Compositions and methods for treating female sexual dysfunction and female sexual arousal disorder

Abstract

The present disclosure relates generally to compositions and techniques for treating female sexual dysfunction (FSD), including female sexual arousal disorder (FSAD). In some embodiments, a composition, such as a cream, may be applied to the genital organ of a subject. The composition may also contain an active ingredient for the treatment of FSD and / or FSAD, such as sildenafil and / or a pharmaceutically acceptable salt thereof. In addition, certain embodiments described herein generally relate to techniques using such compositions, kits including such compositions, and the like.

Description

Technical Field

[0001] This disclosure generally relates to compositions and methods for treating female sexual dysfunction (FSD), such as female sexual arousal disorder (FSAD) and its symptoms. Background Technology

[0002] Female sexual dysfunction (FSD) is a recognized serious problem affecting quality of life. One type of FSD is called female sexual arousal disorder (FSAD), which is estimated to affect approximately 20% of women in the United States. Currently, women with FSAD typically receive counseling treatment. Another type of FSD is female sexual interest / arousal disorder (FSIAD). DSM-5 defines FSIAD as a lack or significant reduction in sexual interest / arousal, measured by the presence of three of the following six symptoms: lack or reduced interest in sexual activity; lack or reduced sexual thoughts or fantasies; no or reduced initiation of sexual activity, and usually unacceptable to a partner's attempts to initiate; lack or reduced sexual arousal or pleasure in almost all or all sexual encounters; lack or reduced sexual interest / arousal to any internal or external sexual cues; and loss or reduction of genital or non-genital sensation during sexual activity in all or almost all sexual encounters. These symptoms must cause significant clinical distress and persist for at least six months.

[0003] Phosphodiesterase type 5 (PDE5) inhibitors are medications that block the degradation of cyclic GMPs by PDE5 in the smooth muscle cells of the lining of the blood vessels supplying the corpora cavernosa of the penis. These medications are commonly used to treat erectile dysfunction (ED). PDE5 inhibitors are typically delivered orally, and there are currently no FDA-approved transdermal formulations. Previous studies have shown that when PDE5 inhibitors are taken orally daily to treat pulmonary hypertension, the most common treatment-emergent adverse events (TEAEs) are similar to those when PDE5 inhibitors are taken orally as needed to treat erectile dysfunction (ED) (headache, hot flashes). Because pulmonary hypertension is more common in women than men, FDA safety data on the use of daily oral PDE5 inhibitors are primarily (75-78%) for women with serious cardiac and respiratory complications due to an underlying diagnosis of pulmonary hypertension. Therefore, women using significantly higher daily systemic doses of oral PDE5 inhibitors to treat pulmonary hypertension do not experience more severe adverse events compared to those using PDE5 inhibitors to treat ED. There are no FDA-approved treatments for fibrillary stenosis (FSSD), fibrillary fibrodysplasia (FSAD), or fibrillary intraepithelial hypertension (FSIAD). Therefore, there is a need for systems and methods for the transdermal delivery of clinically useful doses of phosphodiesterase type 5 inhibitors, as well as treatments for FSD (including FSAD and FSIAD) and the improvement of their symptoms. Summary of the Invention

[0004] This disclosure generally relates to compositions and methods for treating female sexual dysfunction (FSD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. This disclosure also relates to compositions and methods for treating female sexual arousal disorder (FSAD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. This disclosure further relates to compositions and methods for treating female sexual interest / arousal disorder (FSIAD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, a nitric oxide donor, and an ionic salt. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, and an ionic salt. In embodiments, the composition further comprises a moisturizing agent. In embodiments, the composition further comprises L-arginine or an L-arginine salt. In embodiments stating L-arginine or an L-arginine salt, any moisturizing agent may be used instead of L-arginine or an L-arginine salt. In some embodiments, the composition is a cream. In some embodiments, the composition is a gel. In some embodiments, the composition is a lotion.

[0005] In some embodiments, treating FSAD includes increasing satisfactory sexual events, improving arousal sensation, increasing arousal lubrication, increasing orgasm, reducing anxiety about sexual arousal, reducing pain or discomfort during and / or after sexual activity, and / or increasing satisfaction with sexual activity. In some embodiments, treating FSAD includes improving arousal sensation. In some embodiments, treating FSAD includes increasing arousal lubrication. In some embodiments, treating FSAD includes increasing orgasm. In some embodiments, treating FSAD includes reducing anxiety about sexual arousal. In some embodiments, treating FSAD includes increasing satisfaction with sexual activity. In some embodiments, treating FASD includes reducing pain or discomfort during and / or after sexual activity.

[0006] In some implementations, treating FSAD includes increasing satisfying sexual events. In these implementations, increasing satisfying sexual events includes, but is not limited to, increasing orgasm or orgasm frequency, feeling close to or connecting with a sexual partner, experiencing pleasure, increasing physical sensations, arousal, passion, and / or having pleasurable sexual experiences.

[0007] In some implementations, treating FSAD includes increasing sensation in the genital area. In some implementations, genital sensation includes one or more of the following: tingling, pleasure, warmth, pulsating, throbbing, fullness, or engorgement in the genital area.

[0008] In some respects, this article describes a method for increasing satisfactory sexual events in female subjects during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0009] In some respects, this article describes a method for improving arousal in female subjects during sexual activity, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0010] In some respects, this article describes a method for increasing arousal lubrication in female subjects during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0011] In some respects, this article describes a method for increasing female orgasm during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0012] In some respects, this article describes a method for reducing anxiety about sexual arousal or increasing satisfaction with sexual activity in female subjects, including applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0013] In some respects, this article describes a method for relieving pain or discomfort in female subjects during and / or after sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0014] In some respects, this article describes a method for treating female sexual dysfunction (FSD) or its symptoms, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject.

[0015] In some aspects, this document describes a method for treating female sexual interest / arousal disorder (FSIAD) or its symptoms, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject. In embodiments, treating FSIAD includes increasing libido. In embodiments, treating FSIAD includes increasing responsiveness to physical or psychological stimuli. In embodiments, symptoms of FSIAD include a lack of interest in or reduced interest in sexual activity. In embodiments, symptoms of FSIAD include a lack or reduction in erotic thoughts or fantasies. In embodiments, symptoms of FSIAD include decreased libido. In embodiments, symptoms of FSIAD include a diminished response to physical sexual stimuli. In embodiments, symptoms of FSIAD include a diminished response to psychological stimuli.

[0016] In some respects, this article describes a method for increasing the libido of female subjects, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0017] In some aspects, this document describes a method for increasing the response of a female subject to physical or psychological stimuli, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. In one embodiment, the response to physical stimuli is enhanced. In another embodiment, the response to psychological stimuli is enhanced. In yet another embodiment, the response to both physical and psychological stimuli is enhanced.

[0018] In this embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least twice over a period of time. In this embodiment, the period of time is approximately 1 week to approximately 8 weeks.

[0019] In one embodiment, one or more symptoms improve within approximately 1 week to approximately 8 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week to approximately 4 weeks after initial application. In one embodiment, one or more symptoms include arousal and lubrication. In another embodiment, one or more symptoms include libido. In another embodiment, one or more symptoms include achieving orgasm and / or experiencing orgasm.

[0020] In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil, acetildenafil, or thiomethisosildenafil. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil.

[0021] In some embodiments, the composition comprises an L-arginine salt. In some embodiments, the L-arginine salt comprises L-arginine hydrochloride. In some embodiments, L-arginine or an L-arginine salt is present at a concentration of at least about 5% by weight of the composition. In some embodiments, L-arginine or an L-arginine salt is present at a concentration of at least about 7% by weight of the composition. In some embodiments, the ionic salt is capable of driving a type 5 phosphodiesterase inhibitor and / or its salt through the stratum corneum of the subject. In some embodiments, the ionic salt is present at a concentration of at least about 5% by weight of the composition. In some embodiments, the ionic salt comprises potassium chloride. In some embodiments, the stabilizing polymer comprises xanthan gum. In some embodiments, the stabilizing polymer is present at a concentration of at least about 0.8% by weight of the composition. In some embodiments, propylene glycol is present at a concentration of at least about 8% by weight of the composition. In some embodiments, the polysorbate surfactant comprises polysorbate 20. In some embodiments, the polysorbate surfactant is present at a concentration of at least about 2% by weight of the composition.

[0022] In some embodiments, the composition comprises a salt of a phosphodiesterase type 5 inhibitor. In some embodiments, the composition comprises a sodium salt of a phosphodiesterase type 5 inhibitor. In some embodiments, the composition comprises a citrate of a phosphodiesterase type 5 inhibitor. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil. In some embodiments, the phosphodiesterase type 5 inhibitor and / or its salt is present at a concentration of at least about 1% by weight of the composition. In some embodiments, the phosphodiesterase type 5 inhibitor and / or its salt is present at a concentration of at least about 5% by weight of the composition. In some embodiments, the phosphodiesterase type 5 inhibitor and / or its salt is present at a concentration of at least about 7% by weight of the composition. In some embodiments, the phosphodiesterase type 5 inhibitor and / or its salt is present at a concentration of about 1% by weight to about 10% by weight of the composition.

[0023] In some embodiments, the composition comprises glyceryl stearate. In some embodiments, the composition comprises hexadecyl alcohol. In some embodiments, the composition comprises squalane. In some embodiments, the composition comprises isopropyl myristate. In some embodiments, the composition comprises oleic acid. In some embodiments, the composition comprises trisodium citrate dihydrate. In some embodiments, the composition comprises sodium benzoate. In some embodiments, the composition comprises gluconolactone. In some embodiments, purified water is present at a concentration of at least about 40% by weight of the composition. In some embodiments, the subject is a human.

[0024] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising applying a composition for local delivery to the genital area of ​​a subject, wherein at least about 80% by weight of the composition comprises purified water, at least one chloride salt, a stable polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and a phosphodiesterase type 5 inhibitor and / or its salt.

[0025] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising applying a composition comprising an ionic salt, a phosphodiesterase type 5 inhibitor and / or its salt, and optionally L-arginine or an L-arginine salt to the genital area.

[0026] This disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising applying a composition consisting primarily of purified water, potassium chloride, L-arginine hydrochloride, glyceryl stearate, hexadecyl alcohol, squalene, xanthan gum, isopropyl myristate, oleic acid, propylene glycol, polysorbate 20, and sildenafil citrate to the genital area.

[0027] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising applying a composition containing each of the following compounds to the genital area at a concentration not exceeding ±20% of the stated concentration:

[0028] a. Purified water with a concentration of about 35% to about 55% by weight;

[0029] b. Potassium chloride with a concentration of about 2.5% to about 15% by weight;

[0030] c. L-arginine hydrochloride at a concentration of about 2.5% to about 15% by weight;

[0031] d. Glyceryl stearate at a concentration of about 4% to about 10% by weight;

[0032] e. Hexadecyl alcohol at a concentration of about 4% to about 10% by weight;

[0033] f. Squalane at a concentration of about 1% to about 8% by weight;

[0034] g. Xanthan gum at a concentration of about 0.1% to about 5% by weight;

[0035] h. Isopropyl myristate at a concentration of about 0.1% to about 5% by weight;

[0036] i. Oleic acid with a concentration of about 0.1% to about 5% by weight;

[0037] j. Propylene glycol at a concentration of about 1% to about 10% by weight;

[0038] k. Polysorbate 20 at a concentration of about 0.2% to about 5% by weight; and

[0039] l. Sildenafil citrate at a concentration of about 1% to about 10% by weight.

[0040] In some embodiments, the composition comprises the compounds listed above at a concentration not exceeding ±10% of the stated concentration.

[0041] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising administering to a subject a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and an ionic salt.

[0042] In some embodiments, the phosphodiesterase type 5 inhibitor includes sildenafil or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has female sexual arousal disorder (FSAD). In some embodiments, the subject is at risk of developing female sexual arousal disorder (FSAD). In some embodiments, the subject is human. In some embodiments, the composition is a cream. In some embodiments, the composition is applied to the clitoris, vestibule, vulva, and / or vagina of the subject. In some embodiments, the composition is applied to the clitoris, glans, and / or frenulum of the genital region of the subject. In some embodiments, the composition is applied to the clitoris, glans, frenulum, and / or vestibule of the genital region of the subject. In some embodiments, the composition is applied to the clitoris, glans, frenulum, vestibule, and / or labia minora of the genital region of the subject. In some embodiments, the composition is not applied to the labia majora of the genital region of the subject. In some embodiments, the composition is applied intravaginally to the distal anterior vagina of the subject.

[0043] In some embodiments, the composition comprises:

[0044] a. Purified water with a concentration of approximately 40% by weight;

[0045] b. Potassium chloride with a concentration of approximately 5% by weight;

[0046] c. L-arginine hydrochloride at a concentration of approximately 7.5% by weight;

[0047] d. Glyceryl stearate at a concentration of approximately 7% by weight;

[0048] e. A concentration of approximately 7% by weight of hexadecaneol;

[0049] f. Squalane at a concentration of approximately 4% by weight;

[0050] g. Xanthan gum at a concentration of approximately 0.8% by weight;

[0051] h. Isopropyl myristate at a concentration of approximately 1% by weight;

[0052] i. Oleic acid at a concentration of approximately 1% by weight;

[0053] j. Propylene glycol at a concentration of approximately 8.5% by weight;

[0054] k. Polysorbate 20 at a concentration of approximately 2% by weight;

[0055] l. A concentration of approximately 10% by weight of trisodium citrate dihydrate;

[0056] m. Sodium benzoate with a concentration of approximately 0.2% by weight;

[0057] n. Gluconolactone at a concentration of about 0.25% by weight; and

[0058] o. Sildenafil citrate at a concentration of approximately 5% by weight.

[0059] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising selecting a female subject exhibiting one or more FSAD symptoms and applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the subject's genital area. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and its ionic salt. In some embodiments, the one or more symptoms are selected from distress related to decreased genital sensitivity, lack of genital response during sexual activity, reduced genital arousal, and / or difficulty in sexual arousal. In embodiments, one or more symptoms include a diminished response to physical sexual stimulation. In embodiments, the primary complaint of the female subject is a diminished response to physical sexual stimulation.

[0060] This disclosure generally relates to a method for treating female sexual interest / arousal disorder (FSIAD) or its symptoms, comprising: selecting a female subject exhibiting one or more FSIAD symptoms, and applying to the subject's genital area a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt, a stable polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and its ion salt. In embodiments, one or more symptoms of FSIAD are selected from loss or reduced interest in sexual activity or erotic thoughts or fantasies, decreased libido, and / or diminished responsiveness to physical or psychological stimuli. In embodiments, one or more symptoms of FSIAD include a lack of interest or reduced interest in sexual activity. In embodiments, one or more symptoms of FSIAD include a lack or reduction in erotic thoughts or fantasies. In embodiments, one or more symptoms of FSIAD include decreased libido. In embodiments, one or more symptoms of FSIAD include diminished responsiveness to physical sexual stimuli. In embodiments, one or more symptoms of FSIAD include diminished responsiveness to psychological stimuli. In embodiments, the primary complaint of the female subject is diminished responsiveness to physical sexual stimuli.

[0061] In some embodiments, about 50% of the composition is applied externally to the vulva and about 50% of the composition is applied internally to the vagina. In some embodiments, external application of about 50% of the composition includes applying the composition to the anterior commissure, clitoral hood, glans clitoris, and frenulum; applying the composition to the vaginal vestibule; and applying the composition to the labia minora. In some embodiments, the composition is not applied to the labia majora or pubic hair. In some embodiments, internal vaginal application of about 50% of the composition includes applying the composition to the distal anterior part of the vagina at a depth of about 0 cm to about 3 cm. In some embodiments, internal vaginal application of about 50% of the composition includes applying the composition about halfway between the distal and proximal interphalangeal joints to the lower distal third of the vagina.

[0062] In some embodiments, the composition is applied about 10 to about 20 minutes before sexual activity. In some embodiments, the composition is applied up to about 9 times over about 4 weeks. In some embodiments, the composition is applied at least about 24 hours before the second dose of the composition. In some embodiments, the subject has not used at least one of the following in 28 days prior to the administration of the first dose of the composition: a guanylate cyclase stimulant, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha receptor blocker.

[0063] In some implementations, the subject avoids wiping or washing away any genital areas where the composition has been applied.

[0064] In some implementations, any remaining composition is washed off after sexual activity.

[0065] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0066] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0067] In some embodiments, administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a satisfactory sexual event.

[0068] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased genital arousal.

[0069] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased lubrication of the genital area during sexual activity.

[0070] In some embodiments, administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in an increase in cognitive arousal.

[0071] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased libido.

[0072] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in an increase in orgasm during sexual activity.

[0073] In some embodiments, the administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a reduction in the difficulty of achieving orgasm during sexual activity or a decrease in the inability to achieve orgasm.

[0074] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased feeling or sensation in the genital area during sexual activity.

[0075] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased tingling sensation in the genital area during sexual activity.

[0076] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased blood flow to the genital area during sexual activity.

[0077] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased warmth, throbbing, or pulsation in the genital area during sexual activity.

[0078] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in a reduction of pain and / or discomfort during sexual activity.

[0079] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a reduction of pain and / or discomfort after sexual activity.

[0080] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0081] In some implementations, one or more symptoms of female sexual arousal disorder (FSAD) include, but are not limited to, diminished responsiveness to physical sexual stimulation.

[0082] In some implementations, the primary complaint of female subjects is a diminished response to physical sexual stimulation.

[0083] In some embodiments, the subject exhibits one or more of the following after administration of a composition comprising a type 5 phosphodiesterase inhibitor and / or its salt:

[0084] a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28);

[0085] b. SFQ28 score improvement of at least 1 point in the lubrication category;

[0086] c. Improvement of at least 1.5 points in the SFQ28 arousal category score;

[0087] d. Improve your SFQ28 score in the Desire category by at least 2 points;

[0088] The e.SFQ28 score for orgasm improved by at least 1.20 points;

[0089] f. The SFQ28 pain category score improved by at least 1 point;

[0090] g. The Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score improved by at least -7 points;

[0091] h. Arousal score improved by at least 1.45 points;

[0092] i. Genital arousal score improved by at least 1.13 points;

[0093] j. The score for genital arousal anxiety improved by at least 1.49 points;

[0094] k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and

[0095] l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

[0096] In some embodiments, the subject exhibits 2 or more of a1. In some embodiments, the subject exhibits 3 or more of a1. In some embodiments, the subject exhibits 4 or more of a1. In some embodiments, the subject exhibits 5 or more of a1. In some embodiments, the subject exhibits 6 or more of a1. In some embodiments, the subject exhibits 7 or more of a1. In some embodiments, the subject exhibits 8 or more of a1. In some embodiments, the subject exhibits 9 or more of a1. In some embodiments, the subject exhibits 10 or more of a1. In some embodiments, the subject exhibits 11 or more of a1. In some embodiments, the subject exhibits all 12 of a1.

[0097] In some implementations, the subjects include those with a preliminary diagnosis of FSAD, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Text Revision Fourth Edition (DSM-IV-TR).

[0098] In some embodiments, topical compositions comprising a type 5 phosphodiesterase inhibitor and / or its salts do not cause one or more of the following: orthostatic hypotension, headache, flushing, indigestion, light headedness, visual disturbances, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.

[0099] In some implementations, the subject's primary complaint is FSAD or one or more of its symptoms.

[0100] In some implementations, the subject's primary complaint is FSAD or one or more of its symptoms, and the subject exhibits secondary HSDD symptoms. In some implementations, the subject's complaint is FSAD, and the subject does not exhibit female orgasmic disorder (FOD) symptoms.

[0101] This disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising:

[0102] a. Female subjects with primary FSAD as their chief complaint were selected, and

[0103] b. Apply a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject.

[0104] In some embodiments, the subject exhibits symptoms of secondary HSDD. In some embodiments, the subject has FSAD or its symptoms as their sole diagnosis. In some embodiments, the subject has both primary FSAD or its symptoms and secondary HSDD or its symptoms. In some embodiments, the premenopausal subject has FSAD or its symptoms as their sole diagnosis. In some embodiments, the premenopausal subject has both primary FSAD or its symptoms and secondary HSDD or its symptoms.

[0105] This disclosure generally relates to a method for determining the efficacy of FSAD treatment, including:

[0106] a) Obtain baseline scores for one or more of the following: Sexual Function Questionnaire (SFQ28) scores in the arousal cognition category, SFQ28 scores in the arousal lubrication category, SFQ28 scores in the arousal sensation category, SFQ28 scores in the desire category, SFQ28 scores in the orgasm category, SFQ28 scores in the pain category, Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) scores, arousal sensation scores, genital arousal scores, genital arousal anxiety, percentage of arousal diary item 12-SSE, and number of arousal diary item 12-SSE.

[0107] b) FSAD treatment was administered to female subjects; and

[0108] c) Determine the improvement in one or more scores from step a.

[0109] In some implementations, the presence of one or more of the following indicates that FSAD treatment is effective:

[0110] a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28);

[0111] b. SFQ28 score improvement of at least 1 point in the lubrication category;

[0112] c. Improvement of at least 1.5 points in the SFQ28 arousal category score;

[0113] d. Improve your SFQ28 score in the Desire category by at least 2 points;

[0114] The e.SFQ28 score for orgasm improved by at least 1.20 points;

[0115] f. The SFQ28 pain category score improved by at least 1 point;

[0116] g. Improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score;

[0117] h. Arousal of feelings improved by at least 1.45 points;

[0118] i. Improvement in genital arousal by at least 1.13 points;

[0119] j. Genital arousal anxiety improved by at least 1.49 points;

[0120] k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and

[0121] l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

[0122] In some embodiments, the presence of two or more al indicates that FSAD treatment is effective. In some embodiments, the presence of three or more al indicates that FSAD treatment is effective. In some embodiments, the presence of four or more al indicates that FSAD treatment is effective. In some embodiments, the presence of five or more al indicates that FSAD treatment is effective. In some embodiments, the presence of six or more al indicates that FSAD treatment is effective. In some embodiments, the presence of seven or more al indicates that FSAD treatment is effective. In some embodiments, the presence of eight or more al indicates that FSAD treatment is effective. In some embodiments, the presence of nine or more al indicates that FSAD treatment is effective. In some embodiments, the presence of ten or more al indicates that FSAD treatment is effective. In some embodiments, the presence of eleven or more al indicates that FSAD treatment is effective. In some embodiments, the presence of all twelve al indicates that FSAD treatment is effective.

[0123] In some embodiments, the methods disclosed herein include administering one or more additional doses of a topical FSAD treatment composition to a subject. In some embodiments, one or more additional doses are administered if FSAD treatment is determined to be effective.

[0124] Other advantages and novel features of this disclosure will become apparent when considered in conjunction with the accompanying drawings, through the following detailed description of various non-limiting embodiments of this disclosure. Detailed Implementation

[0125] It is estimated that female sexual dysfunction (FSD) will affect approximately 40% of women in the United States at some point in their lives. The prevalence of FSD increases with age and is associated with vascular risk factors and menopause.

[0126] In the DSM IV-TR, FSAD is defined as the persistent or recurrent inability to achieve or maintain adequate lubrication and swelling response before sexual activity is completed, resulting in significant pain or interpersonal difficulties. FSAD is estimated to negatively affect approximately 20% of women in the United States. Furthermore, interruption of sexual arousal affects other aspects of sexual response. Without sexual arousal, orgasm is impossible, and a lack of arousal often leads to a lack of desire, as sexual activity may feel unpleasant or compulsive. Dyspareunia can be intricately linked to a lack of adequate sexual arousal. Unlubricated intercourse can be painful, and recurrent unlubricated intercourse can lead to vulvar infections, chronic irritation, and may result in secondary vaginismus, fear of sex, or complete avoidance of sexual activity.

[0127] The DSM-5 defines FSIAD as a lack or significant reduction in sexual interest / arousal, measured by three of the following six symptoms: lack or reduced interest in sexual activity; lack or reduced sexual thoughts or fantasies; no or reduced initiation of sexual activity and usually unacceptable attempts by a partner to initiate; lack or reduced sexual arousal or pleasure in almost all or all sexual encounters; lack or reduced sexual interest / arousal to any internal or external sexual cues; and loss or reduction of genital or non-genital sensation during sexual activity in all or almost all sexual encounters. These symptoms must cause clinically significant distress and persist for at least six months.

[0128] This disclosure generally relates to compositions and techniques for treating FSD and female sexual arousal disorder (FSAD) using transdermal and / or transmucosal delivery of various compounds. In some embodiments, the compositions and techniques of this disclosure treat FSIAD. In some embodiments, a composition such as a cream may be applied to the genital area of ​​a subject. The composition may contain an active ingredient, such as a phosphodiesterase type 5 inhibitor and / or a salt thereof. In some embodiments, the active ingredient is sildenafil or a salt thereof.

[0129] This invention provides a topical formulation of sildenafil cream that unexpectedly offers several potential clinical advantages compared to oral sildenafil citrate, including: more targeted local delivery at the desired therapeutic level; reduced systemic exposure, thereby reducing known adverse events; and faster onset of action for more immediate therapeutic effect.

[0130] One set of embodiments provides a composition for local delivery comprising a type 5 phosphodiesterase inhibitor and / or its salt, and optionally an ionic salt and / or L-arginine or an L-arginine salt. In some embodiments, a stabilizing polymer (e.g., xanthan gum, ...) may be used. and / or The combination of propylene glycol and polysorbate surfactants (e.g., polysorbate 20) stabilizes the composition, providing stability in combination compared to a composition lacking one or more of these surfactants.

[0131] In one embodiment, the agent is a phosphodiesterase type 5 (PDE5) inhibitor and / or a salt thereof. A PDE5 inhibitor is a drug that blocks the degradation of circulating GMP by PDE5, for example, in the smooth muscle cells of the lining of the blood vessels supplying the corpora cavernosa of the penis. Part of the physiological process of erection involves the release of nitric oxide (NO) from the vascular system of the corpora cavernosa caused by sexual stimulation. NO activates guanylate cyclase, which leads to an increase in cyclic guanosine monophosphate (cGMP) levels, resulting in relaxation of the smooth muscle of the blood vessels supplying the corpora cavernosa, thereby increasing blood flow and erection. Therefore, PDE5 inhibitors inhibit the degradation of cGMP by PDE5, increasing penile blood flow during sexual stimulation.

[0132] Preclinical functional and molecular biological studies have revealed a NO-cGMP-like biological pathway in female reproductive tissues. Immunohistochemistry of female tissue sections has shown that NO-cGMP-dependent PDE-5 isoenzymes are expressed in the vascular smooth muscle cells of the clitoral corpora cavernosa, vagina, and labia minora. These structures play a central role in regulating female sexual arousal. Following sexual stimulation, neurotransmitters regulate increased blood flow to the clitoris, vagina, and labia, leading to increased pressure and swelling within the clitoral corpora cavernosa, protrusion of the clitoral glans, and congestion of the labia minora and vagina. Anatomically, the female clitoris consists of two corpora cavernosa and a clitoral glans. Similar to the male penis, each corpus cavernosum is lined with a fibrous capsule, the tunica albuginea, containing erectile tissue composed of 40-45% smooth muscle. Due to the lack of venous plexuses, the female clitoris swells but does not rigidify during sexual arousal.

[0133] Composition

[0134] Non-limiting examples of type 5 phosphodiesterase inhibitors include, but are not limited to, avanafil, lodenavir, mironafil (pKa 6.0), sildenafil (or its analogues, such as actetildenafil, hydroxyacetildenafil, or dimethylsildenafil), tadalafil (pKa 18), vardenafil (pKa 3.4, 6.7, 8.8, and 14), udenafil (pKa 10.53), rutinavir, or thiomethylsildenafil.

[0135] The structures of these compounds are as follows:

[0136]

[0137]

[0138]

[0139] In some embodiments, the phosphodiesterase type 5 (PDE5) inhibitor is sildenafil or a salt thereof. In some embodiments, the PDE5 inhibitor is sildenafil citrate (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonyl]-4-methylpiperazine citrate). In some embodiments, the PDE5 inhibitor is avanafil or a salt thereof. In some embodiments, the PDE5 inhibitor is lodenavir or a salt thereof. In some embodiments, the PDE5 inhibitor is mironafil or a salt thereof. In some embodiments, the PDE5 inhibitor is hydroxyredenafil or a salt thereof. In some embodiments, the PDE5 inhibitor is dimethylsildenafil or a salt thereof. In some embodiments, the PDE5 inhibitor is tadalafil or a salt thereof. In some embodiments, the PDE5 inhibitor is vardenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is udenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is erythenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is thiomethylsildenafil or a salt thereof.

[0140] This disclosure provides compositions comprising a type 5 phosphodiesterase inhibitor for transdermal and / or mucosal delivery or local application to a subject. Embodiments include other compounds, such as salts or derivatives of type 5 phosphodiesterase inhibitors (including salts or derivatives of the compounds described above); therefore, it should be understood that this is merely illustrative in any embodiment of the use of a type 5 phosphodiesterase inhibitor described herein.

[0141] Phosphodiesterase type 5 inhibitors or other agents (e.g., salts or derivatives of phosphodiesterase type 5 inhibitors) may be present at any suitable concentration. In some embodiments, the agent is sildenafil citrate. In some embodiments, the agent may be present at a concentration of about 0.1% by weight to about 10% by weight of the composition. In some embodiments, the agent may be present at a concentration of about 1% by weight to about 10% by weight of the composition. In some embodiments, the agent may be present at a concentration of about 1% by weight to about 7% by weight of the composition. In some embodiments, the agent may be present at a concentration of about 1% by weight to about 5% by weight of the composition. In some embodiments, the agent may be present at a concentration of about 1% by weight to about 4% by weight of the composition. The concentration may be any value or subrange within the listed range, including endpoints.

[0142] In some embodiments, the agent may be present at a concentration of at least about 0.1% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 0.3% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 0.5% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 0.7% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 1% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 2% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 3% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 4% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 5% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 6% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 7% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 7.5% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 8% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 9% by weight of the composition. In some embodiments, the agent may be present at a concentration of at least about 10% by weight of the composition.

[0143] In some embodiments, the agent may be present at a concentration not exceeding about 1% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 2% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 3% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 4% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 5% by weight of the composition.

[0144] In some embodiments, the agent may be present at a concentration not exceeding about 6% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 7% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 8% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 9% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 10% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 12% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 15% by weight of the composition. In some embodiments, the agent may be present at a concentration not exceeding about 20% by weight of the composition.

[0145] In some embodiments, the agent is a phosphodiesterase type 5 inhibitor. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil. In some embodiments, the compositions of this disclosure include sildenafil citrate and are used to treat FSAD. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 1% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 2% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 3% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 3.6% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 4% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 5% by weight of the composition.

[0146] Furthermore, the agent may be present in its natural form and / or as one or more salts. For example, if a phosphodiesterase type 5 inhibitor is present, it may be used in its natural form and / or as one or more salts, such as sodium, potassium, magnesium, lysine, arginine, lactate, or citrate salts of a phosphodiesterase type 5 inhibitor (e.g., avanafil, lodenavirinafil, mirtenafil, sildenafil, tadalafil, vardenafil, udenafil, erythrodenafil, thiomethylisosildenafil, etc.). These may include, for example, citric acid, citrate monohydrate, sodium citrate, sodium citrate dihydrate, etc. In some embodiments, sildenafil is present in the form of a sodium, potassium, magnesium, lysine, arginine, lactate, or citrate salt. In some embodiments, sildenafil is present in the form of a citrate salt. As a non-limiting example, in one set of embodiments, the composition may include a citrate ion and / or a citrate salt.

[0147] For the salt form of the pharmaceutical agent, "composition by weight" includes the entire salt form of the pharmaceutical agent, such as the agent itself and any counterions, such as sodium, potassium, etc. The amount of the pharmaceutical agent can be determined in the composition, for example, using techniques such as HPLC or HPLC / MS known to those skilled in the art.

[0148] In some embodiments, the composition may further comprise a nitric oxide donor. In some cases, this nitric oxide donor can be used to increase local blood flow at the site of application of the composition, which can enhance drug delivery. The nitric oxide donor can be present in the composition at any suitable concentration. In some cases, the nitric oxide donor is present at a concentration of about 1% to about 20% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of about 1% to about 10% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of about 5% to about 10% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 1% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 2% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 3% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 4% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 5% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 6% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 7% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 7.5% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 8% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 9% by weight of the composition. In some cases, the nitric oxide donor is present at a concentration of at least about 10% by weight of the composition.

[0149] The composition may also contain L-arginine and / or L-arginine hydrochloride. In embodiments, L-arginine and / or L-arginine hydrochloride are humectants. In embodiments, any humectant may be used. L-arginine and / or L-arginine hydrochloride may be present in the composition at any suitable concentration. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of about 1% to about 20% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of about 1% to about 10% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of about 5% to about 10% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 1% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 2% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 3% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 4% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 5% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 6% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 7% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 7.5% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 8% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 9% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride are present at a concentration of at least about 10% by weight of the composition. In some embodiments, L-arginine hydrochloride (HCl) is present at a concentration of about 7.5% by weight of the composition.

[0150] In some cases, one or more nitric oxide donors may be used (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.). In some cases, the composition may contain no more than 3, 5, 7, or 10 nitric oxide donors.

[0151] As used herein, a "nitric oxide donor" is a compound capable of releasing nitric oxide and / or chemically transferring a portion of nitric oxide directly or indirectly to another molecule, for example, through biological processes. Nitric oxide donors can release nitric oxide into the skin and / or tissues, such as muscles and / or components of the circulatory system near the skin surface. Non-limiting examples of nitric oxide donors include arginine (e.g., L-arginine and / or D-arginine), arginine derivatives (e.g., L-arginine hydrochloride and / or D-arginine hydrochloride), nitroglycerin, polysaccharide-bound nitric oxide nucleophilic adducts, N-nitroso-N-substituted hydroxylamine, 1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoate, and / or any combination thereof.

[0152] Other non-limiting examples of nitric oxide donors include, but are not limited to, alkyl (e.g., ethyl, methyl, isopropyl, butyl, isobutyl, etc.) esters of D,L-arginine, D-arginine, or L-arginine and / or D-arginine (e.g., methyl, ethyl, propyl, butyl, etc.) and / or their salts, as well as other derivatives of arginine and other nitric oxide donors. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, hydrochloride, glutamate, butyrate, or glycolate (e.g., producing L-arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate, etc.). Other examples of nitric oxide donors include L-arginine-based compounds, such as, but not limited to, L-homarginine, N-hydroxy-L-arginine, nitrosyl-L-arginine, nitrosyl-N-hydroxy-L-arginine, citrulline, ornithine, linsidomine, nipride, glutamine, and their salts (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.), and / or any combination thereof.

[0153] In some embodiments, the composition may also contain an ionic salt. In some embodiments, a composition containing an ionic salt and an agent (e.g., a phosphodiesterase type 5 inhibitor, etc.) can create an environment in which the agent is in a chemically and / or energy-incompatible environment relative to the skin, especially the stratum corneum (e.g., the chemical potential and / or free energy of the agent in the composition environment is significantly greater than the chemical potential and / or free energy of the agent in the skin, thereby being energy-facilitating its transport into the skin).

[0154] Embodiments of this disclosure relate to compositions for local delivery to the skin or mucous membranes of a subject, comprising L-arginine and / or L-arginine hydrochloride, an ionic salt, and an agent such as a phosphodiesterase type 5 inhibitor, or a salt or derivative of a phosphodiesterase type 5 inhibitor.

[0155] Examples of ionic salts include, but are not limited to, lithium chloride, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, sodium fluoride, lithium bromide, and combinations thereof. In some embodiments, the ionic salt is present at a concentration of about 1% to about 10% by weight of the composition. In some embodiments, the ionic salt is present at a concentration of about 2% to about 8% by weight of the composition. In some embodiments, the ionic salt is present at a concentration of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, or at least about 10% by weight of the composition. In some embodiments, the composition comprises an ionic salt having an ionic strength of at least about 0.25 M, at least about 1 M, at least about 2 M, at least about 3 M, at least about 5 M, at least about 10 M, at least about 15 M, at least about 20 M, at least about 25 M, or in some cases, between about 0.25 M and about 15 M, between about 5 M and about 15 M, between about 10 M and about 15 M, etc.

[0156] In some embodiments, the ionic salt is potassium chloride. In some embodiments, potassium chloride is present at a concentration of about 5% by weight of the composition.

[0157] In some embodiments, the composition may include an antioxidant capable of reducing or inhibiting the oxidation of other molecules within the composition. Examples of suitable antioxidants include, but are not limited to, glutathione, vitamin C, and vitamin E, as well as enzymes such as catalase, superoxide dismutase, and various peroxidases. The antioxidant may be present at a concentration of about 0.1% to about 10% of the composition by weight. The antioxidant may be present at a concentration of about 1% to about 5% of the composition by weight. The antioxidant may be present at a concentration of at least about 0.1%, at least about 0.3%, at least about 0.5%, at least about 0.7%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, or at least about 5% of the composition by weight.

[0158] As described herein, "stable polymers" refers to polymers containing xanthan gum, xanthan gum derivatives, and / or xanthan gum equivalents, such as... and / or and / or

[0159] In some embodiments, the compositions of this disclosure may further include a stabilizing polymer, propylene glycol, and a polysorbate surfactant. Non-limiting examples of stabilizing polymers include xanthan gum, and / or An example of a polysorbate surfactant is polysorbate 20.

[0160] In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 20% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 10% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.2% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.3% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.4% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.5% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.6% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.7% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration of at least about 0.8% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration of at least about 0.9% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration of at least about 1% by weight of the composition.

[0161] In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 0.1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 0.2% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 0.4% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 0.6% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 0.8% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 2% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 3% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 4% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 5% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration not exceeding about 7% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration not exceeding about 10% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration not exceeding about 12% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration not exceeding about 15% by weight of the composition. In some embodiments, the stabilized polymer may be present at a concentration not exceeding about 20% by weight of the composition.

[0162] In some embodiments, the stabilizing polymer is xanthan gum. In some embodiments, xanthan gum is present at a concentration of about 0.8% by weight of the composition.

[0163] Propylene glycol may be present in the compositions disclosed herein at a concentration of about 1% to about 25% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of about 1% to about 20% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of about 1% to about 15% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of about 1% to about 10% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 1% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 2% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 3% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 4% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 5% by weight of the composition. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 6% by weight. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 7% by weight. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 8% by weight. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 8.5% by weight. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 9% by weight. Propylene glycol may be present in the compositions disclosed herein at a concentration of at least about 10% by weight.

[0164] In some embodiments, propylene glycol may be present at a concentration not exceeding about 2% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 2% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 4% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 6% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 8% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 10% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 12% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 15% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 20% by weight of the composition. In some embodiments, propylene glycol may be present at a concentration not exceeding about 25% by weight of the composition.

[0165] In some cases, other diols, such as butanediol, may be used in combination with or in place of propylene glycol. In other embodiments described herein, references to propylene glycol should be understood to include other diols (e.g., low molecular weight diols or polydiols) used in combination with or in place of propylene glycol.

[0166] In some embodiments, propylene glycol is present in the compositions of this disclosure at a concentration of about 8.5% by weight of the composition.

[0167] Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of about 1% to about 25% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of about 1% to about 20% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of about 1% to about 15% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of about 1% to about 10% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of about 1% to about 5% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 1% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 2% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 3% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 4% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 5% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 6% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 7% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 8% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 9% by weight of the composition. Polysorbate surfactants may be present in the compositions disclosed herein at a concentration of at least about 10% by weight of the composition.

[0168] In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 2% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 4% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 6% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 8% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 10% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 12% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 15% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 20% by weight of the composition. In some embodiments, the polysorbate surfactant may be present at a concentration not exceeding about 25% by weight of the composition.

[0169] As used in this article, "polysorbate surfactant" refers to a surfactant containing polysorbate. For example, surfactants may include sorbitol monolaurate, sorbitol monopalmitate, sorbitol monostearate, sorbitol monooleate, or another sorbitol salt.

[0170] In some embodiments, the polysorbate surfactant is polysorbate 20. In some embodiments, polysorbate 20 is present at a concentration of about 2% by weight of the composition.

[0171] In some embodiments, the agent may be combined with a penetrant, which is an agent that increases the delivery of the agent to the skin relative to the absence of a penetrant. Examples of penetrants include, but are not limited to, cationic, anionic, or nonionic surfactants such as capsicum oleoresin (e.g., sodium dodecyl sulfate, polyoxamer, etc.); fatty acids and alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g., benzyl bromide, oxyphenyl bromide); ketones (e.g., n-heptane); amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g., butyrate); organic acids (e.g., citric acid); polyols (e.g., ethylene glycol, glycerol); sulfoxides (e.g., dimethyl sulfoxide); terpenes (e.g., cyclohexene); urea; sugars; and / or carbohydrates.

[0172] In some embodiments, the penetrant is oleic acid. In some embodiments, oleic acid is present at a concentration of about 1% by weight of the composition.

[0173] As a specific, non-limiting example, the cream may have one or more of the following (w / w): water (40.75%); potassium chloride (5%); L-arginine hydrochloride (7.5%); glyceryl stearate (7%); hexadecyl alcohol (7%); squalane (4%); xanthan gum (0.8%); isopropyl myristate (1%); oleic acid (1%); propylene glycol (8.5%); polysorbate 20 (2%); trisodium citrate dihydrate (10%); sodium benzoate (0.2%); gluconolactone (0.25%); and / or sildenafil citrate (5%).

[0174] As a specific, non-limiting example, the cream may contain one or more of the following (w / w): water (about 35% to about 55%); potassium chloride (about 2.5% to about 15%); L-arginine hydrochloride (about 2.5% to about 15%); glyceryl stearate (about 4% to about 10%); hexadecyl alcohol (about 4% to about 10%); squalane (about 1% to about 8%); xanthan gum (about 0.1% to about 5%); isopropyl myristate (about 0.1% to about 5%); oleic acid (about 0.1% to about 5%); propylene glycol (about 1% to about 10%); polysorbate 20 (about 0.2% to about 5%); trisodium citrate dihydrate (about 5% to about 20%); sodium benzoate (about 0.05% to about 1%); gluconolactone (about 0.05% to about 1%); and / or sildenafil citrate (about 1% to about 10%).

[0175] deliver

[0176] In some embodiments, topical delivery of a phosphodiesterase type 5 inhibitor, such as sildenafil, provides surprisingly rapid effects (e.g., within about 1-5 minutes). In contrast, oral administration takes about 60 minutes or longer to produce an effect. Aspects of this disclosure provide methods and compositions for treating or preventing FSAD or its symptoms. In some embodiments, a topical composition is provided that can be applied to the genital area (e.g., vulva and / or vagina) of a female subject to treat FSAD or its symptoms within 60 minutes of application. In some embodiments, the topical composition is applied to the genital area of ​​a female subject to treat FSAD or its symptoms within 45 minutes of application. In some embodiments, the topical composition is applied to the genital area of ​​a female subject to treat FSAD or its symptoms within 30 minutes of application. In some embodiments, the topical composition is applied to the genital area of ​​a female subject to treat FSAD or its symptoms within 15 minutes of application. In some embodiments, the topical composition is applied to the genital area of ​​a female subject to treat FSAD or its symptoms within 10 minutes of application.

[0177] In some embodiments, the composition is a cream. In some embodiments, the composition is a lotion. In some embodiments, the composition is a gel or hydrogel.

[0178] Unwilling to be bound by any theory, when the composition is applied to the skin or mucous membranes of a subject, the agent readily enters the tissue from the carrier because the agent is dispersed through local blood flow and does not accumulate in the tissue at a concentration. Therefore, in some embodiments, the agent, such as a phosphodiesterase type 5 inhibitor and / or salts or derivatives of a phosphodiesterase type 5 inhibitor, such as avanafil, lodenaviril, mironafil, sildenafil, tadalafil, vardenafil, udenafil, erythrodenafil, or thiomethylsildenafil, can be introduced into the skin or mucous membranes. The composition can be delivered locally and / or systemically; initially, most delivery is first local (i.e., through the skin or mucous membranes), but in some cases, the agent can also be distributed systemically, for example, upon reaching the blood supply.

[0179] Non-limiting examples of delivery carriers to be carried into tissues include liposomes or emulsions of collagen, collagen peptides, or other components of the skin or basement membrane. Non-limiting examples of charge neutralization include delivery of agents in the form of electronically neutral esters or salts.

[0180] In some embodiments, the composition may be in the form of an emulsion. As known to those skilled in the art, an emulsion typically comprises a first phase (e.g., a discontinuous phase) contained within a second fluid phase (e.g., a continuous phase). The agent (e.g., a phosphodiesterase type 5 inhibitor) may be present in one or both phases. In some embodiments, the emulsion is prepared by mixing a first aqueous formulation (e.g., an aqueous phase) with a second non-aqueous formulation (e.g., an oil phase or a lipid phase). Water-soluble agents may be added to the first aqueous formulation (e.g., before mixing with the second non-aqueous formulation). Water-insoluble (or relatively insoluble in water) agents may be added to the second non-aqueous formulation (e.g., before mixing with the first aqueous formulation). Partially water-soluble agents may be added to one phase or may be separated between the two phases before mixing. Separation between the two phases will depend on the amount of agent added, the composition of the first and second formulations (e.g., the nature and amount of other chemicals or reagents), pH, temperature, other physical or chemical factors, and / or combinations thereof.

[0181] The emulsions disclosed herein can be packaged in any suitable form (e.g., in tubes, pump-actuated containers, or any other suitable form). In some embodiments, the emulsion can be added to the surface of a patch or bandage. The emulsion can also be applied to the skin or mucous membranes of a subject as a cream, gel, liquid, lotion, spray, aerosol, transdermal patch, or transmucosal patch. In some embodiments, the compositions described herein are creams.

[0182] In another aspect, this disclosure relates to a kit comprising one or more compositions discussed herein. As used herein, “kit” means a package or component containing one or more compositions of this disclosure and / or other compositions related to this disclosure, such as those described herein. Each composition of the kit may be provided in liquid form (e.g., a solution) or solid form (e.g., a dry powder). In some cases, some compositions may be composable or processable (e.g., converted to an active form), for example, by adding suitable solvents or other substances, which may or may not be provided with the kit. Examples of other compositions or components related to this disclosure include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, adhesives, fillers, preservatives, desiccants, antimicrobial agents, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, plates, frits, filters, rings, clamps, packaging, patches, containers, etc., for example, for use, application, modification, assembly, storage, packaging, preparation, mixing, dilution, and / or preservation of compositional components for a particular purpose, such as for use in samples and / or subjects.

[0183] In some cases, the kits disclosed herein may include instructions for use in any form associated with the compositions of this disclosure, in a manner that would be recognized by one of ordinary skill in the art as relating to the compositions of this disclosure. For example, the instructions for use may include instructions for the use, modification, mixing, dilution, preservation, administration, assembly, storage, packaging, and / or preparation of the compositions and / or other compositions associated with the kit. In some cases, the instructions for use may also include instructions for the delivery and / or administration of the compositions, for example, for a specific purpose, such as for a sample and / or a subject.

[0184] How to use

[0185] This invention provides a method comprising: applying a composition containing an active ingredient for treating female sexual dysfunction (FSD) to the genital area of ​​a subject. In some embodiments, the active ingredient is sildenafil. In some embodiments, the subject suffers from FSD. In some embodiments, the subject is at risk of developing FSD. In some embodiments, the subject has one or more symptoms of FSD.

[0186] This disclosure provides a method comprising applying a composition containing an active ingredient for treating female sexual arousal disorder (FSAD) to the genital area of ​​a subject. In some embodiments, the active ingredient is sildenafil. In some embodiments, the subject has FSAD. In some embodiments, the subject is at risk of developing FSAD. In some embodiments, the subject has one or more symptoms of FSAD.

[0187] This disclosure provides a method comprising applying a composition containing an active ingredient for treating female sexual interest / arousal disorder (FSIAD) to the genital area of ​​a subject. In some embodiments, the active ingredient is sildenafil. In some embodiments, the subject has FSIAD. In some embodiments, the subject is at risk of developing FSIAD. In some embodiments, the subject has one or more symptoms of FSIAD.

[0188] In some embodiments, the composition includes propylene glycol, a stabilizing polymer, a polysorbate surfactant, L-arginine or an L-arginine salt, and an ionic salt. In some embodiments, the composition is a cream. In some embodiments, the stabilizing polymer is xanthan gum. In some embodiments, the polysorbate surfactant is polysorbate 20. In some embodiments, the composition further includes a nitric oxide donor. In some embodiments, the ionic salt is potassium chloride. In some embodiments, the active ingredient is present at about 1-10 wt%. In some embodiments, the composition is applied to the clitoris, vulva, vagina, and / or vaginal cavity. In some embodiments, the composition is applied to the clitoris, vestibule, vulva, and / or vagina of a subject. In some embodiments, the composition is applied to the clitoris, glans clitoris, and / or frenulum of a subject's genital region. In some embodiments, the composition is applied to the clitoris, glans clitoris, frenulum, and / or vestibule of a subject's genital region. In some embodiments, the composition is applied to the clitoris, glans clitoris, frenulum, vestibule, and / or labia minora of a subject's genital region. In some embodiments, the composition is not applied to the labia majora of the subject's genital area. In some embodiments, the composition is applied intravaginally to the distal anterior vagina of the subject. In some embodiments, the composition is applied as a single dose. In some embodiments, the composition is applied as at least one dose.

[0189] Therefore, as described above, the various embodiments encompass a variety of compositions, including any suitable combination of any of the above-described components, such as xanthan gum and / or another stabilizing polymer, propylene glycol, polysorbate 20 and / or another polysorbate surfactant, L-arginine and / or a nitric oxide donor, potassium chloride and / or another ionic salt, the active ingredient, and water. The active ingredient may include any of those described herein, such as sildenafil and its salts.

[0190] Furthermore, as described above, certain aspects herein generally relate to compositions and methods of applying the composition to treat or prevent indications such as any of the indications described herein, for example, application to the vulva and / or vagina of a subject (such as a human). In embodiments, the subject is female.

[0191] In another set of embodiments, the compositions described herein can be used to treat subjects who have FSAD or are at risk of developing FSAD. In this embodiment, the composition is administered to the subject at least once.

[0192] In some embodiments, a method of treating FSD or its symptoms includes selecting a female subject exhibiting one or more symptoms of FSD and applying a composition comprising a phosphodiesterase type 5 inhibitor to the subject's genitals. In embodiments, the composition includes a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt or other humectant, and an ionic salt.

[0193] In some embodiments, a method of treating female sexual arousal disorder (FSAD) or its symptoms includes selecting a female subject exhibiting one or more FSAD symptoms and administering a composition comprising a phosphodiesterase type 5 inhibitor to the subject's genitals. In embodiments, the composition includes a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and an ionic salt.

[0194] In some embodiments, symptoms of FSAD include, but are not limited to, decreased genital sensitivity, lack of genital response during sexual activity, reduced genital arousal, difficulty in sexual arousal, and any combination thereof. In some embodiments, the compositions of this disclosure are applied to the genital areas of a subject, including but not limited to the clitoris, vestibule, vulva, and vagina. In embodiments, one or more symptoms include a diminished response to bodily sexual stimulation. In embodiments, the primary complaint of a female subject is a diminished response to bodily sexual stimulation.

[0195] In some embodiments, treating FSAD includes increasing satisfactory sexual events, improving arousal sensation, increasing arousal lubrication, increasing orgasm, reducing anxiety about sexual arousal, and / or increasing satisfaction with sexual activity. In some embodiments, treating FSAD includes improving arousal sensation. In some embodiments, treating FSAD includes increasing arousal lubrication. In some embodiments, treating FSAD includes increasing orgasm. In some embodiments, treating FSAD includes reducing anxiety about sexual arousal. In some embodiments, treating FSAD includes increasing satisfaction with sexual activity.

[0196] In some implementations, treating FSAD includes increasing satisfying sexual events. In these implementations, increasing satisfying sexual events includes, but is not limited to, increasing orgasm or orgasm frequency, feeling close to or connecting with a sexual partner, experiencing pleasure, increasing physical sensations, arousal, passion, and / or having pleasurable sexual experiences.

[0197] In some implementations, treating FSAD includes increasing sensation in the genital area. In some implementations, genital sensation includes one or more of the following: tingling, pleasure, warmth, throbbing, palpitation, congestion, or fullness in the genital area.

[0198] In some respects, this article describes a method for increasing satisfactory sexual events in female subjects during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0199] In some respects, this article describes a method for improving arousal in female subjects during sexual activity, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0200] In some respects, this article describes a method for increasing arousal lubrication in female subjects during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0201] In some respects, this article describes a method for increasing female orgasm during sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0202] In some respects, this article describes a method for reducing sexual arousal anxiety or increasing satisfaction with sexual activity in female subjects, including applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

[0203] In some respects, this article describes a method for relieving pain or discomfort in female subjects during and / or after sexual activity, comprising applying a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

[0204] In one embodiment, a method of treating FSIAD or its symptoms includes selecting a female subject exhibiting one or more FSIAD symptoms and administering a composition comprising a phosphodiesterase type 5 inhibitor to the subject's genitals. In another embodiment, the composition comprises a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and an ionic salt.

[0205] In some implementations, treating FSIAD includes increasing libido. In some implementations, treating FSIAD includes increasing responsiveness to physical or psychological stimuli. In some implementations, symptoms of FSIAD include a lack of interest in or reduced interest in sexual activity. In some implementations, symptoms of FSIAD include a lack or reduction in erotic thoughts or fantasies. In some implementations, symptoms of FSIAD include decreased libido. In some implementations, symptoms of FSIAD include a diminished response to physical sexual stimuli. In some implementations, symptoms of FSIAD include a diminished response to psychological stimuli.

[0206] In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the FSDS-DAO item 14 score (feeling worried about difficulty achieving sexual arousal). In this implementation, improvement means an increase of at least one point in the FSDS-DAO score. In this implementation, improvement means an increase of at least one point in the FSDS-DAO item 14 score.

[0207] In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Sexual Function Questionnaire 28 (SFQ28) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the SFQ28 category item 1 (warmth frequency) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the SFQ28 category item 2 (warmth level) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the SFQ28 category item 3 (pulsation / tingling frequency) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the SFQ28 category item 4 (pulsation / tingling level) score. In this implementation, improvement means an increase of at least one point in the SFQ28 score or category item score. In this implementation, improvement means an increase of at least two points in the SFQ28 score or category item score.

[0208] In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on an Arousal Diary (AD) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on an AD Item 1 (pleasure) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on an AD Item 3 (pulsation / throbbing) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on an AD Item 4 (tingling) score. In this implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on an AD Item 5 (congestion / fullness) score. In this implementation, improvement means an increase of at least one point in the AD score or item score. In this implementation, improvement means an increase of at least two points in the AD score or item score.

[0209] In one implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on the Patient General Impression of Change (PGI-C). In another implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on the subject's description of the symptoms as "a little better." In yet another implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on the subject's description of the symptoms as "much better." In yet another implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on the subject's description of the symptoms as "very much better."

[0210] In implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Patient Severity Overall Impression (PGI-S).

[0211] In implementation, improvement in one or more criteria (e.g., symptoms) described herein is measured based on patient benefit assessment (PBE) (meaningful benefit of the investigational drug).

[0212] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0213] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0214] In some embodiments, administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a satisfactory sexual event.

[0215] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased genital arousal.

[0216] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased lubrication of the genital area during sexual activity.

[0217] In some embodiments, administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in an increase in cognitive arousal.

[0218] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased libido.

[0219] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in an increase in orgasm during sexual activity.

[0220] In some embodiments, the administration of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a reduction in the difficulty of achieving orgasm during sexual activity or a decrease in the inability to achieve orgasm.

[0221] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased sensation or feeling in the genital area during sexual activity.

[0222] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased tingling sensation in the genital area during sexual activity.

[0223] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased blood flow to the genital area during sexual activity.

[0224] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in increased warmth, throbbing, or pulsation in the genital area during sexual activity.

[0225] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​a subject results in a reduction of pain and / or discomfort during sexual activity.

[0226] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in a reduction of pain and / or discomfort after sexual activity.

[0227] In some embodiments, application of a composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject results in increased sexual arousal.

[0228] In some implementations, one or more symptoms of female sexual arousal disorder (FSAD) include, but are not limited to, diminished responsiveness to physical sexual stimulation.

[0229] In some implementations, the primary complaint of female subjects is a diminished response to physical sexual stimulation.

[0230] In some embodiments, the subject exhibits one or more of the following after administration of a composition comprising a type 5 phosphodiesterase inhibitor and / or its salt:

[0231] a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28);

[0232] b. SFQ28 score improvement of at least 1 point in the lubrication category;

[0233] c. Improvement of at least 1.5 points in the SFQ28 arousal category score;

[0234] d. Improve your SFQ28 score in the Desire category by at least 2 points;

[0235] The e.SFQ28 score for orgasm improved by at least 1.20 points;

[0236] f. The SFQ28 pain category score improved by at least 1 point;

[0237] g. The Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score improved by at least -7 points;

[0238] h. Arousal score improved by at least 1.45 points;

[0239] i. Genital arousal score improved by at least 1.13 points;

[0240] j. The score for genital arousal anxiety improved by at least 1.49 points;

[0241] k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and

[0242] l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

[0243] In some implementations, the subjects include those with a preliminary diagnosis of FSAD, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revised Edition (DSM-IV-TR).

[0244] In some embodiments, topical compositions comprising a type 5 phosphodiesterase inhibitor and / or its salts do not cause one or more of the following: orthostatic hypotension, headache, flushing, indigestion, dizziness, visual disturbances, nasal congestion, back pain, myalgia, nausea, vertigo, and rash.

[0245] In some implementations, the subject's primary complaint is FSAD or one or more of its symptoms.

[0246] In some embodiments, the subject's primary complaint is FSAD or one or more of its symptoms, and the subject exhibits secondary HSDD symptoms. In some embodiments, the subject has FSAD as its sole diagnosis. In some embodiments, the subject has both primary FSAD and secondary HSDD. In some embodiments, a premenopausal subject has FSAD as its sole diagnosis. In some embodiments, a premenopausal subject has both primary FSAD and secondary HSDD.

[0247] This invention generally relates to a method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising:

[0248] a. Female subjects with primary FSAD as their chief complaint were selected, and

[0249] b. Apply a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject.

[0250] In some implementations, the subject exhibits secondary HSDD symptoms. In some implementations, the subject's primary complaint is FSAD, and the subject does not exhibit female orgasmic disorder (FOD) symptoms (or has not yet been diagnosed with FOD). In some implementations, the subject does not exhibit FOD symptoms (or has not yet been diagnosed with FOD). In some implementations, the method includes selecting female subjects without a complaint of FOD.

[0251] This disclosure generally relates to a method for determining the efficacy of FSAD treatment, including:

[0252] a) Obtain baseline scores for one or more of the following: Sexual Function Questionnaire 28 (SFQ28) scores in the arousal cognition category, SFQ28 scores in the arousal lubrication category, SFQ28 scores in the arousal sensation category, SFQ28 scores in the desire category, SFQ28 scores in the orgasm category, SFQ28 scores in the pain category, Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) scores, arousal sensation scores, genital arousal scores, genital arousal anxiety, the proportion of arousal diary item 12-SSE, and the number of arousal diary item 12-SSE.

[0253] b) FSAD treatment was administered to female subjects; and

[0254] c) Determine the improvement in one or more scores from step a.

[0255] In some implementations, one or more of the following indicate that FSAD treatment is effective:

[0256] a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28);

[0257] b. SFQ28 score improvement of at least 1 point in the lubrication category;

[0258] c. Improvement of at least 1.5 points in the SFQ28 arousal category score;

[0259] d. Improve your SFQ28 score in the Desire category by at least 2 points;

[0260] The e.SFQ28 score for orgasm improved by at least 1.20 points;

[0261] f. The SFQ28 pain category score improved by at least 1 point;

[0262] g. The Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score improved by at least -7 points;

[0263] h. Arousal of feelings improved by at least 1.45 points;

[0264] i. Improvement in genital arousal by at least 1.13 points;

[0265] j. Genital arousal anxiety improved by at least 1.49 points;

[0266] k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and

[0267] l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

[0268] In some embodiments, the methods disclosed herein include administering one or more additional doses of a topical FSAD treatment composition to a subject.

[0269] In this implementation, improvement is measured compared to untreated sexual activity. In this implementation, improvement is measured compared to pre-treatment sexual activity. In this implementation, improvement is measured after a single treatment (e.g., a single application). In this implementation, improvement is measured after multiple treatments (e.g., multiple applications). In this implementation, improvement is measured after multiple treatments over a period of time. In this implementation, the time period is at least one week. In this implementation, the time period is between one and twenty weeks. In this implementation, the time period is between one and eight weeks. In this implementation, improvement is measured after 1 to 100 treatments. In this implementation, improvement is measured after 1 to 50 treatments. In this implementation, improvement is measured after 1 to 20 treatments. In this implementation, improvement is measured after 1 to 10 treatments.

[0270] The compositions disclosed herein may include sildenafil citrate cream. In some embodiments, the sildenafil citrate cream contains about 1% to about 5% by weight of sildenafil citrate. In some embodiments, the sildenafil citrate cream contains about 3.6% by weight of sildenafil citrate.

[0271] In some embodiments, the subject is given about 2 grams to about 5 grams of the composition, such as sildenafil citrate cream. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 2 grams to about 5 grams. In some embodiments, the subject is given about 2 grams of the composition, such as sildenafil citrate cream. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 2 grams.

[0272] In some embodiments, about 0.5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 1 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 1.5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 2 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 2.5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 3 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 3.5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 4 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 4.5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, about 5 g of the composition, such as sildenafil citrate cream, is administered to the subject. In some embodiments, the subject is given about 0.5 grams to about 3 grams of the composition, such as sildenafil citrate cream. In some embodiments, the subject is given about 1 gram to about 4 grams of the composition, such as sildenafil citrate cream. In some embodiments, the subject is given about 2 grams to about 5 grams of the composition, such as sildenafil citrate cream. In some embodiments, the subject is given about 3 grams to about 6 grams of the composition, such as sildenafil citrate cream. In some embodiments, the subject is given about 4 grams to about 7 grams of the composition, such as sildenafil citrate cream.

[0273] In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 1 gram. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 1.5 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 2 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 2.5 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 3 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 3.5 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 4 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 4.5 grams. In some embodiments, a single unit dose of the composition, such as sildenafil citrate cream, is about 5 grams.

[0274] In some embodiments, half a single unit dose of the composition is applied to tissues outside the vagina. In some embodiments, half a single unit dose of the composition is applied inside the vagina.

[0275] In some embodiments, at least about 10% of the composition is applied to the extravagant tissue. In some embodiments, at least about 20% of the composition is applied to the extravagant tissue. In some embodiments, at least about 30% of the composition is applied to the extravagant tissue. In some embodiments, at least about 40% of the composition is applied to the extravagant tissue. In some embodiments, at least about 50% of the composition is applied to the extravagant tissue. In some embodiments, at least about 60% of the composition is applied to the extravagant tissue. In some embodiments, at least about 70% of the composition is applied to the extravagant tissue. In some embodiments, at least about 80% of the composition is applied to the extravagant tissue. In some embodiments, at least about 90% of the composition is applied to the extravagant tissue. In some embodiments, at least about 100% of the composition is applied to the extravagant tissue.

[0276] Extravagine tissues (such as the vulva) include, but are not limited to, the anterior labial commissure, clitoral hood, glans clitoris, frenulum, vaginal vestibule, labia majora, and labia minora. In some embodiments, approximately 50% of the composition is applied to the extravagine tissues. In some embodiments, approximately 50% of the composition is applied to the clitoris, vestibule, vulva, and / or vagina of the subject. In some embodiments, approximately 50% of the composition is applied to the clitoris, glans clitoris, and / or frenulum in the genital region of the subject. In some embodiments, approximately 50% of the composition is applied to the clitoris, glans clitoris, frenulum, and / or vestibule in the genital region of the subject. In some embodiments, approximately 50% of the composition is applied to the clitoris, glans clitoris, frenulum, vestibule, and / or labia minora in the genital region of the subject.

[0277] In some embodiments, at least about 10% of the composition is applied vaginally. In some embodiments, at least about 20% of the composition is applied vaginally. In some embodiments, at least about 30% of the composition is applied vaginally. In some embodiments, at least about 40% of the composition is applied vaginally. In some embodiments, at least about 50% of the composition is applied vaginally. In some embodiments, at least about 60% of the composition is applied vaginally. In some embodiments, at least about 70% of the composition is applied vaginally. In some embodiments, at least about 80% of the composition is applied vaginally. In some embodiments, at least about 90% of the composition is applied vaginally. In some embodiments, at least about 100% of the composition is applied vaginally.

[0278] In some embodiments, about 50% of the composition is applied vaginally. In some embodiments, about 50% of the composition is applied to tissues outside the vagina, and about 50% of the composition is applied vaginally.

[0279] In some embodiments, about 10% of the composition is applied to the extravagant tissue, and about 90% of the composition is applied vaginally. In some embodiments, about 20% of the composition is applied to the extravagant tissue, and about 80% of the composition is applied vaginally. In some embodiments, about 30% of the composition is applied to the extravagant tissue, and about 70% of the composition is applied vaginally. In some embodiments, about 40% of the composition is applied to the extravagant tissue, and about 60% of the composition is applied vaginally. In some embodiments, about 60% of the composition is applied to the extravagant tissue, and about 40% of the composition is applied vaginally. In some embodiments, about 70% of the composition is applied to the extravagant tissue, and about 30% of the composition is applied vaginally. In some embodiments, about 80% of the composition is applied to the extravagant tissue, and about 20% of the composition is applied vaginally. In some embodiments, about 90% of the composition is applied to the extravagant tissue, and about 10% of the composition is applied vaginally. In some embodiments, about 100% of the composition is applied to the extravagant tissue, and about 0% of the composition is applied vaginally. In some embodiments, about 0% of the composition is applied to tissues outside the vagina, and about 100% of the composition is applied vaginally.

[0280] In some embodiments, the composition is not applied to the subject's labia majora or pubic hair with dermis.

[0281] In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 3 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 1 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 1.5 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 2 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 2.5 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 3 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 4 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 5 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 6 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 7 cm. In some embodiments, the composition is applied intravaginally to the anterior distal end of the vagina at a depth of about 0 cm to about 8 cm.

[0282] In some embodiments, the composition is applied between about 1 minute and about 2 hours before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 2 hours before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 1 hour before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 50 minutes before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 40 minutes before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 30 minutes before sexual activity. In some embodiments, the composition is applied between about 10 minutes and about 20 minutes before sexual activity. In some embodiments, the composition is applied about 1 minute before sexual activity. In some embodiments, the composition is applied about 2 minutes before sexual activity. In some embodiments, the composition is applied about 5 minutes before sexual activity. In some embodiments, the composition is applied about 10 minutes before sexual activity. In some embodiments, the composition is applied about 15 minutes before sexual activity. In some embodiments, the composition is applied about 20 minutes before sexual activity. In some embodiments, the composition is applied about 25 minutes before sexual activity. In some embodiments, the composition is applied approximately 30 minutes before sexual activity. In some embodiments, the composition is applied approximately 35 minutes before sexual activity. In some embodiments, the composition is applied approximately 40 minutes before sexual activity. In some embodiments, the composition is applied approximately 45 minutes before sexual activity. In some embodiments, the composition is applied approximately 50 minutes before sexual activity. In some embodiments, the composition is applied approximately 55 minutes before sexual activity. In some embodiments, the composition is applied approximately 60 minutes before sexual activity.

[0283] In some embodiments, the composition is administered in up to about 9 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 20 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 19 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 18 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 15 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 12 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 10 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 8 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 7 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 6 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 5 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 4 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 3 doses over about 4 weeks. In some embodiments, the composition is administered in up to about 2 doses over about 4 weeks. In some embodiments, the composition is applied at least about 24 hours before the second agent composition.

[0284] In some embodiments, the first composition is applied at least about 5 times and at least about 10 times before the second composition. In some embodiments, the first composition is applied at least about 12 times before the second composition. In some embodiments, the first composition is applied at least about 15 times before the second composition. In some embodiments, the first composition is applied at least about 20 times before the second composition. In some embodiments, the first composition is applied at least about 24 times before the second composition. In some embodiments, the first composition is applied at least about 36 times before the second composition. In some embodiments, the first composition is applied at least about 40 times before the second composition. In some embodiments, the first composition is applied at least about 48 times before the second composition. In some embodiments, the first composition is applied at least about 60 times before the second composition.

[0285] In one embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least twice over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least three times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least four times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least five times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least six times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least seven times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least eight times over a period of time. In another embodiment, a type 5 phosphodiesterase inhibitor and / or its salt is administered at least ten times over a period of time.

[0286] In one embodiment, the time period is approximately 1 week to approximately 12 weeks. In another embodiment, the time period is approximately 1 week to approximately 10 weeks. In another embodiment, the time period is approximately 1 week to approximately 8 weeks. In another embodiment, the time period is approximately 1 week to approximately 6 weeks. In another embodiment, the time period is approximately 1 week to approximately 4 weeks. In another embodiment, the time period is approximately 2 weeks to approximately 12 weeks. In another embodiment, the time period is approximately 2 weeks to approximately 10 weeks. In another embodiment, the time period is approximately 2 weeks to approximately 8 weeks. In another embodiment, the time period is approximately 2 weeks to approximately 6 weeks. In another embodiment, the time period is approximately 2 weeks to approximately 4 weeks. In another embodiment, the time period is approximately 1 week. In another embodiment, the time period is approximately 2 weeks. In another embodiment, the time period is approximately 3 weeks. In another embodiment, the time period is approximately 4 weeks. In another embodiment, the time period is approximately 5 weeks. In another embodiment, the time period is approximately 6 weeks. In another embodiment, the time period is approximately 7 weeks. In another embodiment, the time period is approximately 8 weeks. In another embodiment, the time period is approximately 9 weeks. In another embodiment, the time period is approximately 10 weeks. In another embodiment, the time period is approximately 11 weeks. In one implementation, the time period is approximately 12 weeks. In another implementation, the time period is longer than approximately 12 weeks.

[0287] In one embodiment, one or more symptoms improve within approximately 1 week to approximately 12 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week to approximately 10 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week to approximately 8 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week to approximately 6 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week to approximately 4 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 1 week after initial application. In another embodiment, one or more symptoms improve within approximately 2 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 3 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 4 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 5 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 6 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 7 weeks after initial application. In another embodiment, one or more symptoms improve within approximately 8 weeks after initial application. In one embodiment, one or more symptoms improve within approximately 10 weeks after the initial application. In another embodiment, one or more symptoms improve within approximately 12 weeks after the initial application.

[0288] In one embodiment, one or more symptoms include arousal and lubrication. In one embodiment, one or more symptoms include sexual desire. In one embodiment, one or more symptoms include achieving orgasm. In one embodiment, one or more symptoms include the pleasure of orgasm.

[0289] In some embodiments, female subjects exhibiting one or more symptoms of FSAD have not received at least one of the following: a guanylate cyclase stimulant, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha receptor blocker, for approximately 28 days prior to administration of the first dose of the composition. In some embodiments, female subjects exhibiting one or more symptoms of FSAD have not received at least one of the following: a guanylate cyclase stimulant, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha receptor blocker, for approximately 5, 10, 15, 20, 25, 28, 29, 30, 31, 32, 35, 40, 45, or 50 days prior to administration of the first dose of the composition.

[0290] In this implementation, the subject has no history of active peptic ulcer disease. In this implementation, the subject has no history of clinically significant bleeding disorders. In this implementation, the subject has no history of priapism. In this implementation, the subject has no history of conditions that could predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). In this implementation, the subject has no history of myocardial infarction. In this implementation, the subject has no history of stroke. In this implementation, the subject has no history of life-threatening arrhythmias. In this implementation, the subject has no resting hypotension (BP < 90 / 50 mmHg). In this implementation, the subject has no history of coronary artery disease that causes angina. In this implementation, the subject has no history of congestive heart failure requiring medical intervention. In this implementation, the subject has no history of underlying conditions that make them particularly sensitive to the effects of vasodilators, such as left ventricular outflow tract obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) or impaired autonomic blood pressure control. In this implementation, the subject has no history of hearing loss. In this implementation, the subjects did not have retinitis pigmentosa, and the subjects did not have a history of orthostatic hypotension (e.g., a decrease in systolic blood pressure ≥20 mmHg, a decrease in diastolic blood pressure ≥10 mmHg, an increase in pulse rate of 20 beats per minute, or experiencing dizziness or vertigo 1 or 3 minutes after changing from a supine to a standing position).

[0291] In this embodiment, the subject's sexual partner has no history of any disease or disorder that may be contraindicated by the composition. In this embodiment, the subject's sexual partner has no history of myocardial infarction. In this embodiment, the subject's sexual partner has no history of stroke. In this embodiment, the subject's sexual partner has no history of life-threatening arrhythmias. In this embodiment, the subject's sexual partner has no history of resting hypotension (BP < 90 / 50 mmHg). In this embodiment, the subject's sexual partner has no history of coronary artery disease that causes angina. In this embodiment, the subject's sexual partner has no history of congestive heart failure requiring medical intervention. In this embodiment, the subject's sexual partner has no history of underlying conditions that make them particularly sensitive to the effects of vasodilators, such as left ventricular outflow tract obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis). In this embodiment, the subject's sexual partner has no history of impaired voluntary blood pressure control. In this implementation, the subject's sexual partner has no history of orthostatic hypotension (e.g., a decrease in systolic blood pressure ≥20 mmHg, a decrease in diastolic blood pressure ≥10 mmHg, an increase in pulse of 20 beats per minute, or experiencing dizziness or vertigo 1 or 3 minutes after changing position from supine to standing). In this implementation, the subject's sexual partner has no history of priapism or a history of conditions that may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In this implementation, the subject's sexual partner has no history of non-arterial ischemic optic neuropathy (NAION) or any potential risk factors for NAION.

[0292] definition

[0293] While several embodiments of this disclosure have been described and illustrated herein, various other means and / or structures will readily conceive by those skilled in the art for performing the functions described herein and / or obtaining the results and / or one or more advantages, and each such variation and / or modification is considered to be within the scope of this disclosure. More generally, those skilled in the art will readily understand that all parameters, dimensions, materials, and configurations described herein are exemplary, and actual parameters, dimensions, materials, and / or configurations will depend on the specific application using the teachings of this disclosure. Those skilled in the art will recognize or be able to determine many equivalents to the specific embodiments of this disclosure described herein using only conventional experiments. Therefore, it should be understood that the above embodiments are presented by way of example only, and that this disclosure may be practiced in ways different from those specifically described and claimed within the scope of the appended claims and their equivalents. This disclosure pertains to each individual feature, system, article, material, kit, and / or method described herein. Furthermore, any combination of two or more such features, systems, articles, materials, kits, and / or methods that do not contradict each other is included within the scope of this disclosure.

[0294] If this specification and any documents incorporated by reference contain conflicting and / or inconsistent disclosures, this specification shall prevail. If two or more documents incorporated by reference contain conflicting and / or inconsistent disclosures, the document with the later effective date shall prevail.

[0295] All definitions defined and used herein should be understood to take precedence over dictionary definitions, definitions in incorporated documents by reference, and / or the general meaning of the defined terms.

[0296] The terms “treat,” “treatment,” and “treating” encompass treatment of a subject who already suffers from a disease or disorder, particularly one that manifests in an obvious form. Treatment can be symptomatic to alleviate the signs and / or symptoms of the disease or disorder, or it can be causal to reverse, partially reverse, stop, or slow the progression of the disease or disorder. Therefore, the compositions and methods disclosed herein can be used, for example, as therapeutic treatments (e.g., for acute or chronic therapies).

[0297] Furthermore, terms such as “prevent,” “preventing,” or “prevention” generally refer to a statistically significant reduction or delay in the occurrence of a disease or disorder and / or its signs and / or symptoms in a treated sample relative to an untreated control sample. Preventing a disease or disorder and / or its signs and / or symptoms includes preventing or delaying the occurrence of the disease, disorder, signs, and / or symptoms. Prevention also includes preventing the recurrence of the disease, disorder, signs, and / or symptoms.

[0298] In some respects, the composition can be applied to a subject, such as the clitoris, vestibule, vulva and / or vagina, and / or another body cavity, such as the mouth or rectum. Any suitable technique can be used to apply the composition to the subject. For example, the composition can be free-flowing or mass-flowing, such that it can be administered via an applicator or other suitable device. Thus, in some embodiments, the composition can be contained within an applicator, such as a vaginal applicator or syringe, which can be applied by, for example, the subject or another person.

[0299] Subjects can be, but are not limited to, humans.

[0300] The phrase “genital area of ​​a female subject” as used in this article refers to the internal and external sexual organs of a woman. These include, but are not limited to, the vulva and vagina.

[0301] The term "vulva" encompasses all the structures that make up the female external genitalia. The components of the vulva include the mons pubis, labia majora, labia minora, clitoris, vestibular bulbs, vulvar vestibule, Bartholin's gland, Skene's gland, urethra, and vaginal opening.

[0302] The term "vagina" refers to the elastic muscular portion of the female reproductive tract. In humans, the vagina extends from the vestibule to the cervix.

[0303] In one set of embodiments, as discussed, the composition is applied to a subject to treat a subject with a therapeutically effective amount of the active ingredient (as described herein). A therapeutically effective amount can be an amount sufficient to achieve treatment or prevention of a disease or disorder when applied to a subject to treat or prevent such disease or disorder, such as any of those described herein. A therapeutically effective amount can also be an amount sufficient to elicit the desired biological response, i.e., symptom relief. The therapeutically effective amount may vary depending on factors such as the desired biological endpoint, the method of administration, and / or the subject's age and health condition.

[0304] Unless otherwise expressly stated, the indefinite articles “a” and “an” used in the specification and claims shall be understood as “at least one”.

[0305] The phrase “and / or” as used in this specification and claims should be understood to mean “one or two” of the elements so combined, i.e., elements that exist together in some cases and separately in others. Multiple elements listed with “and / or” should be interpreted in the same way, i.e., “one or more” of the elements so connected. In addition to the elements specifically identified by the “and / or” clause, other elements may optionally be present, whether related to or unrelated to those specifically identified. Thus, as a non-limiting example, in one embodiment, when used in conjunction with open-ended language such as “comprising”, reference to “A and / or B” may refer only to A (optionally including elements other than B); in another embodiment only to B (optionally including elements other than A); in yet another embodiment to A and B (optionally including other elements); and so on.

[0306] As used herein in the specification and claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” should be interpreted as inclusive, meaning it includes at least one, but also includes multiple elements or lists of elements, as well as other optional unlisted items. Only terms that explicitly indicate the opposite, such as “only one” or “exactly one,” or “consisting of…” as used in the claims, refer to multiple elements or exactly one element from a list of elements. In general, where preceded by exclusive terms such as “any one of,” “one of,” “only one,” or “exact one,” the term “or” as used herein should only be interpreted as indicating an exclusive alternative (i.e., “one or the other, but not both”).

[0307] As used herein in the specification and claims, the phrase "at least one" referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, nor exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements referred to by the phrase "at least one," regardless of whether such elements are related to those specifically identified elements. Thus, as a non-limiting example, in one embodiment, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and / or B") may refer to at least one, optionally including multiple A's, without B (and optionally including elements other than B); in another embodiment, it may refer to at least one, optionally including more than one B, without A (and optionally including elements other than A); in yet another embodiment, it may refer to at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including other elements); and so on.

[0308] When used before numerical names such as temperature, time, quantity, concentration, etc. (including ranges), the term "about" indicates an approximate value that may vary (+) or (-) 10%, 5%, 1%, or any subrange or subvalue in between. Preferably, when used with a quantity, the term "about" means that the quantity may vary by + / - 10%. When the word "about" is used herein to refer to a number, it should be understood that another embodiment of this disclosure includes the number without the presence of the word "about".

[0309] When a range is given by specifying its lower end separately from its upper end, it is understood that the range can be defined by selectively combining any lower variable with any mathematically possible upper variable. Where ranges are enumerated, it is understood that any subranges or values ​​within the enumerated range, including endpoints, are considered.

[0310] It should also be understood that, unless there is an explicit instruction to the contrary, in any method claimed herein that includes more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are stated.

[0311] In the claims and description, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” etc., should be understood as open-ended, meaning including but not limited to. As stated in Section 2111.03 of the U.S. Patent Examination Procedure Manual, only the transitional phrases “consisting of” and “consisting essentially of” should be closed or semi-closed transitional phrases, respectively.

[0312] List of abbreviations

[0313] Abbreviation Definition

[0314] AE adverse events

[0315] CD Cognitive Inquiry

[0316] CE concept inspiration

[0317] COS Clinical Outcomes Solution

[0318] DHIF Population Health Information Form

[0319] FDA (U.S. Food and Drug Administration)

[0320] FSAD (Female Sexual Arousal Disorder)

[0321] FSDS-DAO Female Sexual Distress Scale - Desire, Arousal, Orgasm

[0322] FSDS-R Female Sexual Distress Scale - Revised Edition

[0323] FSEP Female Sexual Contact Overview

[0324] FSFI Female Sexual Function Index

[0325] GAS Genital Arousal Screening Device

[0326] GSM urogenital syndrome menopause

[0327] HRQL (Health-Related Quality of Life)

[0328] HSDD (Hyposexuality Disorder)

[0329] ICF Informed Consent Form

[0330] IRB Institutional Review Committee

[0331] MHF Medical History Form

[0332] N is a number (uppercase indicates the total population; lowercase indicates a subgroup).

[0333] PRO Patient Report Results

[0334] SAE Serious Adverse Events

[0335] SAS Statistical Analysis System

[0336] SD standard deviation

[0337] SFQ-28 Sexual Function Questionnaire-28

[0338] SOP (Standard Operating Procedure)

[0339] API active pharmaceutical ingredients

[0340] BMI (Body Mass Index)

[0341] BP (blood pressure)

[0342] CFR Federal Regulations

[0343] cGMP cyclic guanosine monophosphate

[0344] CRO (Contract Research Organization)

[0345] CSR Clinical Research Report

[0346] eCRF Electronic Case Report Form

[0347] ECG (electrocardiogram)

[0348] ED (erectile dysfunction)

[0349] FSD (Female Sexual Dysfunction)

[0350] Good Clinical Practice (GCP) Clinical Trial Management Guidelines

[0351] GLP Laboratory Testing Management Standards

[0352] HBsAg (Hepatitis B surface antigen)

[0353] HCV (Hepatitis C Virus)

[0354] HDPE (High Density Polyethylene)

[0355] HED Human Equivalent Dose

[0356] HIPAA Health Insurance Portability and Accountability Act

[0357] HIV (Human Immunodeficiency Virus)

[0358] HPV (Human Papillomavirus)

[0359] ICF Informed Consent Form

[0360] ICH International Harmonization Meeting

[0361] IND (Investigational New Drug)

[0362] IP research products

[0363] IRB Institutional Review Committee

[0364] IRT (Interactive Response Technology)

[0365] MedDRA Regulatory Activities Medical Dictionary

[0366] NF National Drug Collection

[0367] NO Nitric oxide

[0368] No adverse reaction levels were observed with NOAEL.

[0369] OTC (over-the-counter)

[0370] PANAS Positive and Negative Impacts Timeline

[0371] PDE5 type 5 phosphodiesterase

[0372] PI Principal Researcher

[0373] PK Pharmacokinetics

[0374] QA Quality Assurance

[0375] QC Quality Control

[0376] SAE Serious Adverse Events

[0377] SHBG (sex hormone-binding globulin)

[0378] SOC (Systemic Organ Classification)

[0379] Adverse events during TEAE treatment

[0380] TMF test master file

[0381] USP (United States Pharmacopeia)

[0382] VPA vaginal pulse amplitude

[0383] VPP vaginal photoplethysmography

[0384] WHODE (World Health Organization Drug Dictionary Enhanced Edition)

[0385] Example

[0386] The following examples are intended to illustrate certain implementations of this disclosure, but do not represent the full scope of this disclosure.

[0387] Example 1: Content verification for patient-reported outcomes (PRO) measurement of female sexual arousal disorder

[0388] Research Design

[0389] In order to gather evidence of the validity of the content of the Arousal Diary, SFQ-28 and FSDS-DAO, qualitative interviews were conducted on individuals clinically diagnosed with FSAD.

[0390] Preliminary eligibility was assessed prior to the first visit. Informed consent was obtained if participants were deemed likely to be eligible. Following consent, inclusion / exclusion criteria were confirmed, and a clinical interview was conducted. The clinical interview was used to gather further information and confirm the diagnosis of primary FSAD (N=35; n=20 premenopausal women; n=15 postmenopausal women). At the second visit, participants underwent an in-depth, qualitative, one-on-one interview consisting of CE and CD discussions, lasting approximately 90 minutes.

[0391] During the second visit, the interviews with CE and CD consisted of three parts:

[0392] 1. The first part of the interview involves a CE discussion to explore the participants' experiences with FSAD, and is expected to last approximately 45 minutes;

[0393] 2. Part Two involves participants who completed three questionnaires; and

[0394] 3. After completing each questionnaire, participants completed several questions on the questionnaire. The questioning was expected to last approximately 45 minutes. As part of this study, no drug intervention or treatment was administered.

[0395] Study population

[0396] Up to 50 in-depth one-on-one, face-to-face qualitative interviews were conducted, including discussions of CE and CD; at least 20 premenopausal women and at least 15 postmenopausal women were included. Up to 50 women were included in the study to account for the possibility that some women might be excluded from the final analysis based on their responses to interview questions during their second visit, questions that indicated they did not meet the diagnostic criteria for FSAD. However, qualitative interviews were conducted to saturation, meaning no new concepts emerged. This was assessed for premenopausal women in the seven, seven, and six-interview groups and for postmenopausal women in the five-interview group. A saturation matrix was developed to record this. If new concepts were still under discussion after 20 interviews in the premenopausal group and 15 interviews in the postmenopausal cohort, further interviews in that cohort could be recommended.

[0397] Inclusion criteria

[0398] Each potential participant must meet all of the following criteria to participate in this study.

[0399] 1. The patient's age must be between 21 and 70 years old, including 21 and 70 years old.

[0400] 2. The patient understands and complies with the treatment plan and agrees to sign the informed consent form.

[0401] 3. The patient is sexually active (in the past 4 weeks). Sexual activity can include any activity that leads to sexual stimulation or pleasure, such as intercourse, caressing, foreplay, masturbation, and oral sex.

[0402] 4. Based on clinical interviews, the patient had previously experienced "normal" sexual function (i.e., normal libido, arousal, orgasm, and painlessness) for at least 2 years or more.

[0403] 5. Postmenopausal women (surgically induced or naturally) must meet one of the following criteria:

[0404] a. Bilateral oophorectomy, with or without hysterectomy, performed at least 1 year prior to screening (self-report).

[0405] b. Spontaneous amenorrhea for 12 months

[0406] c. Spontaneous amenorrhea for 6 months, serum FSH level >40 mIU / mL (excluding women receiving hormone replacement therapy)

[0407] 6. The patient's body mass index (BMI) is between 18 and 33 kg / m². 2 Includes 18kg / m 2 and 33kg / m 2 .

[0408] 7. The patient is fluent in English.

[0409] 8. The patient agrees not to use products containing cannabinoids within 24 hours after the first and second medical visits.

[0410] Exclusion criteria

[0411] Any potential participant who meets any of the following criteria was excluded from the study:

[0412] 1. The researchers believe that the patient has any obstacles that may hinder the successful completion of the study or has any history of such obstacles.

[0413] 2. Patients self-report or are currently diagnosed with an uncontrolled medical condition (such as cardiovascular, liver, metabolic, kidney, respiratory, gastrointestinal, endocrine, immune, skin, blood, neurological, genitourinary, or psychiatric medical condition).

[0414] 3. The patient reported a history of sexual trauma or abuse that was identified in a clinical interview as causing any sexual dysfunction problems (desire, arousal, orgasm, pain, etc.).

[0415] 4. Patients with a history of myocardial infarction, stroke, or life-threatening arrhythmia within 6 months prior to the clinical interview, or any history of coronary artery disease that causes angina; or congestive heart failure requiring medical intervention.

[0416] 5. Based on clinical interviews, the patient's primary complaint was determined to be anorexia, pain, vaginismus, low libido, or any other primary sexual complaint other than genital arousal problems.

[0417] 6. The patient has symptoms or is currently diagnosed with dyspareunia, vulvovaginal infection or inflammation, vulvar or vaginal inflammatory disorder, vestibular pain, clitoral pain, or vulvovaginal atrophy (patients with vaginal dryness without pain as the only symptom of vulvovaginal atrophy are still eligible), or symptoms of any other vulvar or vaginal disorder identified on clinical visit.

[0418] a. Patients with bacterial vaginosis or yeast infection can be re-screened after the infection has been treated and resolved.

[0419] 7. The patient has undergone major pelvic surgery that may cause nerve damage, including but not limited to vulvectomy, colostomy, cystostomy, or severe bladder (including incontinence), rectal, or abdominal surgery.

[0420] 8. Patients report or have been diagnosed with nerve damage due to conditions such as diabetes, stroke, post-traumatic pelvic nerve injury, cancer treatment, myasthenia gravis, multiple sclerosis, spinal cord injury, etc.

[0421] a. Patients with symptoms of peripheral neuropathy will be excluded, including those who report “numbness” or “lack of sensation” in their genitals during sexual activity.

[0422] 9. In addition to anxiety and depression, participants have current and / or previously reported diagnoses of DSM-IV-TR Axis I disorders, including organic mental syndromes and disorders.

[0423] a. Patients diagnosed with anxiety or depression must be controlled, depending on the researcher's decision; and if they have been taking a stable medication and dosage for at least 6 months prior to the clinical interview.

[0424] b. A patient's total score of <10 on the Patient Health Questionnaire-8 (Depression Screening and Assessment Tool) indicates minimal depression or mild depression.

[0425] c. A total score of <6 indicates mild anxiety according to the Generalized Anxiety Disorder (GAD)-7 (an anxiety screening and assessment tool).

[0426] 10. A patient's history of gynecological cancer, or active treatment for any cancer, could interfere with their ability to successfully complete the study. Patients who have previously received treatment for atypical hyperplasia (precancerous lesions) may be included, provided they have received local treatment (such as cryotherapy or laser therapy).

[0427] 11. The patient has a history of substance abuse within one year prior to the first visit. Patients reporting a history of substance abuse must have been in remission or sobriety for at least one year prior to the clinical interview.

[0428] 12. The patient has a history of alcohol abuse within one year prior to the first visit. Patients reporting a history of alcohol abuse must have been in remission or sober status for at least one year prior to the clinical interview.

[0429] 13. The patient is currently receiving treatment, or has received treatment within the past three months, for FSAD symptoms (medication or non-medication).

[0430] 14. The patient's urine drug screening result is positive (e.g., amphetamine, barbiturates, benzodiazepines). Drugs such as methadone, cocaine, methadone, and opioids, unless they are known impairments that will not interfere with a patient’s ability to successfully complete the study (such as ADHD).

[0431] 15. The patient has had symptoms or has been diagnosed with chlamydia, gonorrhea or syphilis within the past 3 months.

[0432] 16. Patients who report an HPV or HSV outbreak (blister, wart, or vesicle) on their genitals or anus at any point within the past month. Once the outbreak is treated and resolved, the patient can be re-screened. Patients who report broken skin, irritation, dermatitis or lesions on the genitals, or any other abnormal vulvovaginal findings will also be excluded.

[0433] 17. The patient participated in any clinical study evaluating another investigational drug or therapy within 3 months prior to the first visit.

[0434] 18. In the past 6 months prior to the clinical interview, the patient has been exposed to any ongoing measurement, including arousal diaries, sexual function questionnaires (SFQ), female sexual distress scale-desire, arousal, orgasm (FSDS-DAO), or other sexual dysfunction questionnaires (such as FSFI, FSDS-R, FSEP).

[0435] 19. The patient has symptoms or is currently diagnosed with a pelvic or urinary tract infection. Once the infection is treated and resolved, the patient can be re-screened.

[0436] 20. The patient self-reported that she was breastfeeding or pregnant, planned to start breastfeeding during the study, or was pregnant or breastfeeding within 6 months prior to her first visit.

[0437] Clinical diagnosis of FSAD

[0438] Patients who met all of the above inclusion and exclusion criteria underwent a formal semi-structured clinical interview at their first visit to confirm the diagnosis of primary FSAD as defined by DSM-IV-TR.

[0439] Primary FSAD, as defined by DSM-IV-TR, is acquired (i.e., not lifelong) and generalized (i.e., present regardless of background setting), and is characterized by symptoms that have been present for at least 6 months prior to the clinical interview. Eligible patients must have a primary complaint of lack of genital arousal during sexual activity and consider their genital response significant to their overall sexual experience. Eligible patients must also experience distress due to difficulty in sexual arousal. Secondary complaints of low libido related to lack of genital arousal [hypopractic sexual desire disorder] are considered eligible, provided that the problem associated with decreased genital arousal is considered the most troubling symptom and precedes the low libido. Patients with cognitive arousal problems (i.e., not feeling mentally aroused during sexual activity) are also considered eligible, provided that the problem associated with decreased genital arousal is considered the most troubling symptom and precedes the cognitive arousal problem.

[0440] Because FSAD is an exclusionary diagnosis, clinical interviews also focus on excluding patients with vulvar or vaginal symptoms, including but not limited to vulvovaginal infections or inflammation, dyspareunia, menopausal urogenital syndrome (GSM) or vulvovaginal atrophy, vulvar or vaginal inflammatory disorders (lichen sclerosus, lichen planus, plasma cell vulvitis, mucosal pemphigoid, desquamative inflammatory vaginitis, Sjögren's syndrome, contact dermatitis, allergic vaginitis, vestibular pain, and clitoral pain).

[0441] Recruitment and Screening

[0442] Recruitment strategy

[0443] The clinic is a women's sexual health professional center or medical institution. Recruitment is open until the research recruitment target is reached (N=35; n=20 premenopausal women, n=15 postmenopausal women). Unsuccessful screenings are not counted in the total number of participants.

[0444] All recruitment procedures were in accordance with the protocol approved by the Institutional Review Board (IRB). Potential participants scheduled their first screening appointment.

[0445] Participants may freely withdraw from the study for any reason and may revoke / cancel their authorization / withdraw from the study at any time by providing written notice without penalty or harm. Participants may also terminate their participation in the study at any time if their clinical condition requires it.

[0446] The specific objectives are as follows:

[0447] • Phase 1: Concept Heuristic (CE) Interviews, with the following objectives:

[0448] Explore the experience of disease-related symptoms and the relative importance of FSAD symptoms, including their severity, distress, and impact on patients' health-related quality of life (HRQL).

[0449] Phase 2: Cognitive Questioning (CD) Interview, with the following methods:

[0450] Explore the relevance of the selected PRO measures based on the patient's own experience.

[0451] To determine the patient's understanding of the selected PRO measures, instructions, and answer options.

[0452] ο Evaluate the appropriateness of the specified review period for the selected PRO measurement, with a focus on the 24-hour review period and the 4-week review period.

[0453] Screening procedure (first visit)

[0454] Participants were also asked to undergo semi-structured clinical interviews to confirm the diagnosis of primary FSAD. Once eligibility was confirmed, participants were scheduled for a second visit, CE, and CD interviews.

[0455] Sampling stratification

[0456] Interview Procedure (Second Visit)

[0457] If a face-to-face interview is not possible, the second consultation interview can be conducted either in person or by telephone. The CE portion of the interview is the first part and lasts approximately 45 minutes. Participants are then asked to complete an arousal diary, SFQ-28, and FSDS-DAO, which takes approximately 10 minutes. Following this, the CD portion of the interview begins and lasts approximately 45 minutes.

[0458] Conceptual inspiration

[0459] The face-to-face qualitative interviews began with each participant being presented with a short set of CE questions. This took the form of an open discussion, where each participant discussed her personal experience with sexual arousal issues and any related impacts. This was used to obtain a comprehensive and personally-led description of the impact of FSAD, ensuring adequate coverage of the key arousal issues experienced and their effects. Following this, participants discussed the severity of their triggering symptoms and ranked the symptoms that bothered them most and those they considered most important for treatment. Participants also discussed the emotional impact of FSAD to determine what language women spontaneously used to describe it, such as annoyance, distress, or frustration.

[0460] Cognitive Inquiry

[0461] Following the CE section, each participant completed each questionnaire. The purpose of the CD interview was to explore participants' understanding and relevance to these measures. Participants completed each measure first, as they would in a clinical trial (i.e., without interviewer interference). Participants were asked about the relevance and experience of the concepts evaluated for each item. For items that participants considered relevant and / or that they had experienced, additional questions were asked to evaluate the item content, answer options, and scores to further inquire about the item. To test whether there was an order effect (i.e., a preference for the questions they were exposed to first) in women's preferences for exposure-based items, the questionnaire order was modified. Half of the premenopausal women and the first eight postmenopausal women were treated in the following order: SFQ-28, FSDS-DAO, and Arousal Diary; the other half of the premenopausal women and seven postmenopausal women were treated in the following order: Arousal Diary, SFQ-28, and FSDS-DAO.

[0462] The interviews also discussed any “new” questions mentioned in the CE section of the interviews that were not included in the measurement, in order to explore whether participants felt these “new” concepts should have been added, or whether the measurement allowed them to adequately describe these experiences.

[0463] analyze

[0464] Participant characteristics

[0465] Participant characteristics were summarized to describe the features of the enrolled population and to provide context for the qualitative data. Continuous data were summarized as number (n), mean, and standard deviation (SD). Categorical data were summarized based on the number (n), frequency count, and percentage of participants who provided data at the relevant time points. Percentages were based on participants with non-missing parameters. Reported percentages were accurate to two decimal places. Analyses were performed using Statistical Analysis System (SAS) v9.4.

[0466] Qualitative data analysis

[0467] CE Data Analysis

[0468] The transcribed data was fed into NVivo v.12, a software package designed to facilitate the storage, coding, and analysis of qualitative data. This software allows grouping of topics, concepts, or categories by different variables, such as ethnicity and age. Analysis of the CE interview data was guided by research objectives and key concepts of interest, and coded by topic. An initial codebook was developed based on the research objectives and key concepts of interest. This codebook was used to code the interview transcripts and to identify new codes in subsequent interviews. Revisions to the coding structure were monitored to ensure that all codes were clearly defined and consistently applied.

[0469] Saturation analysis

[0470] To support the validity of the selected PRO measure, it is important to demonstrate that all important concepts are present in the interview sample, a process known as “saturation analysis.” Concept saturation was evaluated in the CE interviews, where no new topics or concept descriptions were introduced after the final interview. Concept-inspired interviews reach a saturation point (when no new concepts emerge in subsequent interviews), and therefore additional interviews may be conducted until the saturation point is reached.

[0471] Because CD is inherently confirmatory, saturation analysis was performed only on the CE portion of the interviews. Saturation analysis was only applicable to intentionally exploratory interviews (i.e., CE interviews). To determine this, CE interview transcripts (N=35) were divided into premenopausal and postmenopausal women. Premenopausal interview transcripts were divided into three groups (n=7, n=7, and n=6 in each group), and postmenopausal interview transcripts were divided into three groups of n=5 in the order they were performed. Conceptual saturation was then compared between groups within each group. The process for determining whether adult participants had reached conceptual saturation is as follows:

[0472] The concepts derived from the topic are converted into two ordered arrays: "Not discussed" equals 0, and "Discussed" equals 1.

[0473] • The concepts that appeared in the first set of interviews were compared with those that appeared in the second set of interviews.

[0474] Then, the concepts that appeared in the first two groups of interviews were compared with the concepts that appeared in the third group of interviews.

[0475] The point where no new concepts emerge is considered to be the point of saturation.

[0476] If saturation is not reached after analyzing all interviews, suggestions are made regarding the utility of conducting additional interviews.

[0477] CD Data Analysis

[0478] CD data analysis focused on citations relevant to the main research questions: including relevance, understanding, and any rewriting suggestions. The first two CD transcripts were coded to develop an initial codebook for the CD interviews. This codebook was used to code the remaining interview transcripts to identify any new codes appearing in subsequent interviews. Revisions to the coding structure were monitored to ensure all codes were clearly defined and consistently applied.

[0479] Example 2: A phase 2b, multicenter, multidose, randomized, double-blind, placebo-controlled study to evaluate 3.6% sildenafil. The efficacy and safety of nafee cream in premenopausal women with female sexual arousal disorder (FSAD).

[0480] There are currently no approved treatments for female sexual arousal disorder (FSAD). The aim of this study was to test the systemic and local genital safety of topical 3.6% sildenafil cream in healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period.

[0481] To evaluate female patient-reported outcomes (PROs) in women with FSAD, several PRO measures were used, including the Sexual Function Questionnaire 28 (SFQ28), the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO), Patient Severity Global Impression (PGI-S), Patient Change Global Impression (PGI-C), Patient Frequency Global Impression (PGI-F), Patient Change in Worry about Sexual Difficulty Global Impression (PGI-C Worry), Patient Change in Satisfactory Sexual Events Global Impression (PGI-C SSE), and an arousal diary, to assess changes in female sexual function following administration of 3.6% sildenafil cream in a double-blind, placebo-controlled phase 2b study.

[0482] The Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV-TR) defines female sexual arousal disorder (FSAD) as a persistent or recurrent inability to achieve or maintain adequate lubrication and swelling response to sexual arousal until sexual activity is completed, resulting in significant distress or interpersonal difficulties. It is estimated that FSAD negatively affects approximately 20% of women in the United States, and the interruption of sexual arousal can affect other aspects of sexual response. Without arousal, orgasm is unlikely to occur, and FSAD often leads to a lack of desire because sexual activity is unpleasant or fails to enhance. Despite the high prevalence of FSAD and its potential impact on other aspects of female sexual function, the U.S. Food and Drug Administration (FDA) has not yet approved any pharmacological treatment for FSAD. The most common treatment is the application of topical lubricants, which help mask insufficient vaginal lubrication associated with FSAD, but are ineffective in increasing genital / clitoral blood flow or alleviating the reduced genital sensation associated with FSAD.

[0483] Published placebo-controlled trials of oral sildenafil citrate in premenopausal and postmenopausal women with broad-spectrum FSDs (such as hyposexuality disorder (HSDD), FSAD, female orgasmic disorder (FOD), and dyspareunia) unrelated to comorbidities or medication use have shown that its efficacy is negligible compared to placebo.

[0484] This invention provides a 3.6% topical sildenafil cream for the treatment of FSAD. By delivering sildenafil topically, specifically targeting the genital anatomy at the vascular reactivity center, systemic exposure is reduced, subsequently reducing systemic side effects, thus resulting in a more favorable safety profile. The co-primary objective of this study was to evaluate the safety and efficacy of the 3.6% sildenafil cream in healthy premenopausal women with FSAD.

[0485] Patient assessment

[0486] Healthy premenopausal women aged 18 years or older and their sexual partners were screened. Volunteers and their sexual partners provided written informed consent before undergoing any study-related procedures. Women at risk of pregnancy used effective contraception during the study. Women or their partners were excluded if they had uncontrolled hypertension, a history of serious cardiac events (such as myocardial infarction, stroke), orthostatic hypotension, or other serious medical complications. A one-on-one individual clinical interview was conducted with each potential participant. The interviewer was not an employee of the study sponsor and was a recognized expert in the field to determine the diagnosis of FSAD and to verify that FSAD was the woman's primary sexual dysfunction concern if other secondary FSDs were present. Table 2 outlines the assessment timeline.

[0487] Volunteers and their sexual partners received informed consent and underwent screening and safety procedures during their first visit. Approximately one year into the study, the protocol was revised to allow participation from women who were required to consent to and participate in adverse event (AE) reporting, a barrier to recruitment due to many volunteers' reluctance to disclose their FSAD symptoms to their sexual partners. Specifically, Amendment 3 of the protocol allows women to participate in the trial without a sexual partner or whose sexual partner is unwilling to participate in the informed consent and safety monitoring process. In the latter case, the investigational product (IP) is used only for unpartnered, solitary sexual experiences, and if the participant has a sexual partner, no partnered sexual events must occur within 72 hours of IP administration. If a partnered sexual experience is documented with a non-consenting partner, the participant will discontinue the study.

[0488] The study included a 28-day drug-free induction period, followed by a 28-day single-blind placebo induction period. Screening failed during these two months if participants did not adhere to recording sexual experiences and adverse events (AEs) in an electronic diary, or if they had a pre-defined placebo response (total score ≤18) on the Female Sexual Distress Scale-Arousal and Orgasm (FSDS-DAO) during the single-blind placebo induction period. Eligible participants were randomly assigned 1:1 at their fourth visit to receive either 3.6% sildenafil cream or a placebo cream.

[0489] The double-blind treatment period lasted 12 weeks, from the 4th to the 7th visit. During this period, participants were examined monthly, and investigators determined any treatment-emergent adverse events (TEAEs), their severity, and their relationship to the study product or procedure. Participants recorded TEAEs using an eDiary between visits.

[0490] Patients and Partners - Study Involvement and Safety Evaluation

[0491] Eligible patients and their respective partners completed separate informed consent forms (ICF) prior to their first visit to participate in the study. Both the patient and her partner also met all applicable inclusion and exclusion criteria for study participation assessed at the first visit. Both the patient and her partner completed assessments (if applicable) and documented any adverse events at home using a separate eDiary. Furthermore, the patient completed PRO assessments (SFQ28, FSDS-DAO, PGI-S, PGI-C, and PBE) using the eDiary at her scheduled clinic visit.

[0492] The eDiary instructs patients to complete it within 24 hours of each sexual event and at any time during the study if an adverse event (AE) occurs. If a sexual event occurs, patients use the eDiary to record the application of an IP (Intense Pulse), any adverse events, and to complete an arousal diary. The eDiary also prompts partners every 24 hours to evaluate for any partner-related sexual events and to collect any adverse events.

[0493] If a sexual event has occurred, eDiary will provide the patient and partner with the following prompt: "Have you had any complaints since your sexual event?" If the patient or partner answers "yes," eDiary will further inform them of some of the more common side effects associated with oral phosphodiesterase type 5 (PDE5) inhibitors. Assuming a wireless connection, within 24 hours of receiving the message, the patient's or partner's response reporting a post-sexual activity complaint will be electronically sent to the site for evaluation and triage. Additionally, patients who answered "yes" to their complaint and their partners will be reminded to contact their site.

[0494] Patient number, demographic characteristics and baseline characteristics

[0495] Informed consent was obtained from volunteers (n=833) and their sexual partners (n=605). Of the consenting participants, 277 eligible participants entered the drug-free induction period, and 252 entered the single-blind placebo induction period. 200 participants were randomly assigned to either 3.6% sildenafil cream (n=101) or placebo cream (n=99). The 99 women assigned to 3.6% sildenafil cream and the 94 women assigned to placebo cream received at least one dose of their assigned IP during the double-blind treatment period. There were no allocation errors. An additional 40 women exposed to at least one dose of placebo cream during the single-blind induction period were also included in the safety analysis population, bringing the total number of participants exposed to placebo to 134. Table 1A shows the demographic and baseline characteristics of the participants included in the safety analysis population.

[0496] Table 1A: Demographic and baseline characteristics of participants and sexual partners in the safe sex population.

[0497]

[0498] Main objectives:

[0499] • SFQ28(AS) - 28-Day Retrospective: The efficacy of 3.6% sildenafil cream versus placebo cream in patients with FSAD was evaluated by measuring changes in the arousal category of the Sexual Function Questionnaire (SFQ28) from baseline to the end of the study (i.e., the end of the 12-week double-blind dosing period). SFQ28(AS) scores at the end of the single-blind placebo induction period were used as baseline, and results from the 3.6% sildenafil cream group were compared with those from the placebo cream group.

[0500] The SFQ28 is a 28-item PRO questionnaire covering most aspects of the sexual response cycle (desire, arousal, orgasm) as well as pain or discomfort. Specifically, the SFQ28 has eight categories (desire, arousal sensation, arousal lubrication, arousal cognition, orgasm, pain, pleasure, and partner), asking women about their sexual activity and sex life with their partner over the past four weeks. The SFQ28 defines sex life as physical sexual activity and emotional connection with a partner.

[0501] • FSDS-DAO (Q14) - 28-Day Retrospective: The efficacy of 3.6% sildenafil cream versus placebo cream in patients with sexual dysfunction disorder (FSAD) was evaluated by the change in the score of concern about sexual arousal difficulties from baseline to the end of the study. This score is only item 14 of the Women's Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DOA). The FSDS-DAO (Q14) score at the end of the single-blind placebo induction was used as the baseline for comparing the results of the 3.6% sildenafil cream group with those of the placebo cream group.

[0502] The FSDS-DAO is a 15-item PRO questionnaire that includes a list of feelings and questions women sometimes have about sexual anxiety. Specifically, women were asked to rate each item on a frequency scale from 0 (never) to 4 (always), which best describes "how often this problem has bothered or caused you distress in the past 30 days, including today." To calculate a total score for this measure, the items were summed up to a total score from 0 to 60, with higher scores indicating more sexually related distress. In this study, item 14 was scored using values ​​associated with the selected response options.

[0503] Secondary objectives:

[0504] • Arousal Diary (SSE): The efficacy of 3.6% sildenafil cream in patients with FSAD was assessed by the change in the number of satisfactory sexual events reported daily within 24 hours after each sexual event (question 11 in the arousal diary) from baseline to the end of the study (i.e., the last four weeks of the double-blind dosing period). The arousal diary (SSE) score during the single-blind placebo induction period was used as the baseline, and the results of the 3.6% sildenafil cream group were compared with the results of the placebo cream group.

[0505] Exploratory goals:

[0506] Completed by eDiary (using daily reminders) within 24 hours after each sexual event.

[0507] • Arousal Diary (AS): The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by measuring changes in the arousal-feeling category of the modified SFQ28 (questions 1-5 in the arousal diary) completed within 24 hours after each sexual event at week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) compared to baseline.

[0508] The arousal diary questions included: “How much pleasure did you feel in your vaginal / genital area during sexual activity?” (Item 1), “How much ‘warmth’ (e.g., a feeling of increased temperature) did you feel in your vaginal / genital area during sexual activity?” (Item 2), “How much ‘pulsation’ or ‘throbbing’ did you feel in your vaginal / genital area during sexual activity?” (Item 3), “How much ‘tingling’ did you feel in your vaginal / genital area during sexual activity?” (Item 4), and “How much ‘congestion’ or ‘fullness’ did you feel in your vaginal / genital area during sexual activity?” (Item 5). Responses were on a 5-point scale, from 1 (no pleasure / no ‘warmth’ / no ‘pulsation’ or ‘throbbing’ / no ‘tingling’ / no ‘congestion’ or ‘fullness’) to 5 (very strong pleasure / extremely ‘warmth’ / very strong ‘pulsation’ or ‘throbbing’ / very strong ‘tingling’ / very strong ‘congestion’ or ‘fullness’).

[0509] • Arousal Diary (AL): The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by measuring changes in the arousal lubrication category of the modified SFQ28 (question 6 of the arousal diary) completed within 24 hours after each sexual event, compared to baseline, at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0510] • Arousal Diary (GA): The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by measuring changes in genital arousal issues (items 7-9 of the arousal diary) completed within 24 hours after each sexual intercourse at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit) compared to baseline.

[0511] • Arousal Diary (SSE): In addition to the secondary objectives mentioned above, the efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by the change in the number of satisfactory sexual events completed daily (question 11 in the arousal diary) from baseline to week 4 (5th visit) and week 8 (6th visit).

[0512] Completed at the end of no-drug inoculation, single-blind placebo inoculation, and each month during double-blind dosing.

[0513] • SFQ28(AS) - 28-day review: In addition to the secondary objectives mentioned above, the efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in arousal range compared to baseline at week 4 (5th visit) and week 8 (6th visit).

[0514] • FSDS-DAO (Q14) 28-day review: In addition to the secondary objectives mentioned above, the efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by the change in FSDS-DOA item 14 from baseline at week 4 (5th visit) and week 8 (6th visit).

[0515] • SFQ28(AL)-28 Day Retrospective: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in arousal lubrication range compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0516] • SFQ28 (Orgasm) - 28-day retrospective: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in orgasmic range from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0517] • SFQ28 (Arousal of Cognition) - 28-Day Retrospective: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in arousal of cognitive domains from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0518] • SFQ28 (Desire) - 28-day review: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in desire levels from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0519] • FSDS-DAO-28-day retrospective: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by changes in total score from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0520] •PGI-S: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by overall impression of patient severity at week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit).

[0521] •PGI-C: The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by measuring overall patient impression changes at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit) during the double-blind dosing period.

[0522] It was completed at the end of the double-blind dosing period.

[0523] • PBE (Patient Benefit Assessment): The efficacy of 3.6% sildenafil cream in patients with FSAD was evaluated by a PBE assessment using yes / no questions at the end of a double-blind treatment.

[0524] Table 1B shows an overview of the PRO tools and evaluations used for the clinical diagnosis of FSAD in the trial, the inclusion criteria for FSAD, and the primary, secondary, and exploratory endpoints.

[0525] Table 1B: Summary of PRO tools and evaluations used for FSAD diagnosis, FSAD eligibility criteria, and primary, secondary, and exploratory endpoints.

[0526]

[0527]

[0528] Note: PRO tools or evaluations will not be performed during the second visit.

[0529] (a) The arousal diary should be completed within 24 hours after each sexual activity (as per the daily reminder).

[0530] (b) Baseline was established using responses and scores after a 4-week single-blind placebo induction period.

[0531] Additional notes for Table 1B

[0532] Primary endpoint

[0533] • SFQ28 (AS): Changes in the arousal (AS) category score of the SFQ28 from baseline to the end of the study.

[0534] •FSDS-DAO (Q14): Change in scores for concern about sexual arousal difficulties from baseline to the end of the study (FSDS-DAO Project 14)

[0535] Secondary endpoint

[0536] • Arousal Diary (SSE): Change in the number of satisfying sexual events (SSE) from baseline to the end of the study.

[0537] Exploratory endpoint

[0538] • Arousal Diary (AS): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0539] • Arousal Diary (AL): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0540] • Arousal Diary (GA): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0541] • Arousal Diary (SSE): Changes from baseline to week 4 (5th visit) and week 8 (6th visit) of the double-blind dosing period, in addition to the secondary endpoint analysis described above.

[0542] •SFQ28(AL): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0543] •SFQ28(AC): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0544] •SFQ28 (desire): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0545] •SFQ28 (orgasm): Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0546] •SFQ28(AS): In addition to the primary endpoint analysis described above, changes from baseline to week 4 (5th visit) and week 8 (6th visit) of the double-blind dosing period.

[0547] •FSDS-DAO: Changes in the total FSDS-DOA score from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0548] •FSDS-DAO(Q14): In addition to the primary endpoint analysis described above, the changes in FSDS-DOA item 14 from baseline to week 4 (5th visit) and week 8 (6th visit) of the double-blind dosing period.

[0549] •PGI-S: Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0550] •PGI-C: Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0551] •PGI-F: Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0552] • PGI-C concerns: Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0553] • PGI-C SSE: Changes from baseline to week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) of the double-blind dosing period.

[0554] • PBE: Patient Benefit Assessment

[0555] Table 2: Security Assessment Event Timeline

[0556]

[0557]

[0558] a. Patients and their partners (all partners are required to attend the first and second appointments; same-sex partners of reproductive potential will also attend the seventh appointment). Partners are allowed to monitor their vital signs at home using the study-assigned blood pressure cuff. If self-assessment is selected, the partner will be viewed remotely via telemedicine access.

[0559] b. At each visit, an external scopy (using a colposcope) will be used to perform a vulvovaginal examination to determine the degree of irritation.

[0560] c. After successfully completing the first visit, laboratory evaluations will be conducted (including chemistry, hematology, thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), albumin, sex hormone-binding globulin (SHBG), total testosterone, estradiol, prothrombin time, and urinalysis), urine drug screening, serum pregnancy test, serology (including HIV antibody), sexually transmitted infection (gonorrhea, chlamydia, trichomoniasis), bacterial vaginosis, and nucleic acid amplification test (NAAT) for yeast.

[0561] d. A Pap smear will be performed unless the patient has had one within 3 years of their first visit and is able to provide documentation.

[0562] e. If the patient’s partner is a woman of childbearing age, a urine pregnancy test will be performed on her during the screening visit and the 7th visit (or early termination of pregnancy).

[0563] f. At the first visit, a standard 12-lead ECG will be collected for medical screening.

[0564] g. Following the second visit, the patient's adverse events will be initially documented using an eDiary and evaluated by the PI or a designated person. Study site staff will document any partner-reported adverse events in the source file and the eCRF.

[0565] h. All patients received a placebo cream at their third visit.

[0566] Study product (IP), dosage, and administration method:

[0567] Throughout the protocol, the single-blind IP and the two double-blind IPs are collectively referred to as the investigational product (IP). The single-blind IP is a placebo cream. The double-blind IP is either 3.6% sildenafil cream or a placebo cream. IPs are packaged in 30-gram tubes. Patients were randomized 1:1 to the double-blind dosing period using interactive response technology (IRT) and were provided with the appropriate tubes. There were no allocation errors. Dosage cards were provided to ensure accurate measurement of the administered dose. Patients were instructed that approximately 50% of the IP would be applied externally to the vulva (i.e., clitoris, vestibule, labia minora) and approximately 50% would be applied internally to the vagina. Patients were instructed to use the dosage card to measure the appropriate amount of cream to be applied internally and externally. Patients were told to gently apply the cream internally and externally as instructed.

[0568] Research Design and Methods:

[0569] This article describes a phase 2b, multicenter, multidose, double-blind, placebo-controlled study to evaluate the efficacy and safety of 3.6% sildenafil cream in premenopausal women with FSAD.

[0570] The study consisted of four phases: a medical screening phase, a drug-free phase, a single-blind placebo phase, and a double-blind dosing phase. All patients were also contacted after their last outpatient visit during the safety follow-up period (by telephone). Table 2 outlines the study's event timeline and visit requirements, as well as the tools and assessments used—(i) diagnosis, (ii) inclusion and exclusion criteria, and (iii) primary, secondary, and exploratory endpoints.

[0571] Medical screening period: (first visit)

[0572] After completing telephone screening (<28 days before the first visit) or face-to-face discussion, eligible participants were scheduled for their first visit and completed the following five steps to confirm their eligibility for the drug-free phase (second visit). Table 1B provides a complete list of required evaluations.

[0573] Step 1 - FSAD screening tools are used to include and establish baseline functional status.

[0574] After the patient provides written informed consent, FSAD symptoms (including decreased genital sensitivity and pain related to sexual problems) and baseline levels of sexual function are evaluated using the following two patient-reported outcomes (PRO) tools:

[0575] 1. Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO)

[0576] a. Total score > 18 points, confirming distress related to sexual dysfunction.

[0577] 2. Sexual Function Questionnaire - SFQ28

[0578] Step 2 - Additional Inclusion Criteria - Patients can be enrolled in the study if they meet all of the following criteria:

[0579] 1. The patient must be a premenopausal woman aged 21 or older.

[0580] 2. The patient is fluent in English.

[0581] 3. The patient understands and complies with the treatment plan and agrees to sign the informed consent form.

[0582] 4. Prior to the first visit, the patient had been in a stable, monogamous, safe, and communicative relationship for at least six months. This relationship was established with a sexually functional partner, both psychologically and physically. The partner remained consistent and contactable throughout the study period.

[0583] 5. Based on clinical presentation, the patient has experienced "normal" sexual function for at least 2 years or more in the past. The patient has engaged in sexual activity at least twice a month for the past 6 months and agrees to engage in sexual activity at least twice a month during the study period. Sexual activity can include any activity that may lead to sexual stimulation or pleasure, such as intercourse, caressing, foreplay, masturbation, and oral sex.

[0584] a. Patients who have recently experienced significant life stress (such as loss of income, death of a family member) or relationship discord that may interfere with their activities (excluding distress related to FSAD) will be excluded.

[0585] 6. Women of childbearing potential must agree to continue using an acceptable form of contraception during the study period, and to take a stable dose or an insert / implant without complications for at least 6 months prior to their first visit, and agree to maintain their dose of the contraceptive form throughout the study period.

[0586] a. Acceptable forms of contraception include the following: intrauterine system [IUS], hormonal oral contraceptives containing progestin and / or estrogen, contraceptive patches, contraceptive implants, contraceptive inserts, or copper-containing intrauterine devices (IUDs).

[0587] b. Vaginal forms of contraception, such as contraceptive foam / gel, cervical cap, penile or vaginal condoms, contraceptive vaginal rings and sponges, were not considered acceptable methods of contraception in this study.

[0588] c. Although latex and polyisoprene condoms are not acceptable forms of contraception, they can be used to prevent sexually transmitted infections.

[0589] 7. The patient's body mass index (BMI) is between 18 and 35 kg / m². 2 Includes 18kg / m 2 and 35kg / m 2 .

[0590] 8. The patient had a Pap smear within three years prior to the first visit and can provide documentation showing a normal test result (based on current guidelines published by the US Preventive Services Task Force).

[0591] a. If the patient is unable to provide documentation, a Pap smear will be performed at the first visit. Patients with abnormal findings will be excluded from the study and referred for follow-up medical care as appropriate.

[0592] 9. The patient is in good health and has no significant clinical history, physical examination, gynecological history and examination, laboratory findings (such as hematology, urinalysis), vital signs (such as uncontrolled hypertension) or ECG.

[0593] a. Patients with clinically significant ECG abnormalities at their first visit will be excluded.

[0594] b. Patients whose hypertension is controlled and treated (i.e., <140 / 90 mmHg, using no more than two antihypertensive medications in the past 6 months, excluding alpha-blockers and nitrates, with stable doses) will be considered eligible.

[0595] c. Patients with thyroid disease who have received stable medication and dosage control within the past 6 months will be considered eligible. TSH levels must be within the normal range (confirmed by laboratory testing).

[0596] 10. Participants must agree not to use vaginal hormone treatments (such as vaginal estrogen, vaginal praserotonin), vaginal or vulvar lubricants, spermicides, creams or gels, contraceptive foams, or vaginal douches throughout the study.

[0597] a. Women who self-report abnormal physiological vaginal discharge will be excluded until the symptoms of abnormal physiological discharge are resolved.

[0598] b. Patients using systemic (transdermal or oral) therapy must have been on a stable dose for at least 6 months prior to their first visit.

[0599] Step 3 - Exclusion Criteria - Patients meeting any of the following criteria will not be included in the study:

[0600] 1. The patient is currently breastfeeding or pregnant (based on a positive serum pregnancy test) and wishes to become pregnant or begin breastfeeding during the study period, or became pregnant or breastfeeding within 6 months prior to the first visit.

[0601] 2. The patient has more than one sexual partner.

[0602] 3. The patient is postmenopausal (surgically induced or naturally) and meets any of the following criteria:

[0603] a. Bilateral oophorectomy, with or without hysterectomy;

[0604] b. Spontaneous amenorrhea for 12 months;

[0605] c. Spontaneous amenorrhea for 6 months, serum FSH level >40 mIU / mL (except for women receiving hormone replacement therapy).

[0606] 4. The patient has any disease or medical history that may hinder the successful completion of the study.

[0607] 5. Patients with serious cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, skin, blood, neurological, genitourinary, or other unstable medical conditions that would preclude the use of the investigational drug, interfere with the study evaluation, limit study participation, or obscure the interpretation of the study results.

[0608] 6. The patient has a history of unresolved sexual trauma or sexual abuse, which has led to any sexual dysfunction problems (desire, arousal, orgasm, etc.) identified during clinical consultation.

[0609] 7. Patients with any history of active peptic ulcer or clinically significant bleeding disorders.

[0610] 8. Patients with a history of priapism or conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

[0611] 9. Patients with a history of myocardial infarction, stroke, or life-threatening arrhythmia within 6 months prior to their first visit; patients with resting hypotension (blood pressure <90 / 50 mmHg); or any history of coronary artery disease that causes angina; or congestive heart failure requiring medical intervention; patients with underlying conditions that are particularly sensitive to the effects of vasodilators, including patients with left ventricular outflow tract obstruction (such as aortic stenosis, idiopathic hypertrophic subaortic stenosis) and patients with impaired autonomic blood pressure control, or patients who are not suitable for sexual activity due to their underlying cardiovascular condition.

[0612] 10. Patients with a history of hearing loss.

[0613] 11. The patient has retinitis pigmentosa, even if the patient feels clinically well at the first visit. Patients with retinitis pigmentosa will be identified by specifically asking them if they have the condition, whether they have visual signs and symptoms of the condition (including asking if the patient has difficulty seeing at night or in low light, and whether they have any visual field defects indicating peripheral or central vision loss), or whether they have a family history of the condition.

[0614] 12. Patients with a history of orthostatic hypotension or who have orthostatic hypotension at their first visit are defined as a decrease in systolic blood pressure ≥20 mmHg, a decrease in diastolic blood pressure ≥10 mmHg, an increase in pulse rate of 20 beats per minute, or experiencing dizziness or vertigo 1 or 3 minutes after changing from a supine to a standing position.

[0615] 13. A patient’s primary complaint is anorexia, vaginismus, low libido, or any other primary sexual complaint other than genital arousal problems, as determined by a clinical interview.

[0616] 14. The patient has untreated dyspareunia, vulvovaginal infection or inflammation, vulvar or vaginal inflammatory disorder, vestibular pain, clitoral pain, or symptomatic vulvovaginal atrophy (defined as ≤5% superficial cells on vaginal smear at baseline, vaginal pH >5, and the patient presents with moderate or severe vulvovaginal atrophy symptoms).

[0617] 15. The patient underwent major pelvic or abdominal surgery that could cause nerve damage, including vulvectomy, colostomy, cystostomy, hysterectomy, and bladder neck suspension.

[0618] 16. Patients with comorbidities that may lead to potential neurological damage (i.e., type 1 or type 2 diabetes, metabolic syndrome, stroke, myasthenia gravis, multiple sclerosis, or spinal cord injury).

[0619] a. Patients with symptoms of peripheral neuropathy will be excluded.

[0620] 17. Patients with pelvic nerve injury secondary to trauma will be excluded.

[0621] 18. In addition to anxiety and depression, the patient has any current and / or previously reported diagnosis of DSM-IV-TR Axis I disorder (such as schizophrenia, bipolar disorder), including delirium, dementia, and amnesia.

[0622] a. Based on the researcher's decision, patients diagnosed with anxiety or depression must be controlled, and if they are taking medications (i.e., SSRIs, SNRIs, buspirone, bupropion, and benzodiazepines) For drugs of this class, the dosage has been stable for at least the past 6 months.

[0623] b. Patients must have a total score of <10 on the Patient Health Questionnaire-8 (PHQ-8, Appendix G) (Depression Screening and Assessment Tool) to indicate mild depression.

[0624] c. The patient's total score must be <6, indicating mild anxiety disorder according to the Generalized Anxiety Disorder (GAD-7, Appendix H) (Anxiety Disorder Screening and Evaluation Tool).

[0625] d. Patients with a history of antipsychotic treatment within the past year will be excluded.

[0626] 19. Patients with a history of gynecological cancer or who are actively undergoing treatment (or have completed treatment within the last 6 months) for any cancer that would interfere with their ability to successfully complete the study will be excluded.

[0627] a. Patients who have previously received treatment for atypical hyperplasia (precancerous lesions) can be included, provided they have received local treatment (such as cryosurgery or laser therapy).

[0628] b. Patients with a history of pelvic radiation will be excluded.

[0629] 20. The patient has any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the test sample.

[0630] 21. Patients self-report a history of substance abuse within two years prior to their first visit or show signs of current substance abuse.

[0631] 22. The patient self-reports a history of alcohol abuse within two years prior to the first visit, or shows signs of current alcohol abuse.

[0632] 23. The patient has a history of non-arterial ischemic optic neuropathy (NAION) or any potential risk factors for NAION.

[0633] 24. Patients whose sexual function was affected (enhanced or worsened) by any medication within 28 days prior to their first visit and at any time before the drug-free period of the study.

[0634] 25. The patient is currently receiving treatment or has received any of the following medications within 1 month (28 days) prior to the first visit: guanylate cyclase stimulators (such as Riociguat), clonidine, potent CYP3A4 inhibitors, nitric oxide donors such as organic nitrates or organic nitrites, and alpha receptor blockers.

[0635] a. Patients currently receiving treatment or who have received FSAD symptoms, pharmacological treatment (e.g., any form of PDE5 inhibitor other than 3.6% sildenafil cream, or other experimental therapies to enhance arousal) or non-pharmacological treatment (e.g., sexual therapy) within the past 3 months will also be excluded.

[0636] 26. The patient's urine drug screening (such as amphetamines, barbiturates, cocaine, methadone, and opioids) or breath alcohol test results are positive.

[0637] 27. The patient tested positive for antibodies against sexually transmitted infections (trichomoniasis, gonorrhea, chlamydia) and human immunodeficiency virus (HIV).

[0638] 28. Patients report an outbreak (vesicles, warts, or blisters) of any of the following sexually transmitted diseases at any point in the past three months, caused by genital herpes or HPV.

[0639] 29. The patient has been diagnosed with chlamydia, trichomoniasis, or gonorrhea within the past 3 months.

[0640] 30. The patient participated in any clinical study evaluating another investigational drug or therapy within 30 days prior to the first visit (or 6 half-lives of the investigational drug, whichever is longer) and agreed not to participate in another clinical study during the entire study period.

[0641] 31. During the physical and gynecological examinations performed on the patient at the first visit, any clinically significant abnormalities were found in the vulva and vagina (e.g., genital skin abrasions, irritation, skin diseases, or lesions).

[0642] 32. Based on the nucleic acid amplification test (NAAT), the patient currently has moderate to severe vaginitis, vaginal infection (including bacterial vaginosis), yeast infection, or the presence of yeast.

[0643] a. If a patient develops a vaginal infection or tests positive for yeast during a screening appointment, they may receive treatment and have their screening appointment rescheduled.

[0644] b. If a patient develops a vaginal infection after joining the study, the study medication will be withheld, and the patient will receive treatment for the infection. If the infection cannot be resolved within two weeks, the patient will be withdrawn from the study. Two treatments for vaginal infections will be permitted upon enrollment in the study. If a patient develops a third vaginal infection, they will be withdrawn from the study.

[0645] 33. The patient has a pelvic or urinary tract infection.

[0646] 34. Patient self-reporting of known hypersensitivity or adverse reactions to any component of IP.

[0647] Step 4 - Laboratory Evaluation

[0648] Blood, urine, and vaginal samples were collected from all patients who still met the study criteria (successfully completing steps 1-3 above). Patients who continued to meet the inclusion criteria after reviewing laboratory results were scheduled for clinical diagnosis of FSAD.

[0649] Step 5 - Clinical Diagnosis of FSAD

[0650] Patients meeting all the above inclusion and exclusion criteria underwent a formal clinical interview for a diagnosis of primary FSAD, which is acquired (i.e., not lifelong) and systemic (i.e., present regardless of circumstances), and has had symptoms for at least 6 months prior to the first visit. Eligible patients must have a primary complaint of a lack of genital response during sexual activity and believe their genital response is significant to their overall sexual experience. Eligible patients must also experience distress due to difficulty in sexual arousal.

[0651] Patients who present with a secondary complaint of hypoactive libido due to a lack of genital arousal (hypophidrosis) are considered eligible, provided that the problem associated with decreased genital arousal is considered the most troubling symptom.

[0652] Following the completion of the clinical interview, the diagnosis of FSAD will be confirmed according to the DSMIV-TR criteria. Eligible patients will be scheduled for a second visit within 14 days of their first visit.

[0653] No drug delivery period - 4 weeks (second visit)

[0654] After successfully completing all medical screenings (including laboratory evaluations) and confirming all inclusion and exclusion criteria, eligible patients and their partners were enrolled in a 4-week drug-free trial period. The second visit marked the first day of the 4-week drug-free trial period. During these 4 weeks, patients were prohibited from using any oral or topical products (such as Dream Cream, etc.). They addressed their arousal issues using OTC lubricants, PDE-5 inhibitors, or non-pharmacological interventions (i.e., sex therapy). Both patients and their partners received individual eDiary devices and instructions for use. During the drug-free period, patients and their partners used the individual eDiary devices to record adverse events. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete a daily eDiary within 24 hours after each sexual activity. Additionally, if a sexual event occurred, the eDiary prompted the patient to acknowledge their partner's sexual activity and complete an arousal diary. Eligible patients were scheduled for a third visit within four weeks. Single-blind placebo induction period – 4 weeks (3rd visit)

[0655] After completing the 4-week drug-free induction period, eligible patients entered a 4-week single-blind placebo induction period. The third visit was the first day of the 4-week single-blind placebo induction period. At the start of the single-blind placebo induction period, inclusion and exclusion criteria for the study were established, and patient adherence to completing the eDiary was assessed.

[0656] Eligible patients completed the following tools and assessments at the clinic using eDiary during their third visit.

[0657] 1. Sexual Function Questionnaire (SFQ28)

[0658] 2. Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO)

[0659] a. A total score of 18 or higher is required to confirm distress related to sexual dysfunction.

[0660] 3. Patient Severity Overall Impression (PGI-S)

[0661] 4. Overall Impression of Patient Changes (PGI-C)

[0662] Patients were provided with a 30g single-blind IP tube and instructed to apply the cream 10 to 20 minutes before each sexual activity. Patients and their partners were also instructed to wash off any remaining treatment cream after all sexual activity. During the single-blind placebo induction period, patients and their partners recorded adverse events using a separate eDiary device. During the 4-week drug-free induction period, patients and their partners were instructed (via daily prompts) to complete a daily eDiary within 24 hours after each sexual activity.

[0663] In addition, if a sexual event occurs, patients are prompted on the eDiary to record the application of IP, confirm sexual activity with their partner, and complete an arousal diary. Baseline responses are established using eDiary responses, including an arousal diary, SFQ28, and FSDS-DAO scores, after a 4-week single-blind placebo induction period (4th visit). Eligible patients are scheduled for their 4th visit within four weeks.

[0664] Double-blind dosing period - 12 weeks (4th-7th visit)

[0665] After completing the 4-week single-blind placebo induction period, eligible patients entered the double-blind dosing period. The fourth visit marked the first day of the double-blind dosing period. At the start of the double-blind dosing period, inclusion and exclusion criteria were confirmed, and patient adherence to the eDiary and use of the study product was assessed.

[0666] Eligible patients completed the following tools and assessments at the clinic using eDiary during their fourth visit.

[0667] 1. Sexual Function Questionnaire (SFQ28)

[0668] 2. Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO)

[0669] a. A total score of >18 points is required to confirm distress related to sexual dysfunction.

[0670] 3. Patient Severity Overall Impression (PGI-S)

[0671] 4. Overall Impression of Patient Changes (PGI-C)

[0672] Baselines were established using eDiary responses, including an arousal diary, SQF28, and FSDS-DAO scores after a 4-week single-blind placebo induction (4th visit).

[0673] During the double-blind dosing period, patients returned to the clinic every four weeks for efficacy and safety evaluations. The fourth visit marked the first day of the double-blind dosing period, and the seventh visit marked the end of the 12-week double-blind dosing period.

[0674] At visits 4–6, patients were provided with a 30g double-blind IP tube according to a randomized schedule. Patients returned the tube at subsequent visits (i.e., visits 5–7) and were assigned a new tube for the following month's double-blind treatment. Patients were instructed to apply the cream 10–20 minutes before each sexual activity. Patients and their partners were also instructed to wash off any remaining treatment cream after all sexual activity. During the double-blind treatment period, patients and their partners recorded adverse events using a separate eDiary device. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete a daily eDiary within 24 hours after each sexual activity. Additionally, if a sexual event occurred, the eDiary prompted the patient to record the application of the IP, confirm the partner's sexual activity, and complete an arousal diary.

[0675] Patients used eDiary to complete the following tools and assessments at the clinic during their 5th-7th visits.

[0676] 1. Sexual Function Questionnaire (SFQ28)

[0677] 2. Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO)

[0678] 3. Patient Severity Overall Impression (PGI-S)

[0679] 4. Overall Impression of Patient Changes (PGI-C)

[0680] The patient completed a patient benefit assessment (PBE) at the clinic during their 7th visit. During the double-blind treatment period, the patient and their partner recorded adverse events using a separate eDiary device. During the 4-week drug-free period, the patient and their partner were instructed (via daily prompts) to complete a daily eDiary within 24 hours of each sexual activity. Additionally, if a sexual event occurred, the eDiary prompted the patient to record the application of IP, confirm the partner's sexual activity, and complete an arousal diary.

[0681] At the end of the study (7th visit) or after study withdrawal, a selected number of patients were interviewed by telephone in a semi-structured exit manner to provide a more in-depth, qualitative description of patients’ symptoms, responses to treatment, the composition and causes of meaningful changes in PGI-S and PGI-C, and treatment satisfaction, in order to enhance the qualitative assessment obtained by the PRO tool.

[0682] Safety assessment follow-up (by phone):

[0683] Each patient and their partner were contacted by telephone 7 ± 3 days after the last visit during the double-blind dosing period to record any changes in concomitant medications and potential adverse events that may have occurred since the last study visit (7th visit). The longest study duration was approximately six (6) months.

[0684] Retrospective assessment

[0685] At the end of the single-blind placebo induction period and at weeks 4, 8, and 12 of the double-blind treatment period, the correlation between the 24-hour and 4-week review periods was assessed in all patients who completed both the arousal diary and the SFQ28. Additionally, at the same time intervals, a subset (n=30) of patients randomly selected via interactive response technique (IRT) who completed the SFQ28 but not the arousal diary were assessed to investigate whether diary completion affected patients' SFQ28 arousal (feeling) category scores.

[0686] Patient withdrawal

[0687] Patients who signed informed consent forms at their first visit and those who withdrew from the study early and received at least one dose of IP were instructed to complete the relevant PRO tools (SFQ28, FSDS-DAO, etc.). These patients were also listed in the final study forms, lists, and graphs according to the reason for discontinuation.

[0688] Exit Criteria

[0689] Patients may choose to withdraw from the study at any time for any reason. In addition, patients may withdraw from the study for any of the following reasons:

[0690] • The patient or their partner is unwilling or unable to adhere to the protocol.

[0691] • During the study, if a patient exhibits any of the symptoms or conditions listed in the exclusion criteria,

[0692] • During the study, if any of the following conditions occur in the patient: adverse visual reactions, severe skin reactions, symptomatic orthostatic tachycardia, symptomatic hypotension, asymptomatic hypotension, or asymptomatic orthostatic hypotension,

[0693] • Any SAE, clinically significant AE, serious laboratory abnormalities, comorbidities, or other medical conditions that indicate to investigators that continued participation is not in the best interests of the patient, or

[0694] Other medical reasons

[0695] Stop criteria

[0696] The trial will be stopped if more than 1% of patients or partners treated with the active cream report significant post-dose symptoms associated with low blood pressure (dizziness, lightheadedness, nausea), leading to syncope (fainting) and significant injury.

[0697] Inclusion criteria - eligibility of patient partners

[0698] The patient's partner can be included in the study if they meet all of the following criteria at the first visit:

[0699] 1. The partner must be 21 years of age or older.

[0700] 2. The partner must be fluent in English.

[0701] 3. The partner is able to understand and comply with the plan and agrees to sign an informed consent form.

[0702] 4. Prior to the first visit, the partner must have maintained a stable, monogamous, secure, and communicative relationship with the patient for at least six months. The partner must be sexually functional both psychologically and physically. The partner will remain consistent and contactable throughout the study period.

[0703] Exclusion criteria - Eligibility of patient's partner

[0704] Couples who meet any of the following criteria at their first visit will not be included in the study:

[0705] 1. The partner is breastfeeding or pregnant (based on a positive urine pregnancy test) or hopes to become pregnant during the study period.

[0706] 2. The partner has any obstacles or medical history that could hinder the successful completion of the research.

[0707] 3. Any of the following treatments received by the partner within the past month (28 days) or immediately prior to the first visit will be excluded: vaginal hormone products (such as estrogen or prastorone), guanylate cyclase stimulants (such as Riociguat), phosphodiesterase (PDE) type 5 inhibitors, nitric oxide donors such as organic nitrates or organic nitrites.

[0708] 4. The partner has a significant cardiovascular, liver, metabolic, kidney, respiratory, gastrointestinal, endocrine, immune, skin, blood, neurological, genitourinary, or mental illness or other unstable medical condition, or any concomitant medication that may contraindicate the use of the investigational drug, interfere with the study evaluation, limit study participation, or obscure the interpretation of study results.

[0709] 5. Partners with a history of myocardial infarction, stroke, or life-threatening arrhythmia within 6 months prior to the first visit; patients with resting hypotension (BP < 90 / 50 mmHg); or patients with a history of any coronary artery disease that causes angina; or partners with congestive heart failure requiring medical intervention; partners with underlying conditions that are particularly sensitive to the effects of vasodilators, including patients with left ventricular outflow tract obstruction (such as aortic stenosis, idiopathic hypertrophic subaortic stenosis) and partners with impaired blood pressure control, or partners who are not suitable for sexual activity due to their underlying cardiovascular condition.

[0710] 6. The partner has a history of orthostatic hypotension or orthostatic hypotension at the first visit, defined as a decrease in systolic blood pressure ≥20 mmHg, a decrease in diastolic blood pressure ≥10 mmHg, an increase in pulse rate of 20 beats per minute, or experiencing dizziness or vertigo 1 or 3 minutes after changing position from supine to standing.

[0711] 7. The partner has a history of priapism or a condition that may make them susceptible to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

[0712] 8. Your partner currently has a pelvic or urinary tract infection.

[0713] 9. The partner self-reports any sexually transmitted infection (including gonorrhea, trichomoniasis, and chlamydia) in the past 3 months.

[0714] 10. Partner self-reported diagnosis of human immunodeficiency virus (HIV).

[0715] 11. The partner self-reports an outbreak of any of the following sexually transmitted diseases at any point in the past three months: genital herpes or HPV (blisters, warts, or small blisters).

[0716] 12. The partner has a history of non-arterial ischemic optic neuropathy (NAION) or any potential risk factors for NAION.

[0717] 13. The partner must have participated in any clinical study evaluating another investigational drug or therapy within 30 days prior to the first visit (or 6 half-lives of the test drug, whichever is longer). The partner must agree not to participate in another clinical trial throughout the study period.

[0718] 14. The partner reported a known hypersensitivity or adverse reaction to any component of the study product (IP).

[0719] Research Products (IP)

[0720] In this protocol, the single-blind IP and double-blind IP are collectively referred to as the investigation product (IP). The single-blind IP is a placebo cream, and the double-blind IP is either a placebo cream or 3.6% sildenafil cream, depending on the randomization protocol. Both single-blind and double-blind IPs will be provided in 30-gram white aluminum tubes. One 30-gram tube holds nine (9) applications of 2 grams each. Dosage cards will also be provided for patient use to ensure dosage accuracy. The cream is aqueous, white to off-white in appearance, and has the same color, odor, and consistency as the sildenafil cream and placebo cream.

[0721] 3.6% Sildenafil Cream is a white to off-white cream containing 5% (w / w) sildenafil citrate and the salts and excipients listed in Table 3, resulting in a sildenafil concentration of 3.6%. IP's packaging and labeling comply with all applicable regulatory requirements. IP should be stored at room temperature (20-25°C) in a safe temperature and humidity monitored area.

[0722] Table 3: Formulation of 3.6% Sildenafil Cream

[0723]

[0724]

[0725] The placebo cream will contain the same ingredients as the 3.6% sildenafil cream, but without the active ingredient sildenafil citrate. Its appearance, odor, consistency, and color will match those of the 3.6% sildenafil cream. Table 4 below lists the complete ingredient list.

[0726] Table 4: Formulation of placebo cream

[0727]

[0728] Single-blind placebo introductory period

[0729] One 30-gram tube of placebo cream will be administered to the patient during the single-blind induction period at the third visit, allowing for nine (9) applications of 2-gram cream. The patient will be instructed to apply 2-gram cream 10 to 20 minutes before each sexual activity. Specific instructions for administration will be provided to the patient individually.

[0730] Double-blind dosing period

[0731] Each month, IP is dispensed into a 30-gram tube and nine 2-gram dose cards. Participants are instructed to use no more than one 2-gram application every 24 hours, for a maximum of nine applications per month. After dispensing the 2-gram portion onto the dose card, participants apply 2 grams of IP with their index finger approximately 10–20 minutes before sexual activity. One gram is applied to the anterior commissure, clitoral hood, glans clitoris, frenulum, vestibule, and labia minora. The other gram is applied to the distal anterior vagina, to a depth of approximately 0–3 cm, or about halfway between the distal and proximal interphalangeal joints, targeting the lower distal third of the vagina. Participants are instructed to wash off the cream after sexual activity, and, if appropriate, have their partners wash off the cream. Applications exceeding nine times per month are recorded as a violation of the protocol.

[0732] IP Dose Application Procedure

[0733] During the single-blind placebo induction and double-blind dosing periods, a dose card must be used to measure the correct amount of cream according to the following instructions. Patients are instructed to measure the correct amount of cream as follows: "To measure the correct amount of cream, place the dose card on a flat surface. Squeeze the cream onto the dose card by evenly filling the rectangle outlined on the card. Ensure that the cream covers the entire area of ​​the rectangle outlined on the dose card."

[0734] Divide the rectangle on the dosage card (sized to deliver 2 grams of cream) into two equal parts, one for applying the cream from the outside to the pre-designated vulvar area and the other for applying it from the inside to the vagina.

[0735] Approximately 50% of the cream will be applied externally to the vulva (i.e., clitoris, vestibule, labia minora), and approximately 50% will be applied internally to the vagina. Patients are instructed to note the application time on the eDiary and use a dosage card to apply the appropriate amount of cream to the vagina and vulva, as shown below:

[0736] Apply cream externally:

[0737] The patient was instructed to apply approximately half of the cream on the dosage card externally using their index finger, as described below:

[0738] Step 1. Starting from the labial junction, gently apply the cream to the clitoral hood, glans clitoris, and frenulum.

[0739] Step 2. Continue to gently apply the cream to the vestibule.

[0740] Step 3. Continue to gently apply the cream to the labia minora.

[0741] (Note: Avoid applying to the labia majora and avoid applying the product to pubic hair.)

[0742] Apply cream internally:

[0743] Step 4. Use your index finger to take the other half of the cream and gently apply it to the distal anterior part of the vagina with a sweeping motion (to a depth of about 0-3 cm, or about halfway between the distal and proximal interphalangeal joints, targeting the lower 1 / 3 of the distal vagina).

[0744] Prior to the single-blind placebo induction period, patients underwent extensive site training to ensure they understood the product's instructions for use. Patients were instructed to wash their hands and avoid rubbing or washing off any areas where the cream had been applied. Patients and their partners were also instructed to wash off any remaining treatment cream after all sexual activity.

[0745] IP Dosing Frequency

[0746] The IP was allocated to apply a total of nine (9) 2-gram doses of cream at monthly intervals (the nine 2-gram doses could be reliably delivered from a 30-gram tube). Patients were instructed to apply the cream 10 to 20 minutes before each sexual activity, but not more than nine (9) doses in every four weeks. Patients were further instructed not to apply the cream within 24 hours of the previous application.

[0747] Dosing schedule

[0748] Single-blind placebo induction period (3rd visit)

[0749] After completing a 4-week drug-free induction period, eligible patients entered a 4-week single-blind placebo induction period. In this 4-week study, patients received a single-blind IP (intravenous injection), administered monthly in a single-blind manner via a 30-gram tube. Patients were instructed to apply 2 grams of the cream 10 to 20 minutes before each sexual activity.

[0750] Double-blind dosing period (4th-7th visits)

[0751] After completing a 4-week single-blind placebo induction period, eligible patients entered a 12-week double-blind dosing period. During the 12-week study period, patients received the same double-blind IP, delivered in 30-gram tubes, at each visit according to a randomization schedule. At the 4th, 5th, and 6th visits, patients were assigned a 30-gram tube, supplied monthly. Patients were instructed to apply 2 grams of the cream 10 to 20 minutes before each sexual activity.

[0752] Previous and combined medications

[0753] Permitted concomitant medication

[0754] Patients and their respective partners may take concomitant medications as needed under the guidance of a medical supervisor, except for the medications listed below.

[0755] From 28 days before the first visit to the end of the seventh visit, all concomitant medications used by the patients and their respective partners were recorded.

[0756] Changes in concomitant medications were recorded in the patient's and their partner's eDiary.

[0757] Contraindications for concomitant medication use - patients and their partners

[0758] Patients with positive urine drug screening results (such as amphetamines, barbiturates, cocaine, methadone, and opioids) or alcohol breath tests will be excluded from further study participation. Patients currently taking or who received any of the following medications within the last 28 days prior to their first visit will be excluded from the study: guanylate cyclase stimulants (such as Riociguat), clonidine, potent CYP3A4 inhibitors, nitric oxide donors such as organic nitrates or organic nitrites, or alpha-receptor blockers. Patients currently receiving treatment or who have received FSAD symptom treatment, pharmacological treatment (e.g., any form of PDE5 inhibitor other than 3.6% sildenafil cream or other experimental therapies to enhance arousal), or non-pharmacological treatment (i.e., sexual therapy) within the past 3 months will also be excluded.

[0759] Throughout the study, patients are prohibited from using vaginal hormonal products (such as vaginal estrogen, intravaginal prazoserotonin), vaginal or vulvar lubricants, spermicides, creams or gels, contraceptive foams, or vaginal douches. Partners currently taking or who have taken within one month (28 days) prior to their first visit a guanylate cyclase stimulant (such as Riociguat), clonidine, a potent CYP3A4 inhibitor, a phosphodiesterase (PDE) type 5 inhibitor, or a nitric oxide donor (such as an organic nitrate or organic nitrite) will be excluded. Patients using contraceptive vaginal sponges will be excluded. Patients or their partners currently taking or have taken any of the contraindicated medications listed in the relevant study inclusion and exclusion criteria will be excluded from the study.

[0760] Safety assessment for patients and partners

[0761] Adverse events (AEs)

[0762] Adverse events were collected from the patient and their respective partners at each visit, starting with the signing of the informed consent form. AEs reported before the first administration of the intraperitoneal injection (IP) were recorded in the AE eCRF but not included in the summary of treatment-emergent AEs (TEAEs). AEs reported after the first administration of the IP were recorded in the AE eCRF. AEs occurring since the completion of the last clinical visit were recorded 7 ± 3 days after the end of the double-blind dosing period (7th visit).

[0763] Adverse event reporting

[0764] Patients and their partners are instructed to immediately report any serious medical problems that occur during the study. Patients and their partners are instructed to call 911 in the event of a life-threatening emergency. Patients record all adverse events (AEs) in the eDiary as provided. Patients complete the eDiary within 24 hours of each sexual encounter and at any time during the study when AEs may occur. Partners record all AEs in a separate eDiary as provided. Partners complete the eDiary within 24 hours of each sexual encounter and at any time during the study when AEs may occur. The eDiary prompts patients and partners every 24 hours to assess whether a sexual encounter has occurred. If a sexual event occurs, the eDiary will provide the patient and partner with the following prompt: “Have you had any complaints since your sexual event?” If the participant or partner answers “yes,” the eDiary will further prompt them with some of the more common side effects associated with oral sildenafil or genital cream, such as: (1) “Have you experienced any local irritation or discomfort?” (2) “Have you experienced any dizziness or lightheadedness?” and (3) “Do you have any other complaints to report?” Participants who report complaints after sexual activity will have their responses sent electronically to the site within 24 hours for evaluation and triage. In addition, participants who answer “yes” to their complaints will be reminded to contact their study site. Subjects will be instructed to call the investigator’s emergency number if they do not receive a response within 24 hours of sending their complaints electronically. Participants will also be instructed to promptly report any complaints of local irritation or discomfort to the investigator for follow-up.

[0765] If a participant confirms a sexual encounter with their partner via eDiary, research site staff will be instructed to contact the partner within 72 hours of the event to confirm if the partner has any complaints. If so, they will inquire further about common side effects associated with oral sildenafil (such as dizziness) or genital cream exposure (such as genital irritation). If the partner does not receive a call within 72 hours of the sexual activity, they will be instructed to contact the investigator.

[0766] Participants recorded TEAEs in the eDiary. If participants and their sexual partners had TEAEs they wished to be evaluated for, or if the researchers decided on the TEAEs based on the reported TEAEs, they would be invited for unscheduled appointments.

[0767] At each visit, participants underwent postural vital sign checks, with heart rate and blood pressure measured in the supine position, and 1 minute and 3 minutes after standing. The same postural vital sign measurements were also performed on the participants' sexual partners at each visit, either in the clinic or via telemedicine.

[0768] Adverse events

[0769] An adverse event is any unfortunate medical event related to the use of a drug in a human, whether or not it is considered to be related to the drug. An AE (also known as an adverse experience) can be any unfavorable and unexpected sign (e.g., an abnormal laboratory finding), symptom, or illness that is temporarily related to the use of the drug and does not imply any judgment of causation. AEs may be related to any use of the drug (e.g., off-label use, use in combination with another drug) and any route of administration, formulation, or dosage (including overdose).

[0770] Suspected adverse reactions

[0771] A suspected adverse reaction (AE) refers to any adverse event (AE) that the drug has a reasonable probability of causing. In the context of Investigational New Drug (IND) safety reports, "reasonable probability" means there is evidence of a causal relationship between the drug and the AE. A suspected AE implies a lower certainty of causation than an adverse reaction, which is any AE caused by the drug.

[0772] Life-threatening adverse reactions or suspected life-threatening adverse reactions

[0773] An AE or suspected adverse reaction is considered "life-threatening" if it puts the patient or their partner at immediate risk of death. This does not include AEs or suspected adverse reactions that could lead to death if they occur in a more serious form.

[0774] Serious adverse events (AEs) or serious suspected adverse reactions

[0775] An adverse reaction (AE) or suspected adverse reaction is considered "serious" if it leads to any of the following results:

[0776] ·die,

[0777] • Life-threatening AEs - see definition above,

[0778] • Hospitalization or extension of existing hospital stay

[0779] • The ability to sustain or significantly impair normal daily living functions, and

[0780] • Congenital abnormalities / birth defects.

[0781] Important medical events may be considered serious events when, based on appropriate medical judgment, they are unlikely to result in death, are life-threatening, or require hospitalization, but may endanger the patient or their partner and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood abnormalities or seizures that do not lead to hospitalization, or the development of drug dependence or substance abuse.

[0782] Relationship with investigational drugs

[0783] Causality assessment must be performed on all adverse events (serious and non-serious). Causality assessment determines whether there is a reasonable probability that the research product (IP) caused or contributed to the adverse event.

[0784] None: There is no relationship between the experience and the administration of the study drug; it is related to other causes, such as concomitant medication or the patient's clinical condition.

[0785] Impossible: Current knowledge indicates that it is impossible to establish a relationship.

[0786] Possible: A response that begins with administration of the study drug, follows a reasonable time sequence, and conforms to known response patterns to the suspected study drug. This response may be caused by the patient's clinical condition or other treatments administered to the patient, but this is currently uncertain.

[0787] Highly probable: A response that begins with administration of the investigational drug, follows a reasonable temporal sequence, and conforms to a known response pattern to the suspected investigational drug. This response cannot be reasonably explained by known characteristics of the patient's clinical condition or by other treatments administered to the patient.

[0788] Clearly defined: A response that begins with administration of the study drug, follows a reasonable time sequence, conforms to a known response pattern to the suspected study drug, and can be confirmed by a positive rechallenge test or supporting laboratory data.

[0789] Severity

[0790] In the eCRF of adverse events, the terms mild, moderate, severe, or life-threatening will be used to describe the maximum intensity of the adverse event (AE). For consistency, these intensity levels are defined as follows.

[0791] Mild: Aware of signs or symptoms, but easily tolerated.

[0792] Moderate: Discomfort not enough to interfere with normal daily activities

[0793] Severe: Unable to perform normal daily activities

[0794] Life-threatening: There is a risk of immediate death due to the reaction when it occurs.

[0795] Screening laboratory evaluation

[0796] The following laboratory evaluations were performed after the successful completion of the first visit.

[0797] Serum chemistry: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin, blood urea nitrogen, creatinine, potassium, total protein, sodium, chloride, and bicarbonate.

[0798] • Hematology: Differences in hematocrit, hemoglobin, platelets, red blood cell count, white blood cell count, and white blood cell count are only observed when total white blood cell count (WBC) is abnormal.

[0799] Prothrombin time

[0800] ·TSH

[0801] ·FSH

[0802] ·Estradiol

[0803] Total testosterone, SHBG, and albumin

[0804] • Urine analysis: bilirubin, blood, glucose, ketones, nitrite, pH, protein, specific gravity, urobilinogen, and leukocyte esterase.

[0805] • HBsAg, HCV, HIV and antibodies

[0806] • NAAT (Nucleic Acid Amplification Test): Bacterial vaginosis, yeast infections (Candida), and sexually transmitted infections (gonorrhea, chlamydia, trichomoniasis).

[0807] • Perform urine drug screening for the following abused drugs: amphetamines, barbiturates, cocaine, methadone, and opioids.

[0808] During the study, women were required to undergo a urine pregnancy test at each visit, except for the first visit, which included a serum pregnancy test. Women testing positive were immediately discontinued from the study.

[0809] electrocardiogram

[0810] A standard 12-lead ECG was collected at the first visit prior to the start of the study's drug-free period. Screening ECGs were performed after the patient had been supine for at least 5 minutes. ECGs were categorized as normal, without clinically significant abnormalities, or with clinically significant abnormalities. All patients with clinically significant ECG abnormalities at the first visit were excluded.

[0811] Vulvar-vaginal clinical examination

[0812] At each visit, a vulvovaginal clinical examination was performed using a vuloscope to determine the degree of irritation (using the scale below). In addition, any patient who complained of local irritation or discomfort during the study period was instructed to contact the investigator for follow-up. The examination included a visual examination of the vagina, observing petechiae, pallor, fragility, dryness, and mucosal redness. As shown in Table 5A, observations were graded on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe).

[0813] Table 5A: Vaginoscopy - Degree of Irritation

[0814]

[0815] Statistical analysis

[0816] Before unlocking the data, a formal Statistical Analysis Plan (SAP) was developed and finalized. The SAP defined the population used for the analysis, outlined all data processing conventions, and specified all statistical methods used for the data analysis. Generally, safety and efficacy variables were presented using descriptive statistics and numbers (as applicable), treatment groups, and time points (where applicable). Continuous variables were summarized using non-missing observations, mean, standard deviation (SD), median, first and third quartiles, and minimum and maximum values. Categorical variables were expressed using the number of patients and percentages. For ordinal categorical variables, cumulative percentages may also be displayed. An unblinded ITT interim analysis was performed after evaluating the primary endpoint in at least 50 patients in the placebo and sildenafil cream groups. The interim analysis included all patients who successfully completed their 7th visit and those who withdrew at the time of the interim analysis. Because this interim analysis was not intended to prematurely terminate the trial for efficacy reasons, a conservative expenditure function based on the Gamma family with a parameter of -40 was applied to each endpoint to compare the matching of the sildenafil 2gm dose with the placebo group at a 0.025α level on one side. The final sample size for the placebo and sildenafil cream groups was determined based on the provisional condition power observed on the co-primary endpoints. For the re-estimation of the sample size for both the placebo and sildenafil cream groups, the sample size will not increase unless the provisional condition power for the two co-primary endpoints is at least 50%, in which case the sample size will be increased to the maximum of the two sample sizes calculated for each endpoint.

[0817] The sample size for this study was based on the common primary product efficacy endpoint. The safety analysis set consisted of all women who received at least one IP treatment during the study period. The frequency of TEAEs was described according to product group, relevance to IP use or study procedure, and severity. TEAE frequencies were compared between treatment groups using chi-square statistics or Fisher's exact test based on expected cell size. Vital signs data were normally distributed, therefore independent samples t-tests were used to compare time and location (e.g., supine) of visit and measurement between the 3.6% sildenafil cream group and the placebo cream group. A p-value <0.05 was considered statistically significant.

[0818] Therapeutic efficacy measurement

[0819] As described below, the primary objective of this study was to demonstrate the efficacy of 2 g 3.6% sildenafil cream compared to a matched placebo cream, based on item 14 of the co-primary endpoints SFQ-AS and FSDS-DAO. Patient scores after the single-blind placebo induction period were used as baseline for each patient.

[0820] The following methods were used to assess the effectiveness of the treatment:

[0821] Common primary endpoint:

[0822] • SFQ28 (AS): Changes in the arousal (AS) category score of the SFQ28 from baseline to the end of the study.

[0823] •FSDS-DAO (Q14): Changes in scores for concern about sexual arousal difficulties from baseline to the end of the study (FSDS-DAO item 14).

[0824] Secondary endpoint:

[0825] • Arousal Diary (SSE): Changes in the number of satisfying sexual events (SSEs) from baseline to the end of the study.

[0826] Exploratory endpoint:

[0827] • Arousal Diary (SSE): In addition to the secondary endpoint analyses described above, changes from baseline were recorded at week 4 (5th visit) and week 8 (6th visit) during the double-blind dosing period.

[0828] • Arousal Diary (AS): After each sexual encounter, the eDiary records changes in patient-reported genital arousal sensations (AS) compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0829] • Arousal Diary (AL): Changes in patient-reported lubrication (AL) compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit) after each sexual event, as recorded in the eDiary.

[0830] • Arousal Diary (GA): Changes in patient-reported sexual arousal (AE) compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit) after each sexual event, as recorded in the eDiary.

[0831] •SFQ28(AS): In addition to the primary endpoint analysis described above, changes from baseline were observed at week 4 (5th visit) and week 8 (6th visit) during the double-blind dosing period.

[0832] • SFQ28(AL): Changes in the SFQ28 arousal lubrication (AL) range from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0833] • SFQ28 (AC): Changes in the arousal cognition (AC) category of SFQ28 compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0834] • SFQ28 (Desire): Changes in the desire category of SFQ28 compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0835] • SFQ28 (Orgasm): Changes in the range of orgasms in the SFQ28 compared to baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0836] •FSDS-DAO: Changes in the total FSDS-DAO score from baseline at weeks 4 (5th visit), 8 (6th visit), and 12 (7th visit).

[0837] •FSDS-DAO(Q14): In addition to the primary endpoint analysis described above, changes in FSDS-DOA item 14 from baseline at week 4 (5th visit) and week 8 (6th visit) during the double-blind dosing period.

[0838] •PGI-S: The proportion of patients who improved by at least one severity category from baseline to the end of the study.

[0839] •PGI-C: The proportion of patients who showed at least a significant improvement in reportable arousal problems from baseline to the end of the study.

[0840] • PBE: Reports the proportion of patients who derive a meaningful benefit from the investigational drug, evaluated with a "yes / no" question at the end of the study.

[0841] Unless otherwise stated, efficacy analyses were randomized, meaning patients were assigned to their initially assigned treatment regardless of the specific treatment administered. Statistical summaries were performed for each efficacy endpoint by treatment and time point (if applicable).

[0842] The primary objective was evaluated by testing the 3.6% sildenafil cream treatment group (2 g) versus the matched placebo cream at the appropriate hypotheses of the SFQ28 (AS) endpoint and the FSDS-DAO co-primary endpoint:

[0843] • Null hypothesis (H0): There was no difference in mean change of SFQ28 (AS) from baseline to week 12 between the 3.6% sildenafil cream treatment group and the matched placebo cream group.

[0844] H0: μ(sildenafil) = μ(placebo)

[0845] • Alternative hypothesis (H1): The mean change in SFQ28 (AS) from baseline to week 12 was different in the 3.6% sildenafil cream treatment group compared with the matched placebo cream group.

[0846] H1: μ(sildenafil) ≠ μ(placebo)

[0847] The comparison was performed using a fixed-sequence backtesting procedure at a statistical significance level of 0.025% (or 0.05) for one-sided treatment. A mixed-model repeated measures (MMRM) model was used to analyze the 3.6% sildenafil cream versus the matched placebo cream, which included the following terms: baseline (as a continuous covariate), treatment group, visit (as a categorical variable), and interaction visit*treatment as a fixed effect, and subjects as a random effect. In-subject error was modeled using an “unstructured” covariance structure. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust the standard errors. As part of this analysis, the estimated treatment means and differences from baseline at the last visit (the 7th visit during the double-blind dosing period) are reported (3.6% sildenafil cream versus matched placebo cream comparison). The ITT dataset will be analyzed. The PP set was also analyzed.

[0848] result

[0849] Of the 252 participants who entered the 28-day single-blind placebo induction period, 227 received at least one dose of IP, and 219 of them completed the single-blind placebo induction period. During this period, participants received placebo cream for a mean of 2.5 (1.3) weeks, with a mean of 4 doses. Median adherence to IP was reported at 75% during the single-blind placebo induction period. During the single-blind period, 51 (22.5%) of the 227 participants who received placebo reported 94 TEAEs. All participants who reported TEAEs during the single-blind placebo induction period rated their severity as mild or moderate. Of these 94 TEAEs, 73 TEAEs reported by 37 participants were rated as treatment-related TEAEs. Six treatment-related TEAEs reported by four participants led to discontinuation of IP during the single-blind placebo induction period. All six TEAEs were symptoms that appeared shortly after IP administration, including genital discomfort, burning, stinging, folliculitis, and erythema. During the single-blind placebo induction period, the most common TEAE reported by 32 participants was discomfort at the genital application site, and COVID-19 infection was the second most common TEAE reported by 12 participants.

[0850] During the single-blind placebo introductory period, 7 out of 197 sexual partners exposed to placebo reported 8 treatment-associated adverse events (TEAEs), all of which were mild to moderate in intensity. Four sexual partners reported 5 TEAEs (headache, penile burning, penile irritation, and perineal irritation), which were considered treatment-related. No TEAEs were reported by partners that led to interruption of the intellectual property (IP) or study.

[0851] During the double-blind dosing period, the mean (standard deviation, SD) duration of IP use was 10.3 (2.5) weeks for sildenafil cream and 9.7 (3.1) weeks for placebo cream. The cumulative doses of sildenafil cream and placebo cream received during this period were 23.5 (14.0) g and 22.9 (14.5) g, respectively. The reported median adherence, defined as IP use 10–20 minutes prior to sexual intercourse, ranged from 78.8% to 98% for 3.6% sildenafil cream and from 85% to 95% for placebo cream. The highest median adherence rate (98%) was reported in the third month of use for 3.6% sildenafil cream and 95% for placebo cream in the first month of use. During the double-blind dosing period, 1357 sexual intercourses were recorded with 3.6% sildenafil cream and 1160 with placebo cream, respectively. Most sexual experiences were with a partner (76% of sildenafil cream exposures and 80% of placebo cream exposures). eDiary did not show any instances of partnered sex with a non-consensual partner, therefore no participants discontinued the study due to protocol violation.

[0852] Table 5B shows the number of participants and sexual partners who reported at least one TEAE, and the total number of TEAEs categorized by severity and relevance. During the double-blind administration period, the frequency of various TEAE reports was not significantly different between participants using the 3.6% sildenafil cream and those using the placebo cream (all p-values ​​>0.50, Table 5B). During the double-blind administration period, the mean (SD) time to onset of the first TEAE reported by participants assigned to sildenafil and placebo creams was 21 (11) days and 20 (8) days, respectively. All TEAEs reported by participants or sexual partners during the double-blind administration period were rated as mild or moderate. During the administration period, two participants assigned to sildenafil reported three TEAEs (burning at the IP application site, erythema at the IP application site, and dyspareunia due to IP use), all of which were considered treatment-related and resulted in IP interruption. During the double-blind treatment period, two placebo cream users reported two TEAEs unrelated to IP use (dyspareunia and vulvar fissure), but which still resulted in IP interruption.

[0853] Table 5B also shows that during the double-blind dosing period, 9 TEAEs were reported by 7 partners exposed to 3.6% sildenafil cream, and 4 TEAEs were reported by 4 partners exposed to placebo cream. There were no statistically significant differences in the reported frequencies of various TEAEs between partners exposed to active or placebo IP (all p-values ​​> 0.25). One TEAE, genital burning upon contact with IP during intercourse, was considered treatment-related and led to IP interruption in partners exposed to 3.6% sildenafil cream.

[0854] Table 5B: TEAEs reported by participants and sexual partners during double-blind treatment

[0855]

[0856]

[0857] Post-hoc analysis (Table 5C) showed that the number of participants in the 3.6% sildenafil cream allocation who reported at least one TEAE was similar when segmented according to the quartiles of the total number of sexual events reported during the double-blind treatment period (all p-values ​​> 0.19). Table 5C: Number of participants in the 3.6% sildenafil cream allocation who reported at least one TEAE category according to the quartiles of sexual events reported during the double-blind treatment period.

[0858]

[0859]

[0860] *For participants with more than one TEAE, the highest severity, relevance, and effect were recorded.

[0861] Table 5D shows the most common treatment-related (probable, very likely, or absolutely relevant) TEAEs reported by subjects or their sexual partners during double-blind dosing, categorized by systemic organ. As shown in Table 5D, there were no significant differences in systemic organ categories (all p values ​​> 0.11) and sexual partners (all p values ​​> 0.25) between sildenafil and placebo cream users regarding reported treatment-related TEAEs.

[0862] Table 5D: Most common treatment-related TEAEs reported by systemic organ category by participants and sexual partners during double-blind dosing.

[0863]

[0864] Because oral sildenafil may be associated with orthostatic hypotension, particularly in patients taking nitrates for angina, postural vital signs were obtained at baseline in participants (Table 6) and their sexual partners, and then monthly during the double-blind dosing period. As shown in Table 6, there were no differences in vital signs collected in different positions between participants assigned to 3.6% sildenafil cream or placebo at any point during the study (all p-values ​​> 0.10). Consistent with normal physiological responses, mean pulse rate began to increase from the supine position, at 1 minute, and 3 minutes of standing. The median change in pulse rate from baseline was 1–4 beats / min in both the 3.6% sildenafil cream and placebo groups, with no outliers observed. For systolic blood pressure, the median change from baseline ranged from -3.5 mmHg to +3.0 mmHg in both treatment groups, showing no clinically significant change. Finally, the median change from baseline for diastolic blood pressure during the double-blind dosing period was -2.0 to +1.0.

[0865] During the double-blind dosing period, one placebo-controlled randomized subject reported mild palpitations, which were considered unrelated to the study IP. No other cardiovascular or neurological disorders were reported by subjects during the double-blind dosing period. Regarding sexual partners, during the double-blind dosing period, one partner exposed to 3.6% sildenafil cream reported mild headaches, but this was considered related to the study IP exposure. No other cardiovascular or neurological TEAEs were reported by sexual partners during the double-blind dosing period.

[0866] Finally, although baseline laboratory and electrocardiogram results were not repeated at the end of the study, no TEAEs required these baseline screening assessments to be repeated.

[0867] Table 6: Participant positional vital signs data by medical visit and product allocation

[0868]

[0869] in conclusion

[0870] This study demonstrates that, during a double-blind treatment period, topical application of 3.6% sildenafil cream was safe and well-tolerated in healthy premenopausal women and their sexual partners in 1357 documented sexual exposures to the cream in a double-blind trial. In previous clinical trials of oral sildenafil citrate in women, the incidence of side effects was high at doses typically administered to men for the treatment of erectile dysfunction (25 mg–100 mg).

[0871] The most common side effects of oral sildenafil are headache, flushing, indigestion, visual disturbances, nasal congestion, back pain, muscle pain, nausea, dizziness, and rash.

[0872] The safety data presented in this study support the finding that side effects associated with topical application of 3.6% sildenafil cream are primarily related to local genital irritation. Post-hoc analysis revealed similar frequencies of TEAEs based on the quartiles of total reported sexual exposures during double-blind treatment, supporting the absence of cumulative toxicity from repeated exposures. Many users of 3.6% sildenafil cream used the product more than nine times per month, as described in the protocol, and these protocol violations did not increase TEAEs. Although sample size could not detect differences in TEAEs, using precise statistical methods, no significant difference was found in the types of TEAEs reported by participants using 3.6% sildenafil cream compared to placebo. This study also describes TEAEs among sexual partners, and these TEAEs were reported directly by the sexual partners, rather than by study participants on their behalf, a common occurrence in clinical trials of sexual intercourse products.

[0873] The advantages of this study include participants reporting TEAEs in detail via an eDiary with daily prompts, and, as described above, reporting TEAEs directly with their sexual partners. Due to the reluctance of some potential volunteers to have their sexual partners participate in the clinical study, a protocol modification was made to allow women without partners or whose partners do not wish to participate in the informed consent or safety monitoring process to enroll. In accordance with Good Clinical Practice (GCP) guidelines, participants whose sexual partners did not consent were instructed to have no sexual activity with a partner within 72 hours of IP administration. Given that TEAEs with sexual partners are uncommon and are generally mild to moderately severe, the potential benefits of topical sildenafil outweigh the risks to the user and their sexual partner.

[0874] Postural vital signs of sexual partners were monitored in clinics or via telemedicine, but could not be measured immediately after using IP. Data from the preliminary safety study in men discussed above support that changes in heart rate during standing may be a benign, normal, physiological response to standing. The extensive vital sign and TEAE data collected in this study indicate that local application of oral sildenafil citrate does not have systemic effects.

[0875] In summary, these data support the safety of topical sildenafil for users and exposed sexual partners. These data also support the clinical development of 3.6% sildenafil cream for the treatment of FSAD.

[0876] Example 3: Exit Interviews for Female Sexual Arousal Disorder - Additional Part of Phase 2B Study

[0877] To assess the patient-reported outcome measure (PROM) used to evaluate the efficacy of treatment for patients with FSAD, premenopausal and postmenopausal women aged 21–70 years with FSAD were interviewed to support the content of the PROM.

[0878] The results confirm that PROM met its purpose, evaluating concepts in FSAD and supporting tools for use as endpoints in clinical trials for FSAD patients. Exit interviews were conducted to better understand meaningful changes in indicators serving as primary or secondary endpoints. Furthermore, determining what patients were considering was crucial if they perceived improvement in the Patient General Impression of Change (PGI-C), improved severity by one or two categories in the Patient General Impression of Severity (PGI-S), or reported a meaningful benefit of the investigational drug in the Patient Benefit Evaluation (PBE).

[0879] At the end of the study (at the 7th visit), a subset of patients will undergo exit interviews.

[0880] Based on the perspective of FSAD patients, the overall goal of this study was to further evaluate:

[0881] • The components of meaningful changes for the following patient-reported outcome measures (PROM):

[0882] o SFQ-AS category,

[0883] o FSDS-DAO Project 14, and

[0884] o Awakening Diary AS Category

[0885] What was considered when answering "yes" or "no" to patient welfare assessment questions?

[0886] Research Design

[0887] This interview study will focus on collecting data from a subset of women participating in the Phase 2b FSAD clinical trial described in Example 2. This study is designed as a sub-study and will be an additional part of the main clinical trial protocol. Out-of-labor interviews will be conducted via video conference or telephone with each willing and eligible patient upon completion of the clinical trial. The interviews will focus on the composition of meaningful changes in PROM (SFQAS category, AS diary category, and FSDS-DAO item 14, PBE) of interest to the patients, as well as the composition of improvements in PGI-C and PGI-S.

[0888] Study population

[0889] A total of 60 adult women (age > 21 years) with FSAD will be recruited from the Phase 2b clinical trial of Example 2, which will recruit approximately 400 to 590 patients (300 to 400 to complete). Women selected for exit interviews will be those who first complete the study and agree to be part of this subset. The sample size is determined by the mixed requirement of different levels of improvement observed during the clinical trial.

[0890] Leaving the interview program

[0891] Given that the exit interview will take place within two weeks of the last clinical trial visit, the interviewer will determine: (a) whether any changes have occurred during the trial; and (b) whether any changes have occurred since the last visit (i.e., the interview date). This will help ensure that the focus of the interview discussion is the patient's experience during the trial, rather than how the patient has felt since the last visit (whether any symptoms have improved or worsened since the discontinuation of study treatment).

[0892] Part 1: Overall Experience with FSAD

[0893] Introduce and discuss the patient's life experiences with FSAD. The purpose of this section is to "warm up" the patient and make them feel relaxed, rather than to delve deeply into their experiences. Therefore, the questions in this section are brief, and the discussion should last about 10 minutes.

[0894] Part 2: Experiences with FSAD-related arousal or feeling problems

[0895] As the interviews continue, the questions will focus on sexual arousal and feelings, as well as the changes experienced during the trial (e.g., whether these changes have improved, remained the same, or worsened, and whether any of these changes are meaningful).

[0896] Patients will be asked whether larger / smaller score changes on each PROM tool response scale are meaningful, and what changes in symptoms or effects each level of score change reflects.

[0897] • The following items will be discussed: treatment on each response scale and changes in MCT over time on each response scale:

[0898] o SFQ28 AS category four (4) items

[0899] o FSDS-DAO Project 14

[0900] o Evoking the five (5) items in the diary AS category

[0901] o Single (1) PGI-S project

[0902] o Single (1) PGI-C project

[0903] o Single (1) PBE item (i.e., the patient's answer to the question "Have you received a meaningful benefit from the investigational drug?" is "yes / no")

[0904] This series of questions will last approximately 45 minutes.

[0905] Part Three: Patient Feedback on Topical Medications in Clinical Trials

[0906] • If time permits, the use of topical medications will be discussed, such as the application process, ease of use, texture, and whether the patient would recommend them to a friend. This discussion should take approximately 5 minutes.

[0907] Example 4: Assessing the relative importance of experience with disease-related symptoms and FSAD symptoms

[0908] Target

[0909] The aim of this study was to conduct in-depth qualitative interviews with premenopausal (n=20) and postmenopausal (n=15) women clinically diagnosed with FSAD (n=35) by trained sex medicine clinicians. The purpose of the interviews was to assess the experience of symptoms related to the condition and the relative importance of FSAD symptoms, including their severity, level of distress, and impact on participants' health-related quality of life.

[0910] method

[0911] Study population

[0912] This study recruited adult female participants aged 21–70 years with a clinical diagnosis of FSAD. Participants must be sexually active (within the past 4 weeks) and have previously experienced at least 2 years or more of “normal” sexual function. Participants meeting all inclusion and exclusion criteria underwent a formal, semi-structured clinical interview to confirm the DSM-IV-TR diagnosis of FSAD as a primary FSD complaint. The DSM-IV-TR classifies FSAD as acquired vs. lifelong, and generalized vs. situational, with symptoms present for at least 6 months prior to the clinical interview. Eligible participants complained of a lack of genital arousal during sexual activity, and this genital response had an adverse and distressing impact on their overall sexual experience.

[0913] recruit

[0914] Women were recruited through an internet-based screening questionnaire and clinically diagnosed with FSAD. Preliminary eligibility was assessed by telephone prior to the first visit. If a participant was deemed potentially eligible, informed consent was obtained and completed by site staff at the first visit to confirm the diagnosis (first visit). After consent was obtained, inclusion / exclusion criteria were confirmed, and a clinical interview was conducted to confirm the preliminary diagnosis of FSAD as defined by DSM-IV-TR. Women with secondary complaints of low libido or orgasmic problems due to lack of genital arousal (HSDD) or cognitive arousal symptoms (i.e., not feeling mentally aroused during sexual activity) were considered eligible, provided that the symptoms associated with decreased genital arousal were considered the most troubling and predated the low libido. If deemed eligible after the first visit, women were asked to return for a second visit (second visit) for an in-depth, qualitative, one-on-one, 90-minute interview.

[0915] Research interviews and medical visits

[0916] Semi-structured interview research, combining concept-based (CE) and cognitive questioning (CD), was identified as the most suitable approach to achieve the research objectives (only the CE portion of the interview is reported here). Semi-structured interviews allow for the exploration of participants' subjective thoughts, experiences, and details that structured interviews cannot. Furthermore, semi-structured interviews allow for the use of relevant probes when necessary to assess participants' responses to specific symptoms, facilitating discussions that would be impossible in unstructured interviews.

[0917] Concept-inspired interviews investigated the symptoms and impacts experienced by women with FSAD. Open-ended questions were used to encourage participants to spontaneously report their experiences. Where necessary, the interviewers employed more direct questioning to elicit further details from the participants. Below are examples of the types of questions asked:

[0918] • “Tell me about the typical arousal problems you have experienced.”

[0919] • “How long has this been going on?” “How serious is this problem?”

[0920] • "How would you feel if this problem happened?"

[0921] • "How does this question make you feel about intimacy with your partner?"

[0922] • "Think about the different types of things you mentioned. Can you rank them from least annoying to most annoying?"

[0923] This data collection approach is used to generate participant-driven insights and allows for bottom-up thematic analysis of the data.

[0924] analyze

[0925] All interviews were recorded and transcribed verbatim into Microsoft Word documents for analysis by a professional transcription company (Rev). Nvivo v12.0 is a qualitative software program designed to assist researchers in coding and analyzing qualitative data. This software allows researchers to apply codes to the text sections using topic analysis. Topic analysis allows four expert researchers coding the data to identify topics or patterns within the data. During the interviews, symptoms and effects were coded as “spontaneous (S)” or “prompting (P)” at the first point to assess which symptoms and effects were most frequently described by participants without interviewer prompting. A codebook was developed to assist coding, and then the four expert coders used this codebook to independently code the transcripts.

[0926] All key concepts appeared in the interview sample (a process known as “saturation analysis”). Researchers assessed whether concept saturation had been reached, as no new topics or conceptual descriptions were introduced in the last set of interviews. To determine this, transcripts from the premenopausal and postmenopausal cohorts were divided into three groups according to the order in which they were transcribed. The inspired concepts were then compared between the groups. The point at which no new concepts appeared was considered the point at which saturation had been reached.

[0927] result

[0928] Study population

[0929] A total of n=23 premenopausal women and n=13 postmenopausal women participated in this study. The majority of the n=23 premenopausal and n=13 postmenopausal women were white (60.9% / 69.2%; premenopausal / postmenopausal). Black / African American was the second highest race reported by six women, with a roughly equal proportion between the premenopausal and postmenopausal samples. Four women in the premenopausal group were identified as Hispanic / Latino. The overall mean age was 49 years, ranging from 23 to 69 years. Most participants (n=17) had a college education, with 10 also holding graduate degrees. Nearly half of the population (n=18) reported full-time employment as their employment status. The most frequently reported relationship status in both the premenopausal and postmenopausal samples was married (n=16), followed by “in a committed relationship with one person” (n=11). 94.4% of the women identified as heterosexual, while 5.6% identified as bisexual.

[0930] Interview results

[0931] sexual activity

[0932] At the start of the interviews, women were asked about the types of sexual activities they frequently engaged in. Women were asked to spontaneously describe and define these activities. Interviewers also followed up with a pre-defined list of activities, including intercourse, caressing, foreplay, masturbation, and oral sex. All premenopausal women reported engaging in intercourse, defined by n=9 participants using terms such as “penetration,” “penetration,” “penetrative sex,” or “penis-vaginal penetration.” Most premenopausal women also reported engaging in oral sex (n=18) and masturbation (n=15), with the latter almost entirely divided into spontaneous and probing responses. n=2 premenopausal participants spontaneously reported anal sex.

[0933] Almost all postmenopausal women reported engaging in sexual intercourse (n=11), defined by n=9 participants using terms such as “penetration,” “penetration,” “penis penetration,” or “penis-vaginal penetration.” Most postmenopausal women also reported engaging in oral sex (n=8) and masturbation (n=10). All postmenopausal participants who mentioned oral sex reported it spontaneously, but for masturbation, the proportion of spontaneous and questioned responses was nearly equal. n=3 postmenopausal participants reported anal sex, all spontaneously. In both the premenopausal and postmenopausal groups, caressing and foreplay were not reported as spontaneously as sexual intercourse, oral sex, and masturbation by many women.

[0934] Symptom frequency

[0935] After answering questions about sexual activity, women were asked, “What bodily / genital sensations or feelings are you experiencing right now?” to elicit spontaneous responses about the types of sexual symptoms caused by FSAD. Premenopausal women spontaneously mentioned ten symptoms, eight of which were bodily / genital arousal, two of which were related to a lack of cognitive arousal (“not feeling turned on” or “excited”) and low libido. Postmenopausal women spontaneously mentioned eight symptoms, seven of which were bodily / genital arousal, and one of which was related to low libido (Table 7).

[0936] The most frequently reported symptom in both the premenopausal (n=21; n=11 spontaneous, n=10 follow-up) and postmenopausal (n=13; n=7 spontaneous, n=6 follow-up) groups was "inability or difficulty in achieving orgasm".

[0937] Lack of lubrication or wetness was the second most frequently reported symptom in the premenopausal group (n=19; n=13 spontaneous, n=6 follow-up), followed by loss of sensation / feeling (n=17; n=13 spontaneous, n=6 follow-up). In the postmenopausal group, lack of lubrication or wetness and loss of sensation / feeling were the second most frequently reported symptoms (loss of lubrication / wetting n=12; n=7 spontaneous, n=5 follow-up; loss of sensation / feeling n=12; n=11 spontaneous, n=1 follow-up).

[0938] Although the inability or difficulty to achieve orgasm was the most reported symptom overall, more participants spontaneously reported lack of lubrication or wetness and loss of sensation / feeling in the premenopausal group (n=13 spontaneously reported) compared to those who agreed that they were unable or difficult to achieve orgasm, and in the postmenopausal group (n=11 spontaneously reported) loss of sensation / feeling.

[0939] Women also discussed some consequences of diminished bodily / genital arousal during sexual activity, namely low libido and cognitive arousal (“not feeling aroused”). Specifically, the effects of genital arousal symptoms on cognitive arousal and libido were discussed: Libido: Premenopausal women: n=12 (n=11 spontaneous, n=1 followed up); Postmenopausal women: n=7, all spontaneously reported; Cognitive arousal issues: Premenopausal women: n=12 (n=5 spontaneous, n=7 followed up); Postmenopausal women: n=4, all followed up. Since no postmenopausal participants reported “not feeling aroused” as a symptom, the concept of “not feeling aroused / excited” included in the premenopausal cohort was only listed as “not feeling aroused” in the postmenopausal cohort.

[0940] Table 7: Frequency of FSAD symptoms reported by participants in premenopausal and postmenopausal women

[0941]

[0942] *This concept is "not exciting" for postmenopausal women.

[0943] The most problematic symptoms

[0944] Participants in both the premenopausal and postmenopausal cohorts were asked to rank their FSAD symptoms from most bothersome to least bothersome to reveal the most problematic symptoms (Table 8). In the premenopausal group, the top three most frequently reported symptoms were lack of lubrication or wetness (n=17), followed by loss of sensation / feeling (n=12), and then inability to achieve orgasm (n=8). Six participants listed lack of lubrication as the most bothersome symptom, and five participants listed loss of sensation / feeling as the primary symptom. Following lack of lubrication and loss of sensation / feeling, difficulty or inability to achieve orgasm was listed as one of the top three symptoms by eight women. Seven and eight participants, respectively, reported lack of tingling sensation (n=6) and lack of arousal / excitement in the top three. In the postmenopausal group, the top three most frequently reported symptoms were loss of sensation / feeling (n=10), followed by lack of lubrication or wetness (n=9), then inability to achieve orgasm and lack of libido (both n=6). Only n=2 women listed lack of arousal as the most difficult symptom. Each woman provided a specific description of the loss of sensation, such as tingling and palpitations, and they all reported it as the third most troubling symptom.

[0945] Table 8: Most problematic FSAD symptoms reported by premenopausal and postmenopausal women

[0946]

[0947] *No participant reported pulsation as the most problematic symptom of FSAD.

[0948] Not all participants listed all three symptoms as their most problematic. Some listed / excluded only two. One woman in the postmenopausal group listed the same problem as her first and third.

[0949] ***A postmenopausal woman said that difficulty achieving orgasm and low libido are her biggest problems.

[0950] Because of the way premenopausal participants described "excitement" and "excitement," these two concepts were merged into one in that group. In the postmenopausal group, "not feeling excited" was not reported as a symptom; the concept was "not feeling aroused."

[0951] The most important symptoms that need treatment

[0952] After answering questions about their most bothersome symptoms, participants were asked which symptom would be most important to treat if products were available on the market. Consistent with the order of the most bothersome FSAD symptoms in Table 8, lack of lubrication and wetness were the most in-demand symptoms in the premenopausal group, ranking them in the top three by 17 women (Table 9). Twelve women reported loss of sensation / feeling, followed by difficulty or inability to achieve orgasm and lack of tingling (both n=7). These numbers, particularly for the two most important symptoms requiring treatment, match the women's ranking of their most bothersome problems. Overall, a total of 22 premenopausal women reported wanting treatment for at least one genital arousal problem, including loss of sensation / feeling (n=12), lack of tingling (n=7), and loss of fullness / filling (n=1). This is more than the number of participants who reported lack of lubrication or wetness as the most important FSAD symptom requiring treatment (n=17).

[0953] In the postmenopausal group, loss of sensation / feeling and lack of lubrication / lubrication were considered the two most in need of treatment (n=9) (Table 9). This was followed by difficulty or inability to achieve orgasm (n=7), and then low libido (i.e., lack of interest in sexual activity) (n=5). Two women listed the lack of arousal (cognitive arousal) during sexual activity as the most important symptom requiring treatment, while one woman reported specific sensory problems of lack of pulsation and lack of warmth, respectively. Although the ranking of the most problematic symptoms (Table 8) and the most in need of treatment differed slightly (i.e., difficulty / inability to achieve orgasm was listed as the most problematic and the third most in need of treatment), the results for these two issues indicate a consistency between the troubling FSAD symptoms in postmenopausal women and the symptoms they most desired to treat. Overall, a total of 11 women reported a desire for treatment for at least one genital arousal sensation problem, including loss of sensation / feeling (n=9), lack of tingling (n=1), and lack of pulsation (n=1). This is more than the number of participants (n=9) who reported that lack of lubrication or moisture was the most important FSAD symptom requiring treatment.

[0954] Table 9: FSAD symptoms most desired for treatment by premenopausal and postmenopausal participants

[0955]

[0956] *No participant reported that pulsation was the most important symptom requiring treatment for FSAD.

[0957] One premenopausal participant listed two symptoms: warmth and tingling, both of which were the second most important symptoms requiring treatment.

[0958] ***One postmenopausal participant listed two symptoms as most important and requiring treatment: low orgasm and low libido.

[0959] Not all participants listed all three symptoms as the most important symptoms requiring treatment. Some only listed / excluded two.

[0960] Because of the way premenopausal participants described "excitement" and "excitement," these two concepts were merged into one in that group. In the postmenopausal group, "not feeling excited" was not reported as a symptom; the concept was "not feeling aroused."

[0961] Frequency of FSAD effects

[0962] In describing their experiences with FSAD, participants also discussed the impact of the disorder on their lives. All effects reported in both the premenopausal and postmenopausal cohorts were spontaneously reported by participants. Participants generally described the impact of FSAD on their HRQoL and, in some cases, described its relationship to specific symptoms they experienced. The effects reported by women were categorized into five main themes: 1) psychological problems, 2) mood problems, 3) relationship problems, 4) cognitive problems, and 5) physical problems. The most frequently reported effects in both cohorts were those related to psychological, mood, and relationship problems.

[0963] Decreased confidence was the most reported effect, reported by almost all premenopausal (n=21) and postmenopausal (n=12) women. Participants' descriptions of decreased confidence included feelings of unease, low self-esteem, inadequacy, insecurity, “abnormal”, sadness about themselves and themselves, lack of attractiveness, feeling like a loser, being ignored, and discussions of “not being a woman”.

[0964] In the premenopausal group, the next two most reported effects were related to relationship problems: the impact of FSAD on their partners (n=18) and the difficulties it caused in the relationship (n=16) (Table 10). Participants described the emotional impact of FSAD on their partners, including feelings of sadness, disappointment, and distress. Furthermore, participants noted that FSAD might lead their partners to question themselves, their sexual performance, and the overall relationship. Following these effects, the next two most frequently discussed issues were mood problems of frustration and depression, both reported by n=15 women. More than half of the women in this cohort reported experiencing anxiety as an effect of FSAD (n=12). Nearly half of the women in this cohort (n=10) also described anger.

[0965] In the postmenopausal group, the next two most reported effects were related to mood problems, namely feeling depressed and disappointed (n=10 each) (Table 10). Women also reported feeling “disheartened” and “discouraged.” The next most frequently reported effects were mood problems, including depression and relationship problems such as difficulties and changes in the relationship, and a lack of interest in sex, each with n=9. Eight postmenopausal women reported feeling “older” because of their FSAD issues. Women (n=7) described feeling sad for their partners, the impact of FSAD on their partners, an inability to connect with their partners, and feeling angry. Participants’ descriptions of the impact of FSAD on their partners included feelings of sadness, disappointment, annoyance, and a general feeling of loss. In addition, n=7 women indicated that it was difficult to approach or connect with their partners due to a lack of sexual intimacy.

[0966] Table 10: Frequency of FSAD effects reported by participants in premenopausal and postmenopausal women

[0967]

[0968]

[0969] When women were asked to choose between the words “troubled,” “worried,” “frustrated,” and “painful,” they were asked to describe their feelings about FSAD using their preferred terminology. The majority of premenopausal (n=19) and postmenopausal (n=7) women chose “frustrated.” Two premenopausal women chose “worried,” two chose “painful,” and none chose “troubled.” Four postmenopausal women chose “painful,” two chose “troubled,” and none chose “worried.” Descriptions of the similarities and differences between these words suggest that women perceived them as interconnected and sequential in intensity, with trouble being the least intense, followed by worry, then frustration, and finally pain.

[0970] Saturation analysis

[0971] For the premenopausal cohort, saturation analysis based on reported FSAD symptom concepts revealed that only one concept, "pulsation," was introduced in the last set of interviews. All other concepts were introduced in the first set of interviews, and all except pulsation were mentioned in all three sets of interviews. Although pulsation was not mentioned until the last set of interviews, only one participant in this cohort mentioned it as a symptom. Therefore, further interviews were not recommended. Saturation analysis also showed that no participants spontaneously reported "not feeling excited," but based on the descriptions given by the participants, this concept seemed similar to "not feeling aroused." Saturation was considered to be satisfied in the sample of all concepts.

[0972] For the postmenopausal cohort, saturation analysis based on reported FSAD symptom concepts indicated that no concepts were introduced in the last set of interviews. In all three sets of interviews, participants spontaneously mentioned four concepts: lack of lubrication / wetting, loss of sensation / feeling, difficulty or inability to achieve orgasm, and low libido. Lack of warmth was not mentioned in the first set of interviews but appeared in the second and third sets. All other concepts, except for discomfort discussed only by participants in the second set of interviews, were introduced in the first set of interviews. Based on these data, saturation was considered reached. Therefore, since no new concepts emerged in the third set of interviews, additional interviews were not recommended for this sample.

[0973] In the interviews, women described a variety of symptoms they experienced related to FSAD. Premenopausal women described ten symptoms, all of which were spontaneously described. Eight of these were physical / genital arousal symptoms, and two were related to cognitive arousal / desire. Postmenopausal women described eleven symptoms, eight of which were spontaneously described. Nine of these were physical / genital arousal symptoms, and two were related to cognitive arousal / desire. Compared to premenopausal women, no postmenopausal women spontaneously recognized throbbing, palpitations, or feelings of excitement or arousal. The most common symptom in both the premenopausal (n=21) and postmenopausal (n=13) cohorts was "inability or difficulty achieving orgasm." Given that the lack of healthy genital arousal responses (e.g., the ability to feel sensation, becoming wet / lubricated) in this group is a necessary component of the pre-orgasmic sexual response cycle, the high number of reports of inability or difficulty achieving orgasm is perhaps not surprising. Many women in both groups reported that their orgasmic problems were particularly due to a lack of genital arousal, suggesting that orgasmic dysfunction is a secondary effect of FSAD.

[0974] The most and second most troubling symptoms for premenopausal and postmenopausal women reversed between the two groups: premenopausal women reported lubrication and wetness as the most problematic symptom (n=17), while postmenopausal women reported loss of sensation / feeling (n=10). The second most problematic symptom for premenopausal women was loss of sensation / feeling (n=12), while the second most problematic symptom for postmenopausal women was lubrication and wetness (n=9). Orgasm was the third most problematic symptom in both groups (n=8 for premenopausal women; n=6 for postmenopausal women). The symptom women most desired to treat was lubrication for premenopausal women, while for postmenopausal women it was the association between lack of lubrication or wetness and loss of sensation / feeling (both n=9). Despite the availability of over-the-counter (OTC) lubricants (and reports from postmenopausal women of needing to use lubricants for sexual comfort), both groups of women expressed interest in treatment for FSAD with lack of lubrication. This suggests that OTC lubricants do not meet the needs of women with FSAD, who reported wanting treatment options to help them produce lubrication.

[0975] Although “loss of sensation / feeling” is the second most troubling symptom and the second most treatable symptom in premenopausal women, and postmenopausal women also require treatment along with lubrication and moisture, both groups of women in this sample used a variety of terms to describe the loss of genital sensation / feeling [e.g., lack of warmth, lack of tingling, lack of pulsation, lack of throbbing, lack of heat, loss of fullness (clitoral and nipple), absence of genital sensation or feeling, “numbness,” a feeling of “genital death,” “lack of genital blood flow or arousal,” and reduced skin sensitivity (including nipples and other parts of the body)]. These descriptions from both groups of women suggest a strong overlap between specific descriptive terms for genital arousal and the broader term “loss of sensation / feeling.” Furthermore, 21 out of 23 premenopausal women and all (n=13) postmenopausal women reported a lack of genital sensation or feeling, indicating that “feeling” is the most relevant and important concept for women with FSAD.

[0976] Postmenopausal women reported additional physical / genital arousal symptoms not present in the premenopausal sample: discomfort. In this study, researchers carefully separated discussions of pain and discomfort as side effects of lack of lubrication and moisture from those discussed as irrelevant items. Therefore, “discomfort” described in the postmenopausal sample included cases described by women as unrelated to lack of lubrication and moisture, including descriptions of “pain and muscle spasms” and “uncomfortable vaginal tightness.” Furthermore, no postmenopausal women reported “lack of arousal,” and the only postmenopausal woman who reported “lack of arousal” also confirmed this upon follow-up questioning by the interviewer.

[0977] Women in both the premenopausal and postmenopausal cohorts also described various ways in which FSAD affected their HRQoL. The most common effect in both groups was decreased confidence. In the premenopausal group, the second largest reported effect was the impact of FSAD on female partners and the difficulties it caused in relationships. In the postmenopausal group, this was followed by feelings of frustration, disappointment, and depression, and the difficulties they experienced in their relationships. Premenopausal women also described several emotional effects, with frustration and depression being the most frequently reported. Anxiety and anger were also frequently reported in this population. Postmenopausal women also described feeling angry and sad towards their partners.

[0978] In both premenopausal and postmenopausal samples, “depression” was spontaneously offered as the term that best described their feelings about FSAD (n=5 and n=7, respectively). When given a choice among four words (distress, worry, depression, anguish), both groups of women again chose depression (n=19 and n=7, respectively). Data from both cohorts suggest that participants perceived these words as a continuum, with distress and worry at one end and depression and anguish at the other. Anguish was perceived as more “extreme” or “intense” among these words. Postmenopausal women were more willing to acknowledge or use the word “anguish” than premenopausal women. This was often related to the feeling that depression had persisted for some time, at which point they felt hopeless or as if nothing would ever change, and therefore felt anguish about the situation.

[0979] One finding of this study was that women in both cohorts consistently differentiated symptoms of reduced arousal unrelated to desire (i.e., they had desire but were unable to translate it into a desired genital arousal response). The emphasis on the lack of genital sensation and orgasmic dysfunction, along with the distressed reports of these issues, underscores the importance of maintaining arousal as a distinct category. This challenges the DSM-5's combination of FSAD and HSDD into FSIAD, particularly considering the reasons why women were unable to distinguish between desire and arousal. In this study, women mentioned both desire and arousal problems, but were able to differentiate between the two. Combining desire and arousal into a single diagnostic entity could potentially exclude women from treatment for these conditions previously meeting the criteria for FSAD or HSDD. The symptoms reported in this study support the view that desire and arousal do not represent the same underlying structure, and therefore the different criteria outlined in DSM-IV are more suitable for diagnosing these conditions. This aligns with the ISSWSH nomenclature, which describes and defines the separate conditions HSDD and FSAD, and differentiates and defines cognitive and genital arousal disorders. The ISSWSH nomenclature is intended for use by interdisciplinary clinicians caring for women with fetal dysplasia (FSD).

[0980] The study results showed no significant difference in how premenopausal and postmenopausal women experienced FSAD. Not only did both groups report similar symptoms, but they also used similar language despite the wide age range.

[0981] in conclusion

[0982] Analysis of qualitative data from the interviews revealed the physical and emotional burdens of FSAD. Results from premenopausal and postmenopausal cohorts indicated that FSAD was present similarly in both populations.

[0983] Example 5: Topline data from the Phase 2b exploratory study

[0984] The topline results of the study outlined in Example 2 showed that patients treated with sildenafil cream exhibited meaningful improvements in the co-primary endpoint assessment of changes in the arousal category of the Sexual Function Questionnaire compared to baseline. Patients treated with sildenafil cream also showed improvements in secondary endpoints and pre-specified exploratory endpoints, which assessed sexual satisfaction, arousal lubrication, and orgasm and pleasure. These data support the continued development of sildenafil cream and the selection of proposed primary endpoint assessments for a Phase 3 study.

[0985] This exploratory study aims to test the sensitivity of several patient-reported outcomes (PROs) and their ability to determine the therapeutic effect of sildenafil cream compared to placebo, providing information for the continued development of sildenafil cream. This study also serves as a validation study for exploratory endpoints that may be candidate endpoints for a Phase 3 study of sildenafil cream. Since there are currently no FDA-approved treatments for FSAD, there are no previously validated efficacy endpoints in pivotal Phase 3 studies of potential treatments for FSAD.

[0986] FSAD (Female Sexual Dysfunction Affect) refers to the inability to achieve or maintain a sufficient physical response to sexual stimulation. Among various types of female sexual dysfunction, FSAD most closely resembles erectile dysfunction (ED) in men. Sildenafil is a phosphodiesterase-5 (PDE-5) inhibitor and is currently the most widely used... The brand markets the active ingredient in oral tablets used to treat erectile dysfunction (ED) in men. Sildenafil cream is an investigational, proprietary topical cream formulation of sildenafil specifically designed to increase blood flow to female genital tissues. If successful, sildenafil cream has the potential to become the first FDA-approved treatment for FSAD. Market research indicates that 16% of women aged 21 to 60 in the United States, or approximately 10 million women, suffer from symptoms associated with FSAD, including lack of or low sexual arousal, and are actively seeking solutions to improve their condition. In contrast, the prevalence of complete erectile dysfunction (ED) in men is estimated at approximately 5% at age 40, increasing to approximately 15% at age 70.

[0987] FSAD differs from female hypoactive sexual desire disorder (HSDD), the latter being characterized by a lack of sexual desire. FSAD is a condition primarily characterized by a persistent or recurrent inability to achieve or maintain adequate genital arousal (sufficient lubrication and swelling response) during sexual activity, often leading to distress or interpersonal difficulties. Like erectile dysfunction (ED) in men, FSAD is associated with insufficient blood flow to the genitals.

[0988] 3.6% sildenafil cream is an investigational proprietary sildenafil cream formulation, a PDE-5 inhibitor, designed for topical application to the vulva-vaginal tissue to increase genital blood flow and improve female genital arousal, while avoiding the systemic side effects observed with oral sildenafil formulations. Sildenafil cream has previously been evaluated in Phase 1 and Phase 2a clinical studies. In a Phase 1 clinical study of 20 healthy postmenopausal women, topical sildenafil cream was safe and well-tolerated at clinically relevant doses, and participants reported favorable product characteristics: easy to use and readily absorbed. In a Phase 2a study of women with FSAD (15 premenopausal and 16 postmenopausal), sildenafil cream increased measurable blood flow to genital tissues compared to placebo cream. In addition, data from a thermal imaging study of six healthy women showed that the increase in genital temperature after application of sildenafil cream was significantly greater than that of placebo cream, indicating a positive effect on genital blood flow during the 30-minute test period and a statistically significant difference from placebo in the first 15 minutes after administration.

[0989] The exploratory Phase 2b RESPOND study was a multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of sildenafil cream in premenopausal women with FSAD (see Example 2). This first-in-class Phase 2b clinical trial included a PRO tool for screening eligible women with FSAD and included two co-primary endpoints, one secondary endpoint, and several exploratory endpoints to measure improvements in local genital arousal, reduction in distress experienced by women with FSAD, and a reduction in satisfactory sexual events, among others. There are no FDA-approved treatments for FSAD, therefore there are no efficacy endpoints from previously approved Phase 3 pivotal studies for potential treatments for FSAD.

[0990] The FDA requires thorough validation of any PRO used to evaluate the efficacy of a Phase 3 study. Part of this validation includes exit interviews conducted as part of the Phase 2b RESPOND study to better qualitatively understand the composition of meaningful changes in participants (see Example 3). These qualitative assessments of meaningful changes are used to determine which endpoints in the sildenafil cream group achieved meaningful improvement.

[0991] Research Review

[0992] The Phase 2b RESPOND study began with 99 participants in the sildenafil cream intention-to-treat population and 93 participants in the placebo intention-to-treat population. Of these, 70 participants in the sildenafil cream intention-to-treat population and 60 participants in the placebo intention-to-treat population completed the study, thus limiting the ability to assess statistical significance. During the study, participants used both sildenafil cream and placebo cream at home and recorded their experience using the PRO tool. This study evaluated the dosing of sildenafil cream versus placebo cream 12 weeks after the non-drug and placebo induction periods.

[0993] Study efficacy and safety

[0994] Top line data summary

[0995] A co-primary endpoint of the Phase 2b RESPOND study was the assessment of the efficacy of sildenafil cream compared to placebo, measured from baseline to the end of the study using the 28-item Sexual Function Questionnaire (SFQ28). The endpoint did not reach statistical significance. However, the changes in the sildenafil cream treatment group at the end of the study were consistent with the meaningful improvements reported by women in their exit interviews after the study.

[0996] Another co-primary endpoint assessed the efficacy of sildenafil cream compared to placebo by the change in perceived anxiety about sexual arousal difficulties from baseline to the end of the study. This change was evaluated using the previously validated Women's Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) survey. This evaluation did not differentiate between sildenafil cream and placebo.

[0997] The secondary endpoint of this study was to assess the efficacy of sildenafil cream compared to placebo by measuring the change in the number of satisfactory sexual events from baseline to the end of the study, based on participants' responses to questions answered and recorded via an electronic diary within 24 hours after each sexual event. This endpoint was chosen because it could serve as the primary endpoint for a phase 3 study based on the FDA's 2016 draft guidance document on female sexual dysfunction. When measured at weeks 4 and 8 after randomization, participants treated with sildenafil cream had a higher proportion of satisfactory sexual events in the first month compared to those treated with placebo (68.6% and 74.1% at weeks 4 and 8, respectively) (p = 0.04 at week 4).

[0998] Exploratory endpoints (selected based on content validity studies, see Examples 1 and 4) included endpoints related to genital arousal, genital blood flow, lubrication, orgasm, concerns about difficulty in sexual arousal, and other evaluation-related endpoints, including questions about satisfactory sexual events. Exploratory endpoints were evaluated at multiple times throughout the study using electronic diaries.

[0999] • The exploratory endpoint of concern about sexual arousal difficulties distinguished sildenafil cream from placebo. Specifically, women treated with sildenafil cream were more likely to report an overall improvement when asked about their overall impression of their concern about sexual arousal difficulties. Based on responses to the questions at weeks 4, 8, and 12 after randomization, 44% to 49% of subjects treated with sildenafil cream reported an overall improvement compared to 37% to 44% of subjects treated with placebo (P < 0.01).

[1000] • Exploratory endpoints related to arousal, lubrication, and the achievement of orgasm and pleasure also showed significant differences between subjects treated with sildenafil cream and those treated with placebo, as measured by changes from baseline to week 8 post-randomization markers, with P = 0.059 and P = 0.066, respectively (for these assessments, although the number of subjects in each group was small, n = 73 in the sildenafil cream intention-to-treat group and n = 64 in the placebo intention-to-treat group, the trend was significant).

[1001] • 48.7% of participants who received sildenafil cream reported improved overall satisfaction with sexual activity at the end of the study, compared to 42.6% of participants who received placebo.

[1002] Table 11 lists some data regarding the common primary endpoint, secondary endpoints, and certain exploratory endpoints. The Phase 2b RESPOND exploratory study was inadequate in assessing statistical significance, although statistical significance was achieved in some assessments.

[1003] Table 11: Summary of Referenced Top Line Data

[1004]

[1005] (1) The numbers in this column represent the number of subjects included in the evaluation at the specified time point.

[1006] (2) The exploratory endpoint was measured periodically from week 4 after randomiz...

Claims

1. A method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject.

2. The method of claim 1, wherein treating FSAD includes increasing satisfactory sexual events, improving arousal sensation, increasing arousal lubrication, increasing orgasm, reducing anxiety about sexual arousal, reducing pain or discomfort during sexual activity, reducing pain or discomfort after sexual activity, and / or increasing satisfaction with sexual activity.

3. The method of claim 2, wherein treating FSAD includes increasing satisfactory sexual events.

4. The method of claim 2, wherein treating FSAD includes improving arousal sensation.

5. The method of claim 2, wherein treating FSAD includes increasing arousal lubrication.

6. The method of claim 2, wherein treating FSAD includes increasing sexual orgasm.

7. The method of claim 2, wherein treating FSAD includes reducing concerns about sexual arousal.

8. The method of claim 2, wherein treating FSAD includes reducing pain or discomfort during sexual activity.

9. The method of claim 2, wherein treating FSAD includes reducing pain or discomfort after sexual activity.

10. The method of claim 2, wherein treating FSAD includes increasing satisfaction with sexual activity.

11. The method according to any one of claims 1-10, wherein treating FSAD includes increasing sensation in the genital area.

12. The method of claim 11, wherein the sensation at the genital site includes one or more of the following: tingling, pleasure, warmth, throbbing, palpitation, congestion, or fullness in the genital area.

13. A method for increasing the satisfaction of a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

14. A method for improving arousal in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

15. A method for increasing arousal lubrication in a female subject during sexual activity, comprising applying a topical composition comprising a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the female subject.

16. A method for increasing orgasm in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

17. A method for reducing anxiety about sexual arousal or increasing satisfaction with sexual activity in female subjects, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

18. A method for relieving pain or discomfort in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

19. A method for relieving pain or discomfort in a female subject after sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

20. A method for treating female sexual dysfunction (FSD) or its symptoms, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject.

21. A method for increasing libido in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

22. A method for increasing the response of a female subject to physical or psychological stimuli, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

23. The method of claim 22, wherein the response to physical stimulation is enhanced.

24. The method of claim 22, wherein the response to psychological stimuli is enhanced.

25. The method of claim 22, wherein the response to physical and psychological stimuli is enhanced.

26. The method according to any one of claims 1-25, wherein the type 5 phosphodiesterase inhibitor and / or its salt are administered at least twice within a time period.

27. The method of claim 26, wherein the time period is from about 1 week to about 8 weeks.

28. The method according to claim 26 or 27, wherein one or more symptoms improve within about 1 week to about 8 weeks after the initial application.

29. The method of claim 28, wherein one or more symptoms improve within about one to four weeks after the initial application.

30. The method according to claim 28 or 29, wherein one or more symptoms include arousal of lubrication.

31. The method according to claim 28 or 29, wherein one or more of the symptoms include libido.

32. The method of claim 28 or 29, wherein one or more symptoms include achieving orgasm and / or experiencing orgasm.

33. The method according to any one of claims 1-32, wherein the type 5 phosphodiesterase inhibitor is sildenafil, avanafil, lodenavir, mironafil, tadalafil, vardenafil, udenafil, sulphenafil, or thiomethylsildenafil.

34. The method of claim 32, wherein the type 5 phosphodiesterase inhibitor is sildenafil.

35. The method according to any one of claims 1-34, wherein the local composition further comprises: a. Stable polymers; b. Propylene glycol; c. Polysorbate surfactant; dL-arginine or L-arginine salt; and e. Ionic salts.

36. The method according to any one of claims 1-35, wherein the composition is a cream, gel, or lotion.

37. The method according to claim 34 or 35, wherein the composition comprises an L-arginine salt.

38. The method according to any one of claims 34-37, wherein the composition comprises L-arginine hydrochloride.

39. The method according to any one of claims 34-38, wherein the L-arginine or L-arginine salt is present at a concentration of at least about 5% by weight of the composition.

40. The method according to any one of claims 34-39, wherein the ionic salt is capable of driving the type 5 phosphodiesterase inhibitor and / or its salt through the stratum corneum of the subject.

41. The method of claim 40, wherein the ionic salt is present at a concentration of at least about 5% by weight of the composition.

42. The method according to any one of claims 34-41, wherein the ionic salt comprises potassium chloride.

43. The method according to any one of claims 34-42, wherein the stable polymer comprises xanthan gum.

44. The method according to any one of claims 34-43, wherein the stable polymer is present at a concentration of at least about 0.8% by weight of the composition.

45. The method according to any one of claims 34-44, wherein the propylene glycol is present at a concentration of at least about 8% by weight of the composition.

46. ​​The method according to any one of claims 34-45, wherein the polysorbate surfactant comprises polysorbate 20.

47. The method according to any one of claims 34-46, wherein the polysorbate surfactant is present at a concentration of at least about 2% by weight of the composition.

48. The method according to any one of claims 1-47, wherein the type 5 phosphodiesterase inhibitor is sildenafil.

49. The method according to any one of claims 1-48, wherein the type 5 phosphodiesterase inhibitor and / or its salt are present at a concentration of about 1% by weight to about 10% by weight of the composition.

50. The method according to any one of claims 1-49, wherein the composition comprises glyceryl stearate, hexadecyl alcohol, squalane, isopropyl myristate, oleic acid, trisodium citrate dihydrate, sodium benzoate and / or gluconolactone.

51. The method according to any one of claims 1-50, wherein purified water is present at a concentration of at least about 40% by weight of the composition.

52. The method according to any one of claims 1-51, wherein the subject is a human.

53. The method according to any one of the preceding claims, wherein the composition comprises primarily the following: a. Purified water; b. Potassium chloride; c. L-arginine hydrochloride; d. Glyceryl stearate; e. hexadecyl alcohol; f. Squalane; g. Xanthan gum; h. Isopropyl myristate; i. Oleic acid; j. Propylene glycol; k. Polysorbate 20; and 1. Sildenafil citrate.

54. The method according to any one of the preceding claims, wherein the composition comprises each of the following compounds at a concentration not exceeding ±20% of the stated concentration: a. Purified water with a concentration of about 35% to about 55% by weight; b. Potassium chloride with a concentration of about 2.5% to about 15% by weight; c. L-arginine hydrochloride at a concentration of about 2.5% to about 15% by weight; d. Glyceryl stearate at a concentration of about 4% to about 10% by weight; e. Hexadecyl alcohol at a concentration of about 4% to about 10% by weight; f. Squalane at a concentration of about 1% to about 8% by weight; g. Xanthan gum at a concentration of about 0.1% to about 5% by weight; h. Isopropyl myristate at a concentration of about 0.1% to about 5% by weight; i. Oleic acid with a concentration of about 0.1% to about 5% by weight; j. Propylene glycol at a concentration of about 1% to about 10% by weight; k. Polysorbate 20 at a concentration of about 0.2% to about 5% by weight; and l. Sildenafil citrate at a concentration of about 1% to about 10% by weight.

55. The method according to any one of claims 1-54, wherein the subject suffers from female sexual arousal disorder (FSAD).

56. The method according to any one of claims 1-55, wherein the subject is at risk of having female sexual arousal disorder (FSAD).

57. The method according to any one of claims 1-56, wherein the composition comprises: a. Purified water with a concentration of approximately 40% by weight; b. Potassium chloride with a concentration of approximately 5% by weight; c. L-arginine hydrochloride at a concentration of approximately 7.5% by weight; d. Glyceryl stearate at a concentration of approximately 7% by weight; e. A concentration of approximately 7% by weight of hexadecaneol; f. Squalane at a concentration of approximately 4% by weight; g. Xanthan gum with a concentration of approximately 0.8% by weight; h. Isopropyl myristate at a concentration of approximately 1% by weight; i. Oleic acid at a concentration of approximately 1% by weight; j. Propylene glycol at a concentration of approximately 8.5% by weight; k. Polysorbate 20 at a concentration of approximately 2% by weight; l. A concentration of approximately 10% by weight of trisodium citrate dihydrate; m. Sodium benzoate with a concentration of approximately 0.2% by weight; n. Gluconolactone at a concentration of about 0.25% by weight; and o. Sildenafil citrate at a concentration of approximately 5% by weight.

58. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. Select female subjects exhibiting one or more symptoms of FSAD, and b. Applying a composition to the genital area of ​​a subject, the composition comprising a type 5 phosphodiesterase inhibitor and / or its salt, a stable polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and its ion salt.

59. The method of claim 58, wherein the one or more symptoms are selected from decreased genital sensitivity, lack of genital response during sexual activity, reduced genital arousal, pain and / or discomfort during sexual activity, pain and / or discomfort after sexual activity and / or distress caused by difficulty in sexual arousal.

60. The method according to any one of claims 1-59, wherein about 50% of the composition is applied externally to the vulva and about 50% of the composition is applied internally to the vagina.

61. The method of claim 60, wherein applying about 50% of the composition externally comprises: a. Apply the composition to the anterior commissure, clitoral prepuce, glans clitoris, and frenulum; b. Apply the composition to the vaginal vestibule; and c. Apply the composition to the labia minora.

62. The method according to claim 60 or 61, wherein the composition is not applied to the labia majora or pubic hair.

63. The method according to any one of claims 60-62, wherein intravaginal application of about 50% of the composition comprises applying the composition to the anterior distal end of the vagina at a depth of about 0 cm to about 3 cm within the vagina.

64. The method according to any one of claims 1-63, wherein the composition is applied about 10 to about 20 minutes before sexual activity.

65. The method according to any one of claims 1-64, wherein the composition is administered in up to about 9 doses over about 4 weeks.

66. The method according to any one of claims 1-65, wherein the composition is administered at least about 24 hours before the second agent of the composition.

67. The method according to any one of claims 1-66, wherein the subject has not been given at least one of guanylate cyclase stimulants, clonidine, CYP3A4 inhibitors, nitric oxide donors, organic nitrates, organic nitrites or α-receptor blockers within 28 days prior to administration of the first dose of the composition.

68. The method according to any one of claims 1-67, wherein the subject avoids wiping or washing away any of the genital areas where the composition has been applied.

69. The method according to any one of claims 1-68, wherein any remaining composition is washed off after the sexual activity has ended.

70. The method according to any one of claims 1-69, wherein sexual arousal is increased.

71. The method according to any one of claims 1-70, wherein sexual arousal is increased.

72. The method according to any one of claims 1-71, wherein the application results in a satisfactory sexual event.

73. The method according to any one of claims 1-72, wherein the application results in an increase in genital arousal.

74. The method according to any one of claims 1-73, wherein the application results in increased lubrication of the genital area during sexual activity.

75. The method according to any one of claims 1-74, wherein cognitive arousal is increased.

76. The method according to any one of claims 1-75, wherein sexual desire is increased.

77. The method according to any one of claims 1-76, wherein the application results in an increase in orgasm during sexual activity.

78. The method according to any one of claims 1-77, wherein the application reduces the difficulty or inability to achieve orgasm during sexual activity.

79. The method according to any one of claims 1-78, wherein the application results in an increase in sensation or feeling in the genital area during sexual activity.

80. The method according to any one of claims 1-79, wherein the application results in an increased tingling sensation in the genital area during sexual activity.

81. The method according to any one of claims 1-80, wherein the application results in increased blood flow to the genital area during sexual activity.

82. The method according to any one of claims 1-81, wherein the application results in increased warmth, throbbing, or pulsation in the genital area during sexual activity.

83. The method according to any one of claims 1-82, wherein the application results in a reduction of pain and / or discomfort during sexual activity.

84. The method according to any one of claims 1-83, wherein the administration results in a reduction of pain and / or discomfort after sexual activity.

85. The method according to any one of claims 1-84, wherein sexual arousal is increased.

86. The method according to any one of claims 58-85, wherein one or more symptoms include a diminished response to physical stimuli.

87. The method according to any one of claims 58-85, wherein the primary complaint of the female subject is a diminished response to bodily sexual stimulation.

88. The method according to any one of claims 1-87, wherein the subject exhibits one or more of the following after administration: a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28); b. SFQ28 score improvement of at least 1 point in the lubrication category; c. Improvement of at least 1.5 points in the SFQ28 arousal category score; d. Improve your SFQ28 score in the Desire category by at least 2 points; The e.SFQ28 score for orgasm improved by at least 1.20 points; f. The SFQ28 pain category score improved by at least 1 point; g. Improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score; h. Arousal score improved by at least 1.45 points; i. Genital arousal score improved by at least 1.13 points; j. The score for genital arousal anxiety improved by at least 1.49 points; k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

89. The method according to any one of claims 1-88, wherein the subject includes a preliminary diagnosis of FSAD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revised Edition (DSM-IV-TR).

90. The method according to any one of claims 1-89, wherein the topical composition comprising a type 5 phosphodiesterase inhibitor and / or its salt does not cause one or more of the following: orthostatic hypotension, headache, flushing, indigestion, dizziness, visual disturbances, nasal congestion, back pain, myalgia, nausea, vertigo, and rash.

91. The method according to any one of claims 1-90, wherein the primary complaint of the subject is FSAD.

92. The method according to any one of claims 1-91, wherein the primary complaint of the subject is FSAD, and wherein the subject exhibits secondary HSDD symptoms.

93. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. Female subjects with primary FSAD as their chief complaint were selected, and b. Apply a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject.

94. The method of claim 93, wherein the subject exhibits secondary HSDD symptoms.

95. A method for determining the efficacy of FSAD treatment, comprising: a. Obtain baseline scores for one or more of the following: Sexual Function Questionnaire (SFQ28) scores in the arousal cognition category, SFQ28 scores in the arousal lubrication category, SFQ28 scores in the arousal sensation category, SFQ28 scores in the desire category, SFQ28 scores in the orgasm category, SFQ28 scores in the pain category, Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) scores, arousal sensation scores, genital arousal scores, genital arousal anxiety, percentage of arousal diary item 12-SSE, and number of arousal diary item 12-SSE. b. Administer the FSAD treatment to female subjects; and c. Identify the improvement in one or more scores from step a.

96. The method of claim 95, wherein one or more of the following indicate that the FSAD treatment is effective: a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28); b. SFQ28 score improvement of at least 1 point in the lubrication category; c. Improvement of at least 1.5 points in the SFQ28 arousal category score; d. Improve your SFQ28 score in the Desire category by at least 2 points; The e.SFQ28 score for orgasm improved by at least 1.20 points; f. The SFQ28 pain category score improved by at least 1 point; g. Improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score; h. Arousal of feelings improved by at least 1.45 points; i. Improvement in genital arousal by at least 1.13 points; j. Genital arousal anxiety improved by at least 1.49 points; k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

97. The method of claim 95 or 96, further comprising administering one or more additional doses of the topical composition to the subject.

98. The method according to any one of claims 1-97, wherein the primary complaint of the subject is FSAD, and wherein the subject does not exhibit symptoms of female orgasmic disorder (FOD).

Images