Temperature Recovery (T = 25 mins) = Final Temperature (°C) - Lowest Temperature (°C)

[0154] In a validation study conducted at an ambient temperature of 32°C ±1°C in accordance with the protocol given in section 6, the test sample gave the following results:

[0155] Example 3: Evaluation of thermal characteristics on ex vivo tissue

[0156] Introduction

[0157] This example documents an evaluation of the thermal characteristics of the composition of the invention under simulated conditions of use: The investigation measured the spatiotemporal temperature changes on an ex vivo tissue surface due to application of the composition.

[0158] Testing was conducted using samples of the final, finished composition, manufactured to the same specification, at the same production scale and packed into the same primary packaging system as proposed for marketing.

[0159] This study was conducted to further demonstrate the thermal characteristics of the composition (i.e. creating a rapid, localized cooling effect followed by a recovering warming effect).

[0160] Test Performed The composition was applied to the surface of an ex vivo porcine muscle tissue block under simulated conditions of use, and the temperature-time history measured via resistance thermometry.

[0161] The composition was applied to an area of tissue. Before application of the composition, the surface of the tissue block was maintained at a temperature relevant to the composition indication for use by submersion of the block in a 37°C water bath, leaving the top surface exposed to the room air for application of the composition.

[0162] The tissue surface temperature-time information was measured using three (3) probe thermometers; one placed at the center of the composition application area on the tissue surface, and two placed at opposite edges of the application area (each equidistant from the centre probe), to profile the complete spatio-temporal temperature distribution on the tissue.

[0163] Objective of the Test

[0164] The aim of the study was to further demonstrate the thermal characteristics of the composition (i.e. that it creates a rapid cooling effect followed by a recovery warming effect) under ex vivo simulated conditions of use.

[0165] The purpose of the study was to perform an ex vivo temperature profiling assessment to investigate the spatio-temporal temperature changes on the skin surface following application of composition when a defined (300 mg) and maximum (800 mg) dose were applied to an ex vivo tissue.

[0166] A 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 aluminium tube, therefore a portion of the gel contained in the tube shoulders cannot be evacuated by squeezing the body of the tube. The tubes are filled to a nominal weight of 800 mg to ensure delivery of at least 300 mg gel. Accounting for the unlikely scenario that a user is able to extract the complete contents of a tube, the thermal effects of both 300 mg and 800 mg dosage amounts have been evaluated. 1

[0167] Description of Test Methods

[0168] Gel

[0169] The study evaluated the composition. The formulation of the composition is shown in Table 2.

[0170] Table 2: gel formulation

[0171] Ex vivo Tissue

[0172] Gel was applied to the skin surface of an ex vivo porcine muscle tissue block.

[0173] The surface of the block was maintained at a steady state temperature of approximately 32-34°C. In a variation of the test method, the surface of the block may be maintained at a steady state temperature of up to approximately 37 °C.

[0174] An area for composition application measuring 3.5 cm (L) x 3.5 cm (W) was marked on the tissue surface.

[0175] The tissue block measured 8 cm (L) x 8 cm (W) x 6 cm (D). A continuous tissue margin of not less than 2 cm in all three dimensions around the area of composition application was present to ensure boundary conditions did not influence the measurements taken at the application site.

[0176] Water Bath The ex vivo tissue block was submerged in a 14-litre capacity digital water bath with internal dimensions of 353 x 325 x (H) 200 mm set to a temperature of 37°C (± 0.1 °C accuracy). Uniformity of temperature throughout the circulating water was confirmed using a calibrated probe at five points in the bath (center and 4 corners).

[0177] Temperature Probe Thermometers

[0178] The surface temperature of the skin was measured throughout the test using three (3) calibrated class A PtlOO temperature probe thermometers with a resolution of 0.1 °C (over a range of -199.9°C to +199.9°C).

[0179] Probes were sited at the centre of the composition application area (1 probe) and at opposite edges of the application area (2 probes).

[0180] A fourth calibrated PtlOO probe was inserted into the centre of the muscle block to measure the core temperature of the tissue.

[0181] The temperature probes were calibrated at 0°C, 10°C and 50°C prior to starting the study.

[0182] The probes have a response time of approximately 7.5 seconds, this is determined sufficient to accurately measure the temperature changes on a tissue occurring over several minutes. Independent measurement of three discrete points on the tissue surface (accurate to 0.1 °C under the study conditions) is preferred as it allows the measurement of the temperature distribution with sufficient spatial and temporal resolution to characterise the thermal effects of the composition over a larger area of the tissue surface.

[0183] Methodology

[0184] 1. The skin surface of the porcine tissue block was marked to identify an area of approximately 12 cm2for gel application.

[0185] 2. The tissue block was submerged - leaving only the top (skin) surface exposed to air - in a water bath maintained at a temperature of 37°C. 3. Three temperature probes were placed on the surface of the skin. One (1) in the centre of the composition application area, and two (2) diagonally opposite at the edge of the marked area on the surface of the skin.

[0186] 4. The tissue block was allowed to equilibrate for approximately 2.5 hours (initial equilibration) in the covered water bath until a steady state temperature of between approximately 32-34°C was measured by the temperature probes at three points on the skin surface, and a core tissue temperature of 37°C was achieved (measured by a fourth probe inserted into the tissue block). In some instances, occlusion of the water bath may be necessary to achieve an initial skin surface temperature in the required range.

[0187] 5. The water bath cover was removed.

[0188] 6. 300 mg of gel was applied to the 12 cm2area marked on the tissue block. The gel was spread over the marked area containing the probes by finger.

[0189] 7. The real-time readings displayed on the temperature probes prior to application of the gel and throughout the 11 -minute experimental duration were recorded on video.

[0190] 8. The water bath was left uncovered following composition application to allow evaporation of the formulation, as would be the case in the clinical setting. After 6 minutes, when the effects of evaporation were judged to be complete, the water bath was recovered to support maintenance of the skin surface temperature.

[0191] 9. All gel residue was removed from the tissue block.

[0192] 10. Steps 3 to 9 were repeated for two further replicates of the 300 mg dose, and three replicates of an 800 mg dose.

[0193] 11. Steps 3-5, 7 and 8 were repeated in triplicate for the experimental control (n= 3) of untreated tissue.

[0194] 12. Video recordings of all experimental runs (replicates) were reviewed and the data documented at the following time-points (minutes 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)

[0195] Test Results

[0196] The change in temperature on the tissue block surface was recorded using 3 class A PtlOO probe thermometers over an 11 -minute experimental duration (by which time, the starting temperature of 32°C was reached) post application of the composition to investigate the temperature profile of the formulation effect on the tissue.

[0197] The temperatures (°C) recorded for the 300 mg dose of the composition (n=3) over the full experimental duration (including 10 second intervals within the first minute, followed by 15 second intervals in the second minute and 30 second intervals in the third and fourth minutes) are shown in Tables 3, 4 and 5 and Figure 5(A-C).

[0198] The temperatures (°C) for the 800 mg dose of the composition (n=3) are shown in Tables 6, 7 and 8 and Figure 6(A-C).

[0199] The temperatures (°C) for the untreated control tissues (n=3) are shown in Tables 9, 10 and 11 and Figure 7(A-C).

[0200] In addition, the following datasets are tabulated to enable comparison:

[0201] The average temperatures (°C) of the tissue block surface (expressed as the mean of the three probe measurements) for the 300 mg and 800 mg dose amounts over the 11 -minute experimental duration are shown in Table 12.

[0202] The average temperatures (°C) of the tissue block surface (expressed as the mean of three replicates) for the 300 mg, 800 mg and control runs over the 11 -minute experimental duration are shown in Table 13.

[0203] Table 3: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 300 mg of the composition to the tissue. Data are shown for replicate #!.

[0204] Table 4: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 300 mg of the composition to the tissue. Data are shown for replicate #2.

[0205] Table 5: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 300 mg of the composition to the tissue. Data are shown for replicate #3.

[0206] Table 6: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 800 mg of the composition to the tissue. Data are shown for replicate #!.

[0207] Table 7: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 800 mg of the composition to the tissue. Data are shown for replicate #2.

[0208] Table 8: Temperatures (°C) of the tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 800 mg of the composition to the tissue. Data are shown for replicate #3.

[0209] Table 9: Temperatures (°C) of the untreated (control) tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes). Data are shown for replicate #1.

[0210] Table 10: Temperatures (°C) of the untreated (control) tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes). Data are shown for replicate #2.

[0211] Table 11: Temperatures (°C) of the untreated (control) tissue surface recorded by three probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes). Data are shown for replicate #3.

[0212] Table 12. Average temperature (°C) of the tissue surface recorded by probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes) after application of 300 mg and 800 mg of the composition to the tissue.

[0213] Table 13. Average mean temperature (°C) of the tissue surface recorded for all replicates for 300 mg doses, 800mg doses and the controls by probe thermometers over an 11 minute experimental duration (with 10 second intervals during the first minute, followed by 15s intervals in the second minute and 30s intervals in the third and fourth minutes).

[0214] Data Analysis

[0215] An immediate decrease in temperature was observed with a maximum temperature drop of 7.5°C (average 6.8°C) achieved during the cooling phase of the experiment (recorded at the 6-minute timepoint) across both dose volumes followed by a gradual increase in temperature over the experimental duration. The greatest temperature decrease was observed when the 800 mg dose of the composition was applied to the tissue (ca. 7.5 °C decrease from the initial starting temperature of ca. 32 °C after 6 minutes). For the 300 mg dose, a decrease of ca. 7.2 °C from the starting temperature was achieved after 6 minutes. In the first 2 minutes post-application of the composition, a maximum temperature drop of 5.9°C was observed at the 2-minute timepoint when the tissue surface was dosed with 800 mg gel; the average temperature drops for the 300 mg dose and the 800 mg dose at the 2-minute timepoint were 5.3°C and 5.1°C respectively. In contrast, over the initial 2- minute timeframe the controls exhibited an average temperature drop of 2.2°C.

[0216] Over the experimental duration, the composition-induced temperature drop reached a plateau after approximately 6 minutes, with a maximum temperature drop of 7.5°C observed at the 6-minute timepoint when the tissue surface was dosed with 800 mg. The average temperature drops at the 6-minute timepoint for the 300 mg dose and the 800 mg dose were 6.7°C and 6.8°C respectively. In contrast, over the initial 6-minute timeframe the controls exhibited an average temperature drop of 3.2°C.

[0217] After 6 minutes, when the composition-induced temperature drop had plateaued, the recovery phase was monitored for a further 5 minutes - until a temperature near the starting temperature was reached. It was observed that the tissue temperature recovery rate following application of a 300 mg dose was marginally faster than that after application of an 800 mg dose. This is to be expected as a smaller mass of gel has a smaller residual thermal capacity.

[0218] Measurements from the three surface probes were consistent at any given time-point, demonstrating uniformity of composition effect across the surface of the tissue. For all replicates of both doses and the control, the RSD did not exceed 5 % at any time point, and in the majority of cases was less than 3.5 %.

[0219] Data were highly consistent between the study replicates. For the 300 mg dose, the relative standard deviation (RSD) did not exceed 2.1 %. For the 800 mg dose, RSD did not exceed 3.3 %. For the untreated tissue control, RSD did not exceed 2.4 %.

[0220] Discussion / Conclusions An evaluation of the spatio-temporal temperature changes on ex vivo tissue following application was successfully performed for the composition, at two dose strengths, to further demonstrate the thermal characteristics of the composition, specifically that the composition exerts a rapid cooling effect followed by a slower recovery warming effect.

[0221] The results from the ex vivo experiment indicate that - at both dose levels evaluated - the composition achieved a rapid cooling effect, followed by a gradual increase in temperature.

[0222] Post application of the composition, immediate cooling of the tissue surface was observed. Cooling effects continued for several minutes reaching a maximum temperature drop of 7.5°C after approximately 6 minutes. After 6 minutes, skin surface temperatures were observed to recover, with a complete return to starting temperatures reached approximately 11 minutes post-application.

[0223] No appreciable difference in the thermal effects on tissue were observed between 300 mg and 800 mg doses. It should be noted that whilst 300 mg represents the ideal dose, the results indicate that an 800 mg dose will also be safe and effective in the unlikely event that an increased amount of gel is extracted during patient use.

[0224] Untreated tissue controls (n=3) were run to demonstrate that the study conditions - particularly occlusion of the water bath - were not responsible for the purported composition effect. The control results - generated under identical experimental conditions to the treated tissue - provide confidence that the thermal profile assigned to the composition is a true composition effect.

[0225] In illustration of this point, Figure 18 shows a comparison of the average temperature profile (mean of 3 replicates) for each dose (300mg and 800mg) versus the control.

[0226] Example 4: Home User Study A home user study was conducted to assess the use of the composition and its effect on symptoms of female sexual dysfunction. The composition tested contained: ethanol: 33%; water: 35%; glycerol: 24%; propylene glycol: 6%; Carbopol® Ultrez 10: 1%. pH was adjusted to 5.5 with potassium hydroxide solution.

[0227] In broad outline, the study had a 1-week pre-treatment subject assessment period followed by a four-week treatment period where subjects were instructed to use the product on at least four occasions with or without a sexual partner. 67 subjects were used for the analysis, including both pre- and post-menopausal women. Subjects were instructed to apply 300 mg of the product to the external genitalia (e.g. the inner labia and clitoris) prior to sexual activity.

[0228] Assessment was conducted in two ways:

[0229] 1. Use of the validated “gold standard” measuring instrument FSFI (female sexual function index) where data is gathered at baseline (pre-treatment) and at the end of the four-week treatment period (recalled information). 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.

[0230] 2. Answers to a number of questions recorded by diary soon after the sexual event. These questions related to the sensorial properties of the product and related likes / dislikes, and included questions relating to changes in vaginal lubrication, sensation / feeling in the genital area, sexual pleasure and ability to have an orgasm.

[0231] Key findings from the study were as follows:

[0232] 1. FSFI measurement: o Across 67 subjects, there was an overall positive change in sexual function after 4 weeks, which was statistically significantly improved over baseline (P=0.004). This was despite a high average baseline FSFI score of 26.9 which exceeds the level generally regarded as the upper limit for sexual dysfunction (26.55). o Across 67 subjects, statistical significance at P = <0.05 was achieved in individual domains for improved lubrication and improved orgasmic function. o A subset analysis was conducted on subjects experiencing some degree of sexual dysfunction, i.e. with baseline FSFI of 26.55 or less (26 subjects; average baseline FSFI of 22.0) and scores improved. Overall, there was a positive shift from baseline of 3.1 (versus 1.5 with all 67 subjects). o Across these 26 subjects, P = <0.05 was achieved in 5 / 6 FSFI domains; arousal, lubrication, orgasm, satisfaction and discomfort (pain). Improvement in desire occurred but did not reach statistical significance. o It is believed that scores could be improved further in a clinical environment by recruiting subjects with multiple symptoms of sexual dysfunction which would likely reduce baseline FSFI scores further and make room for greater improvement. Baseline lubrication and discomfort (pain) scores in this study for example were quite high in the 26 subjects (4.0 / 6.0 and 4.5 / 6.0) and choosing subjects with greater symptomology is likely to improve scores overall. Analysis of diary data: a) Tolerance o 84% (56 / 67) subjects reported “Burning” or “Stinging” sensations on at least one product use. o However, 54% of these women (30 / 56) consider Buming / S tinging to be a positive attribute. o 39% (26 / 67) of women experienced a burning or stinging sensation that they considered negative. o In spite of this, 12 of these 26 women found the gel improved their sexual experience [on at least 40% of usage occasions]: All of these women wished to continue using the product. o Additionally, amongst the 14 women who experienced a negative burning or stinging sensation and for whom their overall experience was not improved, 8 wished to continue using the product. o There were 6 women who reported negative sensations for whom the sexual experience was not improved and who did not wish to continue using the product. Only one woman chose to stop using the product during the study (drop out after two uses). It is judged that this level of rejection is acceptable and “dialling down” the burning / stinging by reducing ethanol content could have a negative impact on overall efficacy as most women appear to find this pleasurable. b) Perceptions of Efficacy

[0233] A rudimentary criterion was set that a subject must report improvement in sexual function on at least 30% of usage occasions to be classed as a responder. o 46% (31 / 67) women reported the gel increased vaginal lubrication. o 63% (42 / 67) reported it increased genital sensation. o 54% (36 / 67) reported it improved genital pleasure. o 61% (41 / 67) reported it improved their satisfaction with the sexual experience. o 28% (19 / 67) reported it improved their ability to orgasm.

[0234] 3. Product Usage during the study:

[0235] '33161 (57%) women used more tubes (5-8 tubes) than the stated minimum of 4 tubes which is a strong indication of women in general liking the product.

[0236] Overall Conclusions

[0237] After detailed consideration of the FSFI data and diary data, and taking into account that essentially a healthy population was studied not recruited as suffering from sexual dysfunction, the overall positive trends coming out of the study were very encouraging. A statistically significant shift over baseline in FSFI was achieved in all subjects, and in the subset analysis of women with baseline scores <26.55, 5 / 6 of the FSFI domains achieved P = <0.05. The diary data indicated that the product was well received, in general being well liked and well tolerated with high product usage of more than the stipulated minimum of 4 tubes in 57% of women and most women stated that they would continue using the product despite some negative buming / stinging. Various modifications whether by way of addition, deletion, or substitution of features may be made to the above-described embodiments to provide further embodiments, any and all of which are intended to be encompassed by the appended claims.

Claims

Claims1. A composition for use in the treatment or amelioration of female sexual dysfunction in a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

2. A composition for use according to claim 1, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator, phosphodiesterase type 5 inhibitors, androgens such as testosterone, flibanserin, bremelanotide, oestrogen, and ospemifene.

3. A composition for use according to claim 1 or 2, wherein the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction.

4. A composition for use according to any preceding claim, wherein the composition does not contain any pharmaceutically active ingredients.

5. A composition for use according to any preceding claim, wherein the composition has a pH above 4.5 and lower than 7.0.

6. A composition for use according to any preceding claim, having the form of a gel.

7. A composition for use according to claim 6, wherein the composition has the form of a gel having a viscosity in the range 500 to 4,500 mPas.

8. A composition for use according to any preceding claim, wherein the lower alcohol is ethanol or isopropanol.

9. A composition for use according to any preceding claim, wherein the polyhydric alcohol is selected from glycerol, sorbitol, erythritol, arabitol and xylitol.

10. A composition for use according to any preceding claim, wherein the glycol is selected from propylene glycol, butylene glycol, pentylene glycol and hexylene glycol.

11. A composition for use according to any preceding claim, wherein the polyhydric alcohol to glycol weight ratio is from 1.5:1 to 6.0:1.

12. A composition for use according to and preceding claim, wherein the polyhydric alcohol to glycol weight ratio is from 3:1 to 5:1.

13. A composition for use according to any preceding claim, further comprising a thickening or gelling agent.

14. A composition for use according to any preceding claim, further comprising aloe.

15. A composition for use according to any preceding claim, further comprising a warming agent such as vanillyl butyl ether.

16. A composition for use according to any preceding claim, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 15-45%- water: 20-55%- polyhydric alcohol: 22-26%- glycol: 4-12%17. A composition for use according to any preceding claim, wherein the water is in the range 30-40% by weight.

18. A composition for use according to any preceding claim, wherein the lower alcohol is in the range 30-35% by weight.

19. A composition for use according to any preceding claim, wherein the combined amount of the poly hydric alcohol and the glycol is not more than 35% by weight.

20. A composition for use according to any preceding claim, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 30-45%- water: 20-40%- polyhydric alcohol: 22-26%- glycol: 4-12%, wherein the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction.

21. A composition for use according to claim 20, wherein the composition does not contain any pharmaceutically active ingredients.

22. A composition for use according to any preceding claim, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 30-40%- water: 30-40%- polyhydric alcohol: 22-26%- glycol: 4-8%23. A composition for use according to any preceding claim, comprising the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 30-35%- water: 33-37%- polyhydric alcohol: 22-26%- glycol: 4-8%24. A composition for use according to any preceding claim, wherein the composition is in the form of a gel and comprises the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 30-35%- water: 33-37%- polyhydric alcohol: 22-26%- glycol: 4-8%- a thickening or gelling agent: 0.5- 1.5%, wherein the composition has a pH as manufactured in the range 5.25 to 5.75.

25. The composition for use according to any preceding claim, consisting of the following ingredients being expressed in percentages by weight of the overall composition:- lower alcohol: 30-40%- water: 30-40%- polyhydric alcohol: 22-26%- glycol: 4-8%- optionally, one or more of a thickening or gelling agent, a pH control agent, an agent for enhancing skin feel, an antimicrobial preservative, aloe, and a warming agent, wherein the composition has a pH as manufactured in the range 4.5 to 7.

26. The composition for use according to any preceding claim, comprising the following ingredients being expressed in percentages by weight of the overall composition:- ethanol: 33%- water: 35%- glycerol: 24%- propylene glycol: 6%- a thickening or gelling agent: 1%- optionally, a pH control agent, an agent for enhancing skin feel, and / or an antimicrobial preservative, wherein the composition has a pH as manufactured in the range 5.25 to 5.75.

27. The composition for use according to any preceding claim, comprising the following ingredients being expressed in percentages by weight of the overall composition:- ethanol: 33%- water: 35%- glycerol: 24%- propylene glycol: 6%- Carbopol® Ultrez 10: 1%- optionally, a pH control agent, an agent for enhancing skin feel, and / or an antimicrobial preservative, wherein the composition has a pH as manufactured in the range 5.25 to 5.75.

28. The composition for use according to any preceding claim, consisting of the following ingredients being expressed in percentages by weight of the overall composition:- ethanol: 33%- water: 35%- glycerol: 24%- propylene glycol: 6%- a thickening or gelling agent: 1%- optionally, a pH control agent, an agent for enhancing skin feel, and / or an antimicrobial preservative, wherein the composition has a pH as manufactured in the range 5.25 to 5.75.

29. The composition for use according to any preceding claim, wherein the composition is for topical application to the vulva.

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

31. The composition for use according to any preceding claim, wherein the female sexual dysfunction comprises one or more of Hypoactive Sexual Desire Disorder (HSDD), Female Sexual Arousal Disorder (FSAD), Female Orgasmic Disorder (FOD), Dyspareunia, Vaginismus, Sexual Aversion Disorder, Female Sexual Interest and Arousal Disorder (FSIAD), and Genito Pelvic Pain Penetration Disorder (GPPPD).

32. The composition for use according to any preceding claim, wherein use of the composition results in an increase in the FSFI total score of the subject of at least 2.

33. The composition for use according to any preceding claim, wherein the subject using the composition has a baseline FSFI total score of 26.55 or less.

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

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

36. A composition for use in increasing the FSFI score of a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

37. Use of a composition in the manufacture of a medicament for treating or ameliorating female sexual dysfunction in a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

38. A method of treating or ameliorating female sexual dysfunction, the method comprising topically applying a biologically effective amount of a composition to the vulva of a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

39. A method of increasing the FSFI score of a subject, the method comprising topically applying a biologically effective amount of a composition to the vulva of a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprisinga polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

40. The composition for use according to any one of claims 1-36, or the use according to claim 37, or the method according to claim 38 or 39, wherein the subject has an existing medical condition, wherein the existence or treatment of the condition precludes the taking of an active ingredient for treating female sexual dysfunction, optionally wherein the existing medical condition is selected from angina, low blood pressure, high blood pressure, benign prostatic hyperplasia, and retinitis pigmentosa.

41. The composition for use or use or method according to claim 40, wherein treatment of the existing medical condition involves administration of an active ingredient selected from PDE-5 inhibitors, nitrates and alpha blockers.

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

43. The composition for use or use or method according to any preceding claim, further comprising administering at least one active agent for treating or ameliorating female sexual dysfunction.

44. The composition for use or use or method according to claim 43, wherein the at least one active agent for treating or ameliorating female sexual dysfunction is selected from hormones such as oestrogen and testosterone, synthetic hormones such as tibolone, oestrogen receptor modulators such as ospemifene, serotonin agonists or antagonists such as flibanserin or bupropion, melanocortin receptor agonists such as bremelanotide, PDE- 5 inhibitors, alprostadil and phentolamine mesilate.

45. The composition for use or use or method according to any preceding claim, wherein the subject has severe female sexual dysfunction.

46. A kit comprising a composition and an active agent for treating or ameliorating female sexual dysfunction, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition is free of glyceryl trinitrate (GTN), an acetylcholinesterase inhibitor, a vasodilator and oestrogen.

47. The kit of claim 46, wherein the active agent is selected from hormones such as oestrogen and testosterone, synthetic hormones such as tibolone, oestrogen receptor modulators such as ospemifene, serotonin agonists or antagonists such as flibanserin or bupropion, melanocortin receptor agonists such as bremelanotide, PDE-5 inhibitors, alprostadil and phentolamine mesilate.

48. The kit of claim 46 or claim 47, wherein the active agent is not for treating or ameliorating erectile dysfunction in male subjects.

49. A composition for treating or ameliorating female sexual dysfunction in a subject, wherein the composition comprises volatile and non-volatile solvents, the volatile solvents comprising a lower alcohol and water and the non-volatile solvents comprising a polyhydric alcohol and a glycol, wherein the composition comprises the following ingredients, the ranges being expressed in percentages by weight of the overall composition:- lower alcohol: 30-45%- water: 30-40%- polyhydric alcohol: 22-26%- glycol: 4-12%, wherein the composition further comprises aloe, and wherein the composition does not contain any pharmaceutically active ingredients for the treatment of female sexual dysfunction.

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

51. The composition according to claim 49 or 50, consisting of the following ingredients being expressed in percentages by weight of the overall composition:- lower alcohol: 30-40%- water: 30-40%- polyhydric alcohol: 22-26%- glycol: 4-8%- aloe: 0.5-5%- optionally, one or more of a thickening or gelling agent, a pH control agent, an agent for enhancing skin feel, an antimicrobial preservative, and a warming agent, wherein the composition has a pH as manufactured in the range 4.5 to 7.

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