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

Abstract

The present disclosure generally relates to compositions and techniques for the treatment of female sexual dysfunction (FSD), including female sexual arousal disorder (FSAD). In some embodiments, a composition, such as a cream, may be applied to a subject's genitals. 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. Additionally, certain embodiments described herein generally relate to techniques for using such compositions, kits containing such compositions, and the like.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to compositions and methods for the treatment of female sexual dysfunction (FSD), such as female sexual arousal disorder (FSAD), and symptoms thereof. [Background technology]

[0002] Female sexual dysfunction (FSD) is a recognized problem that significantly impacts quality of life. One type of FSD, known as female sexual arousal disorder (FSAD), is currently estimated to affect approximately 20% of women in the United States. Currently, patients with FSAD typically receive treatment through counseling. Another type of FSD is female sexual interest / arousal disorder (FSIAD). FSIAD is defined in DSM-5 as a lack of or significantly reduced sexual interest / arousal, measured by the presence of three of the following six symptoms: loss or reduced interest in sexual activity; loss or reduced sexual thoughts or fantasies; absence or reduced initiation of sexual activity, typically unreceptive to a partner's attempts to initiate it; loss or reduced sexual arousal or pleasure in almost all or all sexual encounters; loss or reduced sexual interest / arousal to any internal or external sexual cues; and loss or reduced genital or non-genital sensation during sexual activity in all or almost all sexual encounters. These symptoms cause clinically significant distress and persist for at least six months.

[0003] Phosphodiesterase type 5 inhibitors are drugs used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. These drugs are commonly used to treat erectile dysfunction. Phosphodiesterase type 5 inhibitors are generally delivered orally, and no transdermal formulations are currently approved by the FDA. Previous studies have shown that the most common treatment-emergent adverse events (TEAEs) when oral phosphodiesterase type 5 inhibitors are administered daily for pulmonary hypertension are similar to those observed when oral phosphodiesterase type 5 inhibitors are administered as needed for erectile dysfunction (ED) (headache, flushing). Because pulmonary hypertension is more common in women than men, FDA safety data for daily oral phosphodiesterase type 5 inhibitors are primarily (75–78%) from women with severe cardiac and respiratory comorbidities due to an underlying diagnosis of pulmonary hypertension. Thus, women receiving substantially higher daily systemic doses of oral phosphodiesterase type 5 inhibitors for pulmonary hypertension do not experience more serious adverse events than women receiving phosphodiesterase type 5 inhibitors for erectile dysfunction (ED). There are no FDA-approved treatments for FSD, FSAD, or FSIAD. Therefore, there is a need for systems and methods for transdermally delivering clinically useful amounts of phosphodiesterase type 5 inhibitors, and for improved methods of treating FSD and its symptoms, including FSAD and FSIAD. Summary of the Invention

[0004] The present disclosure generally relates to compositions and methods for treating female sexual dysfunction (FSD) or symptoms thereof, comprising applying a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area. The present disclosure further relates to compositions and methods for treating female sexual arousal disorder (FSAD) or symptoms thereof, comprising applying a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area. The present disclosure further relates to compositions and methods for treating female sexual interest / arousal disorder (FSIAD) or symptoms thereof, comprising applying a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the 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 humectant. In embodiments, the composition further comprises L-arginine or an L-arginine salt. In embodiments where L-arginine or an L-arginine salt is listed, the L-arginine or an L-arginine salt can be substituted with any humectant. 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 comprises increasing satisfying sexual events, improving arousal sensations, increasing arousal lubrication, increasing orgasm, reducing concerns about sexual arousal, reducing pain or discomfort during and / or after sexual activity, and / or improving satisfaction with sexual activity. In some embodiments, treating FSAD comprises improving arousal sensations. In some embodiments, treating FSAD comprises increasing arousal lubrication. In some embodiments, treating FSAD comprises increasing orgasm. In some embodiments, treating FSAD comprises reducing concerns about sexual arousal. In some embodiments, treating FSAD comprises improving satisfaction with sexual activity. In some embodiments, treating FSAD comprises reducing pain or discomfort during and / or after sexual activity.

[0006] In some embodiments, treating FSAD includes increasing satisfying sexual events. In embodiments, increasing satisfying sexual events includes, but is not limited to, increasing orgasm or orgasm frequency, feeling closeness or connection with a sexual partner, experiencing pleasurable sensations, increasing physical sensations, feeling arousal, feeling passion, and / or having a pleasurable sexual experience.

[0007] In some embodiments, treating FSAD comprises increasing sensation in the genital area, hi some embodiments, the sensation in the genital area comprises one or more of numbness, pleasure, warmth, throbbing, tingling, congestion, or fullness in the genital area.

[0008] In some aspects, described herein are methods for increasing satisfying sexual events in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0009] In some aspects, described herein are methods for improving arousal sensations in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0010] In some aspects, described herein are methods for increasing arousal lubrication in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0011] In some aspects, described herein are methods for increasing orgasm in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0012] In some aspects, described herein are methods for reducing sexual arousal concerns or improving satisfaction with sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the female subject's genital area.

[0013] In some aspects, described herein are methods for reducing pain or discomfort during and / or after sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0014] In some aspects, described herein are methods for treating female sexual dysfunction (FSD) or symptoms thereof, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a female subject.

[0015] In some aspects, described herein are methods for treating female sexual interest / arousal disorder (FSIAD) or symptoms thereof, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a female subject. In embodiments, treating FSIAD comprises increasing sexual desire. In embodiments, treating FSIAD comprises increasing response to physical or psychological sexual stimuli. In embodiments, a symptom of FSIAD comprises a loss or decrease in interest in sexual activity. In embodiments, a symptom of FSIAD comprises a loss or decrease in erotic thoughts or fantasies. In embodiments, a symptom of FSIAD comprises a decrease in sexual desire. In embodiments, a symptom of FSIAD comprises a decrease in response to physical sexual stimuli. In embodiments, a symptom of FSIAD comprises a decrease in response to psychological sexual stimuli.

[0016] In some aspects, described herein are methods for increasing sexual desire in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0017] In some aspects, described herein are methods for increasing response to physical or psychological sexual stimulation in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject. In embodiments, the response to physical sexual stimulation is increased. In embodiments, the response to psychological sexual stimulation is increased. In embodiments, the response to both physical and psychological sexual stimulation is increased.

[0018] In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least twice over a period of time, which in embodiments is from about 1 week to about 8 weeks.

[0019] In embodiments, the one or more symptoms improve within about 1 week to about 8 weeks after the initial administration. In embodiments, the one or more symptoms improve within about 1 week to about 4 weeks after the initial administration. In embodiments, the one or more symptoms include arousal and lubrication. In embodiments, the one or more symptoms include sexual desire. In embodiments, the one or more symptoms include orgasmic achievement and / or pleasure.

[0020] In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil, acetyldenafil, 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 HCl. In some embodiments, the L-arginine or L-arginine salt is present at a concentration of at least about 5% by weight of the composition. In some embodiments, the L-arginine or 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 the phosphodiesterase type 5 inhibitor and / or its salt through the stratum corneum of a 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 salt 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 salt thereof 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 salt thereof 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 salt thereof 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 salt thereof is present at a concentration of at least about 1% to about 10% by weight of the composition.

[0023] In some embodiments, the composition comprises glyceryl stearate. In some embodiments, the composition comprises cetyl 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] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or symptoms thereof, comprising applying a topical delivery composition 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 stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and a phosphodiesterase type 5 inhibitor and / or a salt thereof.

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

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

[0027] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or symptoms thereof, comprising administering to a patient a compound selected from the group consisting of: a. purified water having a concentration of about 35% by weight to about 55% by weight; b. potassium chloride at a concentration of about 2.5% by weight to about 15% by weight; c. L-arginine HCl 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. cetyl alcohol at a concentration of about 4% by weight 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% by weight to about 5% by weight; h. isopropyl myristate at a concentration of about 0.1% by weight to about 5% by weight; i. oleic acid at 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% by weight to about 5% by weight; l. sildenafil citrate in a concentration of about 1% to about 10% by weight to the genital area.

[0028] In some embodiments, the compositions include the above compounds at concentrations no greater than ±10% of the stated concentrations.

[0029] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or symptoms thereof, comprising applying to a subject a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and an ionic salt.

[0030] In some embodiments, the phosphodiesterase type 5 inhibitor comprises 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 for 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 subject's genital area. In some embodiments, the composition is applied to the clitoris, glans, frenulum, and / or vestibule of the subject's genital area. In some embodiments, the composition is applied to the clitoris, glans, frenulum, vestibule, and / or labia minora of the subject's genital area. 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 anterior distal vagina of the subject.

[0031] In some embodiments, the composition comprises: a. purified water at a concentration of about 40% by weight; b. potassium chloride at a concentration of about 5% by weight; c. L-arginine HCl at a concentration of about 7.5% by weight; d. glyceryl stearate at a concentration of about 7% by weight; e. cetyl alcohol at a concentration of about 7% by weight; f. squalane at a concentration of about 4% by weight; g. xanthan gum at a concentration of about 0.8% by weight; h. isopropyl myristate at a concentration of about 1% by weight; i. oleic acid at a concentration of about 1% by weight; j. propylene glycol at a concentration of about 8.5% by weight; k. Polysorbate 20 at a concentration of about 2% by weight; l. trisodium citrate dihydrate at a concentration of about 10% by weight; m. sodium benzoate at a concentration of about 0.2% by weight; n. gluconolactone at a concentration of about 0.25% by weight; o. Sildenafil citrate at a concentration of about 5% by weight.

[0032] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising selecting a female subject exhibiting one or more symptoms of FSAD and administering to the subject's genital area a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and an ionic salt. In some embodiments, the one or more symptoms are selected from distress related to decreased genital sensitivity, lack of genital responsiveness during sexual activity, decreased genital arousal, and / or sexual arousal difficulties. In embodiments, the one or more symptoms include decreased response to physical sexual stimulation. In embodiments, the female subject's primary complaint is decreased response to physical sexual stimulation.

[0033] The present disclosure generally relates to a method for treating female sexual interest / arousal disorder (FSIAD) or a symptom thereof, comprising selecting a female subject exhibiting one or more symptoms of FSIAD and administering to the subject's genital area a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and an ionic salt. In embodiments, the one or more symptoms of FSIAD are selected from loss or decreased interest in sexual activity or erotic thoughts or fantasies, decreased sexual desire, and / or decreased response to physical or psychological sexual stimuli. In embodiments, the one or more symptoms of FSIAD include loss or decreased interest in sexual activity. In embodiments, the one or more symptoms of FSIAD include loss or decreased erotic thoughts or fantasies. In embodiments, the one or more symptoms of FSIAD include decreased sexual desire. In embodiments, the one or more symptoms of FSIAD include decreased response to physical sexual stimuli. In embodiments, the one or more symptoms of FSIAD include decreased response to psychological sexual stimuli. In embodiments, the female subject's primary complaint is decreased response to physical sexual stimuli.

[0034] In some embodiments, about 50% of the composition is applied externally to the vulva and about 50% of the composition is applied intravaginally. In some embodiments, administering about 50% of the composition externally comprises applying the composition to the anterior labial commissure, clitoral hood, glans penis, 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, administering about 50% of the composition intravaginally comprises applying the composition to the anterior distal vagina at a depth of about 0 cm to about 3 cm within the vagina. In some embodiments, administering about 50% of the composition intravaginally comprises applying the composition to the distal lower third of the vagina, approximately midway between the distal interphalangeal joint and the proximal interphalangeal joint.

[0035] In some embodiments, the composition is administered about 10 to about 20 minutes before sexual activity. In some embodiments, the composition is administered up to about 9 doses over about 4 weeks. In some embodiments, the composition is administered at least about 24 hours before the second dose of the composition. In some embodiments, the subject has not been administered at least one of a guanylate cyclase stimulator, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha blocker within 28 days prior to administration of the first dose of the composition.

[0036] In some embodiments, the subject avoids wiping or rinsing any of the genital areas where the composition has been applied.

[0037] In some embodiments, after sexual activity has concluded, any remaining composition is washed away.

[0038] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0039] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0040] In some embodiments, administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject results in a satisfying sexual event.

[0041] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases genital arousal sensations.

[0042] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases lubrication in the genital area during sexual activity.

[0043] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases perceived sexual arousal.

[0044] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual desire.

[0045] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases orgasm during sexual activity.

[0046] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject results in a reduction in the difficulty or inability to achieve orgasm during sexual activity.

[0047] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sensitivity or sensation in the genital area during sexual activity.

[0048] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases numbness in the genital area during sexual activity.

[0049] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases engorgement in the genital area during sexual activity.

[0050] In some embodiments, administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases warmth, tingling, or throbbing in the genital area during sexual activity.

[0051] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject reduces pain and / or discomfort during sexual activity.

[0052] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject reduces pain and / or discomfort following sexual activity.

[0053] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0054] In some embodiments, the one or more symptoms of Female Sexual Arousal Disorder (FSAD) include, but are not limited to, decreased response to physical sexual stimulation.

[0055] In some embodiments, the female subject's primary complaint is decreased response to physical sexual stimulation.

[0056] In some embodiments, after administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, the subject may experience one of the following: a. An improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28), b. An improvement of at least 1 in the wake-lubrication domain score of the SFQ28, c. An improvement of at least 1.5 in the score on the SFQ28 sense of arousal domain, d. Improvement of at least 2 in the craving domain score of the SFQ28, e. An improvement of at least 1.20 in the orgasm domain score of the SFQ28, f. Improvement of at least 1 in the pain domain score of the SFQ28, g. Improvement in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score of at least -7; h. An improvement in the sense of wakefulness score of at least 1.45; i. an improvement in genital arousal score of at least 1.13; j. An improvement of at least 1.49 in genital arousal concern score, k. Improvement in the percentage of Item 12-SSE on the Arousal Diary of at least 0.25; l. Demonstrate at least one of the following: Item 12 of the Arousal Diary - Improvement of at least 1.41 in the number of SSEs.

[0057] In some embodiments, the subject exhibits two or more of a-l. In some embodiments, the subject exhibits three or more of a-l. In some embodiments, the subject exhibits four or more of a-l. In some embodiments, the subject exhibits five or more of a-l. In some embodiments, the subject exhibits six or more of a-l. In some embodiments, the subject exhibits seven or more of a-l. In some embodiments, the subject exhibits eight or more of a-l. In some embodiments, the subject exhibits nine or more of a-l. In some embodiments, the subject exhibits ten or more of a-l. In some embodiments, the subject exhibits eleven or more of a-l. In some embodiments, the subject exhibits all twelve of a-l.

[0058] In some embodiments, the subject comprises a primary diagnosis of FSAD as defined by the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR).

[0059] In some embodiments, the topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof does not produce one or more of orthostatic hypotension, headache, flushing, indigestion, lightheadedness, visual disturbances, nasal congestion, back pain, muscle pain, nausea, dizziness, and rash.

[0060] In some embodiments, the subject's primary complaint is FSAD or one or more symptoms thereof.

[0061] In some embodiments, the subject's primary complaint is FSAD or one or more symptoms thereof, and the subject exhibits symptoms of secondary HSDD. In some embodiments, the subject's primary complaint is FSAD, and the subject does not exhibit symptoms of female orgasmic disorder (FOD).

[0062] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising: a. Selecting female subjects with a chief complaint of FSAD; b. applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the subject.

[0063] In some embodiments, the subject exhibits symptoms of secondary HSDD. In some embodiments, the subject has FSAD or symptoms thereof as their only diagnosis. In some embodiments, the subject has primary FSAD or symptoms thereof and secondary HSDD or symptoms thereof. In some embodiments, the premenopausal subject has FSAD or symptoms thereof as their only diagnosis. In some embodiments, the premenopausal subject has primary FSAD or symptoms thereof and secondary HSDD or symptoms thereof.

[0064] The present disclosure generally provides a method for determining the efficacy of a treatment for FSAD, comprising: a) obtaining baseline scores on one or more of the following: the Sexual Function Questionnaire (SFQ28) Arousal Cognition Domain score, the SFQ28 Arousal Lubrication Domain score, the SFQ28 Arousal Sensory Domain score, the SFQ28 Desire Domain score, the SFQ28 Orgasm Domain score, the SFQ28 Pain Domain score, the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) score, the Arousal Sensory score, the Genital Arousal score, the Genital Arousal Concerns, the Arousal Diary Item 12-SSE percentage, and the Arousal Diary Item 12-SSE number; b) administering FSAD treatment to female subjects; and c) determining an improvement in one or more of the scores of step a.

[0065] In some embodiments, the following: a. An improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28), b. An improvement of at least 1 in the wake-lubrication domain score of the SFQ28, c. An improvement of at least 1.5 in the score on the SFQ28 sense of arousal domain, d. Improvement of at least 2 in the craving domain score of the SFQ28, e. An improvement of at least 1.20 in the orgasm domain score of the SFQ28, f. Improvement of at least 1 in the pain domain score of the SFQ28, g. Improvement in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score of at least -7; h. at least a 1.45 improvement in sense of wakefulness; i. at least a 1.13% improvement in genital arousal, j. at least a 1.49 improvement in genital arousal concerns, k. Improvement in the percentage of Item 12-SSE on the Arousal Diary of at least 0.25; l. An improvement of at least 1.41 in the number of items 12-SSE on the Wakefulness Diary, the presence of one or more of the following indicates that FSAD treatment is effective:

[0066] In some embodiments, the presence of two or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of three or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of four or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of five or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of six or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of seven or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of eight or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of nine or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of ten or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of eleven or more of a-l indicates that the FSAD treatment is effective. In some embodiments, the presence of all twelve of a-l indicates that the FSAD treatment is effective.

[0067] 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, if the FSAD treatment is determined to be effective, one or more additional doses are administered.

[0068] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the present disclosure when considered in conjunction with the accompanying drawings. DETAILED DESCRIPTION OF THE INVENTION

[0069] Female sexual dysfunction (FSD) is estimated to 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.

[0070] FSAD is defined in the DSM IV-TR as the persistent or recurrent inability to achieve or maintain an adequate lubrication-swelling response to sexual arousal until the end of sexual activity, causing significant distress or interpersonal difficulties. FSAD is estimated to adversely affect approximately 20% of women in the United States, and furthermore, the disruption of sexual arousal affects other aspects of the sexual response. Orgasm is impossible without arousal, and lack of arousal generally leads to a lack of desire because sexual activity is not enjoyable or reinforcing. Dyspareunia can be intricately linked to a lack of adequate sexual arousal. Intercourse without lubrication can be painful, and repeated intercourse without arousal can lead to vulvar infections, chronic irritability, secondary vaginismus, fear of sexual activity, or total avoidance of sexual activity.

[0071] FSIAD is defined in DSM-5 as a lack of or significantly reduced sexual interest / arousal, measured by the presence of three of the following six symptoms: lost or reduced interest in sexual activity; lost or reduced sexual thoughts or fantasies; no or reduced initiation of sexual activity, typically non-receptive to partner's attempts to initiate; lost or reduced sexual arousal or pleasure in almost all or all sexual encounters; lost or reduced sexual interest / arousal to any internal or external sexual cues; and lost or reduced genital or non-genital sensations during sexual activity in all or almost all sexual encounters. These symptoms cause clinically significant distress and persist for at least six months.

[0072] The present disclosure generally relates to compositions and techniques for treating FSD, female sexual arousal disorder (FSAD), through transdermal and / or transmucosal delivery of various compounds. In some embodiments, the compositions and techniques of the present disclosure treat FSIAD. In some embodiments, the composition, such as a cream, can be applied to the genital area of ​​a subject. The composition can 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.

[0073] The present disclosure provides a topical formulation of sildenafil cream that unexpectedly offers several potential clinical advantages over oral administration of sildenafil citrate, including more targeted local delivery at needed therapeutic levels, reduced systemic exposure and thereby reduced known adverse events, and a more rapid onset of action to achieve more immediate therapeutic benefit.

[0074] One set of embodiments provides a topical delivery composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, and optionally an ionic salt and / or L-arginine or an L-arginine salt. In some embodiments, the composition may be stabilized using a combination of a stabilizing polymer (e.g., xanthan gum, KELTROL® BT and / or KELTROL® RD), propylene glycol, and a polysorbate surfactant (e.g., polysorbate 20), which provides stability to the composition compared to compositions lacking one or more of these.

[0075] In one series of embodiments, the pharmaceutical agent is a phosphodiesterase type 5 inhibitor and / or its salt. Phosphodiesterase type 5 inhibitors are drugs that block the degradative action of phosphodiesterase type 5 on cyclic GMP, for example, in smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. Part of the physiological process of erection involves the release of nitric oxide (NO) in the vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase, which results in an increase in the level of cyclic guanosine monophosphate (cGMP), causing smooth muscle relaxation in the blood vessels supplying the corpus cavernosum, resulting in increased blood flow and an erection. Thus, PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5, increasing blood flow to the penis during sexual stimulation.

[0076] Preclinical functional and molecular biological studies have revealed the presence of a similar NO-cGMP biological pathway in female genital tissues. As estimated by immunohistochemistry in female tissue sections, NO-cGMP-dependent PDE-5 isoenzymes are expressed in vascular smooth muscle cells of the human corpus cavernosum, vagina, and labia minora. These structures play a central role in mediating the female sexual arousal response. Following sexual stimulation, neurotransmitters regulate increased blood flow to the clitoris, vagina, and labia, resulting in increased intracavernosal pressure, swelling and protrusion of the clitoral glans, and engorgement of the labia minora and vagina. Anatomically, the female clitoris consists of two corpora cavernosa and one glans. Like the male penis, each corpus is lined with a fibrous outer membrane, the tunica albuginea, which contains 40–45% smooth muscle-based erectile tissue. Due to the lack of a venous plexus, the female clitoris swells but does not rigidify during sexual arousal.

[0077] composition Non-limiting examples of phosphodiesterase type 5 inhibitors include, but are not limited to, avanafil, lodenafil, mirodenafil (pKa is 6.0), sildenafil (or its analogs, such as actetildenafil, hydroxyacetyldenafil, or dimethylsildenafil), tadalafil (pKa is 18), vardenafil (pKa is 3.4, 6.7, 8.8, and 14), udenafil (pKa is 10.53), acetyldenafil, or thiomethisosildenafil.

[0078] The structures of these compounds are shown below. [ka] [ka]

[0079] In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 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)phenylsulfonyl]-4-methylpiperazine citrate). In some embodiments, the phosphodiesterase type 5 inhibitor is avanafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is lodenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is mirodenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is hydroxyacetyldenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is dimethylsildenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is tadalafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 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 acetyldenafil or a salt thereof. In some embodiments, the phosphodiesterase type 5 inhibitor is thiomethisosildenafil or a salt thereof.

[0080] Aspects of the present disclosure provide compositions comprising a phosphodiesterase type 5 inhibitor for transdermal and / or transmucosal delivery or topical application to a subject. It should be understood that other compounds, such as salts or derivatives of phosphodiesterase type 5 inhibitors (including salts or derivatives of the above compounds), are included in embodiments, and thus any embodiment described herein that uses a phosphodiesterase type 5 inhibitor is merely exemplary.

[0081] The phosphodiesterase type 5 inhibitor or other pharmaceutical agent (e.g., a salt or derivative of a phosphodiesterase type 5 inhibitor) may be present in any suitable concentration. In some embodiments, the pharmaceutical agent is sildenafil citrate. In some embodiments, the pharmaceutical agent may be present at a concentration of about 0.1% to about 10% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of about 1% to about 10% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of about 1% to about 7% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of about 1% to about 5% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of about 1% to about 4% by weight of the composition. The concentration may be any value or subrange within the recited range, including the endpoints.

[0082] In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 0.1% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 0.3% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 0.5% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 0.7% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 1% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 2% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 3% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 4% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 5% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 6% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 7% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 7.5% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 8% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 9% by weight of the composition. In some embodiments, the pharmaceutical agent may be present at a concentration of at least about 10% by weight of the composition.

[0083] In certain embodiments, the pharmaceutical agent may be present at a concentration of about 1% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 2% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 3% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 4% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 5% or less by weight of the composition.

[0084] In certain embodiments, the pharmaceutical agent may be present at a concentration of about 6% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 7% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 8% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 9% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 10% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 12% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 15% or less by weight of the composition. In certain embodiments, the pharmaceutical agent may be present at a concentration of about 20% or less by weight of the composition.

[0085] In some embodiments, the pharmaceutical agent is a phosphodiesterase type 5 inhibitor. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil. In some embodiments, the compositions of the present disclosure comprise sildenafil citrate and are used to treat FSAD. In certain embodiments, sildenafil or a salt thereof may be present at a concentration of about 1% by weight of the composition. In certain embodiments, sildenafil or a salt thereof may be present at a concentration of about 2% by weight of the composition. In certain embodiments, sildenafil or a salt thereof may be present at a concentration of about 3% by weight of the composition. In certain embodiments, sildenafil or a salt thereof may be present at a concentration of about 3.6% by weight of the composition. In certain 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.

[0086] Furthermore, pharmaceutical agents may be present in their 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 of a phosphodiesterase type 5 inhibitor (e.g., avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetyldenafil, thiomethisosildenafil, etc.), such as the sodium salt, potassium salt, magnesium salt, lysine salt, arginine salt, lactate salt, or citrate salt, which may include, for example, citric acid, citric acid monohydrate, sodium citrate, sodium citrate dihydrate, etc. In some embodiments, sildenafil is present as the sodium salt, potassium salt, magnesium salt, lysine salt, arginine salt, lactate salt, or citrate salt. In some embodiments, sildenafil is present as the citrate salt. As a non-limiting example, in one set of embodiments, the composition may include citrate and / or citrate salt.

[0087] For a pharmaceutical agent in a salt form, "by weight of the composition" includes the entire pharmaceutical agent in salt form, e.g., the agent itself and any counterion, such as sodium, potassium, etc. The amount of pharmaceutical agent can be determined in the composition using techniques such as, for example, HPLC or HPLC / MS known to those skilled in the art.

[0088] In some embodiments, the composition may also include a nitric oxide donor. In some cases, such a nitric oxide donor may be used to increase local blood flow at the site where the composition is applied, thereby enhancing delivery of the pharmaceutical agent. The nitric oxide donor may 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.

[0089] The composition may also include L-arginine and / or L-arginine hydrochloride. In embodiments, L-arginine and / or L-arginine hydrochloride is a humectant. 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 is 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 is 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 is 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 is present at a concentration of at least about 1% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 2% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 3% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 4% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 5% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 6% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 7% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is 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 is present at a concentration of at least about 8% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is present at a concentration of at least about 9% by weight of the composition. In some cases, L-arginine and / or L-arginine hydrochloride is 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.

[0090] In some cases, more than one nitric oxide donor may be used (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, etc. nitric oxide donors). In some cases, there may be no more than 3, 5, 7, or 10 nitric oxide donors present in the composition.

[0091] As used herein, a "nitric oxide donor" is a compound capable of releasing nitric oxide and / or chemically transferring a nitric oxide moiety to another molecule, directly or indirectly, for example, via a biological process. The nitric oxide donor can release nitric oxide to tissues such as the skin and / or muscles and / or elements of the circulatory system adjacent to the surface of the skin. 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-nucleophile adducts, N-nitroso-N-substituted hydroxylamines, 1,3-(nitrooxymethyl)phenyl-2-hydroxybenzoates, and the like, and / or any combination thereof.

[0092] Other non-limiting examples of nitric oxide donors include, but are not limited to, D,L-arginine, D-arginine, or alkyl (e.g., ethyl, methyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.) esters (e.g., methyl ester, ethyl ester, propyl ester, butyl ester, etc.) of L-arginine and / or D-arginine, and / or salts thereof, 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 salts (e.g., to produce L-arginine glutamate, L-arginine butyrate, L-arginine glycolate, D-arginine hydrochloride, D-arginine glutamate, etc.). Still other examples of nitric oxide donors include L-arginine-based compounds, such as, but not limited to, L-homoarginine, N-hydroxy-L-arginine, nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, linsidomine, nipride, glutamine, and the like, and salts thereof (e.g., hydrochloride, glutamate, butyrate, glycolate, etc.), and / or any combination thereof.

[0093] In some embodiments, the composition can also include an ionic salt. In some embodiments, a composition including an ionic salt and a pharmaceutical agent (such as a phosphodiesterase type 5 inhibitor) can create an environment in which the pharmaceutical agent is in a chemically and / or energetically unfavorable environment compared to the skin (e.g., the chemical potential and / or free energy of the pharmaceutical agent within the composition environment is significantly greater than the chemical potential and / or free energy of the pharmaceutical agent within the skin, thus energetically facilitating transport into the skin), particularly the stratum corneum.

[0094] Embodiments of the present disclosure relate to compositions for topical delivery to the skin or mucosa of a subject, comprising L-arginine and / or L-arginine hydrochloride, an ionic salt, and a pharmaceutical agent, such as a phosphodiesterase type 5 inhibitor, or a salt or derivative of a phosphodiesterase type 5 inhibitor.

[0095] 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 at least about 1% to about 10% by weight of the composition. In some embodiments, the ionic salt is present at a concentration of at least 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 at an ionic strength of at least about 0.25M, at least about 1M, at least about 2M, at least about 3M, at least about 5M, at least about 10M, at least about 15M, at least about 20M, at least about 25M, or in some cases, between about 0.25M and about 15M, between about 5M and about 15M, between about 10M and about 15M, etc.

[0096] In some embodiments, the ionic salt is potassium chloride, hi some embodiments, the potassium chloride is present at a concentration of about 5% by weight of the composition.

[0097] In some embodiments, the composition may include an antioxidant capable of reducing or inhibiting 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% by weight of the composition. The antioxidant may be present at a concentration of about 1% to about 5% by weight of the composition. 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% by weight of the composition.

[0098] As used herein, "stabilizing polymer" refers to a polymer including xanthan gum, xanthan gum derivatives and / or xanthan gum equivalents, such as KELTROL® BT and / or KELTROL® RD, KELZAN® XC, KELZAN® XCD, KELZAN® D, KELZAN® CC, XANTURAL® 180 and / or XANTURAL® 75.

[0099] In some embodiments, the compositions of the present disclosure may further comprise a stabilizing polymer, propylene glycol, and a polysorbate surfactant. Non-limiting examples of stabilizing polymers include xanthan gum, KELTROL® BT, and / or KELTROL® RD, and an example of a polysorbate surfactant is Polysorbate 20.

[0100] 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 stabilizing polymer may be present at a concentration of at least about 0.8% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.9% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 1% by weight of the composition.

[0101] In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.2% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.4% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.6% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.8% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 1% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 2% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 3% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 4% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 5% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 7% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 10% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 12% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 15% or less by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 20% or less by weight of the composition.

[0102] In some embodiments, the stabilizing polymer is xanthan gum, hi some embodiments, the xanthan gum is present at a concentration of about 0.8% by weight of the composition.

[0103] Propylene glycol may be present in the compositions of the present disclosure at a concentration of about 1% to about 25% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of about 1% to about 20% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of about 1% to about 15% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of about 1% to about 10% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 1% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 2% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 3% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 4% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 5% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 6% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 7% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 8% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 8.5% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 9% by weight of the composition. Propylene glycol may be present in the compositions of the present disclosure at a concentration of at least about 10% by weight of the composition.

[0104] In some embodiments, propylene glycol may be present at a concentration of about 2% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 2% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 4% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 6% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 8% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 10% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 12% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 15% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 20% or less by weight of the composition. In some embodiments, propylene glycol may be present at a concentration of about 25% or less by weight of the composition.

[0105] In some cases, other glycols, such as butylene glycol, may be used in conjunction with or in place of propylene glycol. References herein to propylene glycol should be understood to also include, in other embodiments, other glycols (e.g., low molecular weight glycols or polyglycols) in conjunction with or in place of propylene glycol.

[0106] In some embodiments, propylene glycol is present in the compositions of the present disclosure at a concentration of about 8.5% by weight of the composition.

[0107] The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of about 1% to about 25% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of about 1% to about 20% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of about 1% to about 15% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of about 1% to about 10% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of about 1% to about 5% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of at least about 1% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of at least about 2% by weight of the composition. The polysorbate surfactant may be present in the compositions of the present disclosure at a concentration of at least about 3% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 4% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 5% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 6% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 7% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 8% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 9% by weight of the composition. The polysorbate surfactant may be present in the composition of the present disclosure at a concentration of at least about 10% by weight of the composition.

[0108] In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 2% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 4% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 6% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 8% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 10% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 12% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 15% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of about 20% or less by weight of the composition. In certain embodiments, the polylsorbate surfactant may be present at a concentration of up to about 25% by weight of the composition.

[0109] As used herein, "polysorbate surfactant" refers to a surfactant that includes a polysorbate. For example, the surfactant may include sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, or another sorbitan salt.

[0110] 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.

[0111] In some embodiments, the pharmaceutical agent may be combined with a penetrant, i.e., an agent that increases the transport of the pharmaceutical agent into the skin compared to transport in the absence of the penetrant. Examples of penetrants include, but are not limited to, oleoresin capsicum, cationic, anionic, or nonionic surfactants (e.g., sodium dodecyl sulfate, poloxamers, etc.); fatty acids and alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g., benzilonium bromide, oxyphenonium bromide); alkanones (e.g., n-heptane); amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g., n-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.

[0112] In some embodiments, the penetrating agent is oleic acid, hi some embodiments, the oleic acid is present at a concentration of about 1% by weight of the composition.

[0113] As specific, non-limiting examples, the cream may have (w / w) one or more of water (40.75%), potassium chloride (5%), L-arginine HCl (7.5%); glyceryl stearate (7%), cetyl 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%).

[0114] As a non-limiting example, the cream may contain (w / w) water (about 35% to about 55%), potassium chloride (about 2.5% to about 15%), L-arginine HCl (about 2.5% to about 15%), glyceryl stearate (about 4% to about 10%), cetyl alcohol (about 4% to about 10%), squalane (about 1% to about 8%), xanthan gum (about 0.1% to about 5%), isopropyl myristate (about 0%), PEG-10 glycerin (about 0.1 ... It may contain one or more of the following: hydroxybenzoates (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 sildenafil citrate (about 1% to about 10%).

[0115] delivery In some embodiments, topical delivery of a phosphodiesterase type 5 inhibitor, such as sildenafil, provides a surprisingly rapid effect (e.g., within about 1 to 5 minutes). In contrast, oral counterparts require about 60 minutes or more to produce an effect. Aspects of the present disclosure provide methods and compositions for treating or preventing FSAD or its symptoms. In some embodiments, topical compositions are 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 less than 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 less than 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 less than 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 less than 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 less than 10 minutes of application.

[0116] 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.

[0117] Without being bound by any theory, when the composition is applied to the skin or mucosa of a subject, the pharmaceutical agent is dispersed by the local blood flow and does not accumulate in the tissue, so the pharmaceutical agent leaves the vehicle and easily enters the tissue. Thus, in certain embodiments, a pharmaceutical agent, such as a phosphodiesterase type 5 inhibitor and / or a salt or derivative of a phosphodiesterase type 5 inhibitor, such as avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, acetyldenafil, or thiomethisosildenafil, can be introduced into the skin or mucosa. The composition can be delivered locally and / or systemically, and although most delivery is initially local (i.e., through the skin or mucosa), in some cases, the pharmaceutical agent can also be distributed systemically, for example, once it reaches the blood supply.

[0118] Non-limiting examples of delivery vehicles that can be delivered into tissue 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 pharmaceutical agents in the form of electronically neutral esters or salts.

[0119] In some embodiments, the composition may exist as an emulsion. As known to those skilled in the art, emulsions typically comprise a first phase (e.g., a discontinuous phase) contained within a second fluid phase (e.g., a continuous phase). A pharmaceutical agent (e.g., a phosphodiesterase type 5 inhibitor) may be present in either or both phases. In some embodiments, the emulsion is prepared by mixing a first aqueous preparation (e.g., an aqueous phase) with a second non-aqueous preparation (e.g., an oil or lipid phase). A water-soluble pharmaceutical agent may be added to the first aqueous preparation (e.g., before mixing with the second non-aqueous preparation). A water-insoluble (or relatively water-insoluble) pharmaceutical agent may be added to the second non-aqueous preparation (e.g., before mixing with the first aqueous preparation). A partially water-soluble pharmaceutical agent may be added to one phase or may be divided into two phases before mixing. The partition between the two phases depends on the amount of pharmaceutical agent added, the composition of the first and second preparations (e.g., the nature and amount of other chemicals or drugs), pH, temperature, other physical or chemical factors, and / or combinations thereof.

[0120] The emulsions of the present disclosure can be packaged using any suitable format (e.g., in a tube, a pump-actuated container, or any other suitable form). In some embodiments, the emulsions can be added to the surface of a patch or bandage. The emulsions can also be applied to the skin or mucosa 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.

[0121] In another aspect, the present disclosure relates to a kit comprising one or more of the compositions discussed herein. As used herein, "kit" refers to a package or assembly comprising one or more of the compositions of the present disclosure and / or other compositions related to the present disclosure, for example, as described herein. Each composition of the kit may be provided in liquid form (e.g., solution) or solid form (e.g., dry powder). In certain cases, a portion of the composition may be configurable or otherwise processable (e.g., into an active form), for example, by the addition of a suitable solvent or other species, which may or may not be provided with the kit. Examples of other compositions or components relevant to the present disclosure include, but are not limited to, solvents, surfactants, diluents, salts, buffers, emulsifiers, chelating agents, fillers, antioxidants, binders, bulking agents, preservatives, desiccants, antimicrobial agents, needles, syringes, packaging materials, tubes, bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps, patches, containers, etc., for, e.g., using, administering, modifying, assembling, storing, packaging, preparing, mixing, diluting, and / or storing the composition components for a particular use with a sample and / or subject.

[0122] Kits of the present disclosure may, in some cases, include instructions in any form provided with a composition of the present disclosure, in a manner that one of skill in the art would recognize as being associated with the composition of the present disclosure. For example, the instructions may include instructions for using, modifying, mixing, diluting, preserving, administering, assembling, storing, packaging, and / or preparing the composition and / or other compositions associated with the kit. In some cases, the instructions may also include, for example, instructions for delivery and / or administration of the composition for a particular use, e.g., to a sample and / or subject.

[0123] How to use The present disclosure provides a method comprising applying a composition comprising 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 has FSD. In some embodiments, the subject is at risk for FSD. In some embodiments, the subject has one or more symptoms of FSD.

[0124] The present disclosure provides a method, comprising applying a composition comprising 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 for FSAD. In some embodiments, the subject has one or more symptoms of FSAD.

[0125] The present disclosure provides methods including applying a composition comprising 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 for FSIAD. In some embodiments, the subject has one or more symptoms of FSIAD.

[0126] In some embodiments, the composition comprises 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 comprises 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% by weight. In some embodiments, the composition is administered to the clitoris, vulva, vagina, and / or intravaginally. 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, and / or frenulum of a subject's genital area. In some embodiments, the composition is applied to the clitoris, glans, frenulum, and / or vestibule of a subject's genital area. In some embodiments, the composition is applied to the clitoris, glans, frenulum, vestibule, and / or labia minora of a subject's genital area. 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 anterior distal 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.

[0127] Thus, as discussed above, various embodiments encompass a variety of compositions including any suitable combination of the above-described ingredients, 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, an active ingredient, and water. The active ingredient can include any of those described herein, such as sildenafil and its salts.

[0128] Additionally, as previously mentioned, certain aspects described herein generally relate to compositions for the treatment or prevention of indications, such as any of those described herein, and methods for applying such compositions to the vulva and / or vagina of a subject, e.g., a human, hi some embodiments, the subject is a female.

[0129] In another set of embodiments, compositions such as those described herein may be used to treat a subject having or at risk for FSAD. In embodiments, the composition is administered to the subject at least once.

[0130] In some embodiments, a method for treating FSD or a symptom thereof includes selecting a female subject exhibiting one or more symptoms of FSD and administering to the subject's genitals a composition comprising a phosphodiesterase type 5 inhibitor. In embodiments, the composition comprises 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.

[0131] In some embodiments, a method for treating female sexual arousal disorder (FSAD) or a symptom thereof includes selecting a female subject exhibiting one or more symptoms of FSAD and administering to the subject's genitals a composition comprising a phosphodiesterase type 5 inhibitor. In embodiments, 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.

[0132] In some embodiments, symptoms of FSAD include, but are not limited to, decreased genital sensitivity, lack of genital responsiveness during sexual activity, decreased genital arousal, distress related to difficulty in sexual arousal, and any combination thereof. In some embodiments, the compositions of the present disclosure are administered to the subject's genital area, including but not limited to, the clitoris, vestibule, vulva, and vagina. In embodiments, one or more symptoms include decreased response to physical sexual stimulation. In embodiments, the female subject's primary complaint is decreased response to physical sexual stimulation.

[0133] In some embodiments, treating FSAD comprises increasing satisfying sexual events, improving arousal sensations, increasing arousal lubrication, increasing orgasm, reducing concerns about sexual arousal, and / or improving satisfaction with sexual activity. In some embodiments, treating FSAD comprises improving arousal sensations. In some embodiments, treating FSAD comprises increasing arousal lubrication. In some embodiments, treating FSAD comprises increasing orgasm. In some embodiments, treating FSAD comprises reducing concerns about sexual arousal. In some embodiments, treating FSAD comprises improving satisfaction with sexual activity.

[0134] In some embodiments, treating FSAD includes increasing satisfying sexual events, hi embodiments, increasing satisfying sexual events includes, but is not limited to, increasing orgasm or orgasm frequency, feeling closeness or connection with a sexual partner, experiencing pleasurable sensations, increasing physical sensations, feeling arousal, feeling passion, and / or having a pleasurable sexual experience.

[0135] In some embodiments, treating FSAD comprises increasing sensation in the genital area, hi some embodiments, the sensation in the genital area comprises one or more of numbness, pleasure, warmth, throbbing, tingling, congestion, or fullness in the genital area.

[0136] In some aspects, described herein are methods for increasing satisfying sexual events in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0137] In some aspects, described herein are methods for improving arousal sensations in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0138] In some aspects, described herein are methods for increasing arousal lubrication in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0139] In some aspects, described herein are methods for increasing orgasm in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0140] In some aspects, described herein are methods for reducing sexual arousal concerns or improving satisfaction with sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the female subject's genital area.

[0141] In some aspects, described herein are methods for reducing pain or discomfort during and / or after sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

[0142] In embodiments, a method for treating FSIAD or a symptom thereof includes selecting a female subject exhibiting one or more symptoms of FSIAD and administering to the subject's genitals a composition comprising a phosphodiesterase type 5 inhibitor. In embodiments, 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.

[0143] In embodiments, treating FSIAD comprises increasing sexual desire. In embodiments, treating FSIAD comprises increasing responsiveness to physical or psychological sexual stimuli. In embodiments, a symptom of FSIAD comprises a loss or decrease in interest in sexual activity. In embodiments, a symptom of FSIAD comprises a loss or decrease in erotic thoughts or fantasies. In embodiments, a symptom of FSIAD comprises a decrease in sexual desire. In embodiments, a symptom of FSIAD comprises a decrease in responsiveness to physical sexual stimuli. In embodiments, a symptom of FSIAD comprises a decrease in responsiveness to psychological sexual stimuli.

[0144] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) score. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) item 14 score (feeling concerned about difficulties with sexual arousal). In embodiments, improvement refers to an increase in the FSDS-DAO score of at least one point. In embodiments, improvement refers to an increase in the FSDS-DAO item 14 score of at least one point.

[0145] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on the Sexual Function Questionnaire (SFQ28). In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on domain item 1 (frequency of warmth) of the SFQ28. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on domain item 2 (degree of warmth) of the SFQ28. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on domain item 3 (frequency of throbbing / numbness) of the SFQ28. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on domain item 4 (degree of throbbing / numbness) of the SFQ28. In embodiments, improvement means an increase in the SFQ28 score or domain item score of at least 1 point. In embodiments, improvement means an increase in the SFQ28 score or domain item score of at least 2 points.

[0146] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on the Arousal Diary (AD). In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on Item 1 (pleasant sensation) of the AD. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on Item 2 (warm sensation) of the AD. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on Item 3 (pulsating / tingling sensation) of the AD. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on Item 4 (numbness sensation) of the AD. In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on a score on Item 5 (congestion / fullness) of the AD. In embodiments, improvement means an increase in the AD score or item score of at least 1 point. In embodiments, improvement means an increase in the AD score or item score of at least 2 points.

[0147] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Patient Global Impression of Change (PGI-C). In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the subject's description of the symptoms as "a little better." In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the subject's description of the symptoms as "much better." In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the subject's description of the symptoms as "much, much better."

[0148] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Patient Global Impression of Severity (PGI-S).

[0149] In embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on Patient Benefit Evaluation (PBE) (meaningful benefit obtained from the test drug).

[0150] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0151] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0152] In some embodiments, administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject results in a satisfying sexual event.

[0153] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases genital arousal sensations.

[0154] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases lubrication in the genital area during sexual activity.

[0155] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases perceived sexual arousal.

[0156] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual desire.

[0157] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases orgasm during sexual activity.

[0158] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject results in a reduction in the difficulty or inability to achieve orgasm during sexual activity.

[0159] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sensitivity or sensation in the genital area during sexual activity.

[0160] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases numbness in the genital area during sexual activity.

[0161] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases engorgement in the genital area during sexual activity.

[0162] In some embodiments, administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases warmth, tingling, or throbbing in the genital area during sexual activity.

[0163] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject reduces pain and / or discomfort during sexual activity.

[0164] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject reduces pain and / or discomfort following sexual activity.

[0165] In some embodiments, administering a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a subject increases sexual arousal.

[0166] In some embodiments, the one or more symptoms of Female Sexual Arousal Disorder (FSAD) include, but are not limited to, decreased response to physical sexual stimulation.

[0167] In some embodiments, the female subject's primary complaint is decreased response to physical sexual stimulation.

[0168] In some embodiments, after administration of a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, the subject may experience one of the following: a. An improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28), b. An improvement of at least 1 in the wake-lubrication domain score of the SFQ28, c. An improvement of at least 1.5 in the score on the SFQ28 sense of arousal domain, d. Improvement of at least 2 in the craving domain score of the SFQ28, e. An improvement of at least 1.20 in the orgasm domain score of the SFQ28, f. Improvement of at least 1 in the pain domain score of the SFQ28, g. Improvement in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score of at least -7; h. An improvement in the sense of wakefulness score of at least 1.45; i. an improvement in genital arousal score of at least 1.13; j. An improvement of at least 1.49 in genital arousal concern score, k. Improvement in the percentage of Item 12-SSE on the Arousal Diary of at least 0.25; l. Demonstrate at least one of the following: Item 12 of the Arousal Diary - Improvement of at least 1.41 in the number of SSEs.

[0169] In some embodiments, the subject comprises a primary diagnosis of FSAD as defined by the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR).

[0170] In some embodiments, the topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof does not produce one or more of orthostatic hypotension, headache, flushing, indigestion, lightheadedness, visual disturbances, nasal congestion, back pain, muscle pain, nausea, dizziness, and rash.

[0171] In some embodiments, the subject's primary complaint is FSAD or one or more symptoms thereof.

[0172] In some embodiments, the subject's primary complaint is FSAD or one or more symptoms thereof, and the subject exhibits symptoms of secondary HSDD. In some embodiments, the subject has FSAD as their only diagnosis. In some embodiments, the subject has primary FSAD and secondary HSDD. In some embodiments, the premenopausal subject has FSAD as their only diagnosis. In some embodiments, the premenopausal subject has primary FSAD and secondary HSDD.

[0173] The present disclosure generally relates to a method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising: a. Selecting female subjects with a chief complaint of FSAD; b. applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the subject.

[0174] In some embodiments, the subject exhibits symptoms of secondary HSDD. In some embodiments, the subject's primary complaint is FSAD, and the subject does not exhibit symptoms of (or has not been diagnosed with) female orgasmic disorder (FOD). In some embodiments, the subject does not exhibit symptoms of (or has not been diagnosed with) FOD. In some embodiments, the method includes selecting a female subject who does not have complaints of FOD.

[0175] The present disclosure generally provides a method for determining the efficacy of a treatment for FSAD, comprising: a) obtaining baseline scores on one or more of the following: the Sexual Function Questionnaire (SFQ28) Arousal Cognition Domain score, the SFQ28 Arousal Lubrication Domain score, the SFQ28 Arousal Sensory Domain score, the SFQ28 Desire Domain score, the SFQ28 Orgasm Domain score, the SFQ28 Pain Domain score, the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) score, the Arousal Sensory score, the Genital Arousal score, the Genital Arousal Concerns, the Arousal Diary Item 12-SSE percentage, and the Arousal Diary Item 12-SSE number; b) administering FSAD treatment to female subjects; and c) determining an improvement in one or more of the scores of step a.

[0176] In some embodiments, the following: a. An improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28), b. An improvement of at least 1 in the wake-lubrication domain score of the SFQ28, c. An improvement of at least 1.5 in the score on the SFQ28 sense of arousal domain, d. Improvement of at least 2 in the craving domain score of the SFQ28, e. An improvement of at least 1.20 in the orgasm domain score of the SFQ28, f. Improvement of at least 1 in the pain domain score of the SFQ28, g. Improvement in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score of at least -7; h. at least a 1.45 improvement in sense of wakefulness; i. at least a 1.13% improvement in genital arousal, j. at least a 1.49 improvement in genital arousal concerns, k. Improvement in the percentage of Item 12-SSE on the Arousal Diary of at least 0.25; l. An improvement of at least 1.41 in the number of items 12-SSE on the Wakefulness Diary, indicates that FSAD treatment is effective.

[0177] In some embodiments, the methods disclosed herein include applying one or more additional doses of a topical FSAD treatment composition to the subject.

[0178] In embodiments, the improvement is measured relative to sexual activity without treatment. In embodiments, the improvement is measured relative to sexual activity before treatment. In embodiments, the improvement is measured after a single treatment (e.g., a single application). In embodiments, the improvement is measured after multiple treatments (e.g., multiple applications). In embodiments, the improvement is measured after multiple treatments over a period of time. In embodiments, the period is at least 1 week. In embodiments, the period is 1 week to 20 weeks. In embodiments, the period is 1 week to 8 weeks. In embodiments, the improvement is measured after 1 to 100 treatments. In embodiments, the improvement is measured after 1 to 50 treatments. In embodiments, the improvement is measured after 1 to 20 treatments. In embodiments, the improvement is measured after 1 to 10 treatments.

[0179] The compositions disclosed herein may include a sildenafil citrate cream. In some embodiments, the sildenafil citrate cream contains about 1% to about 5% sildenafil citrate by weight. In some embodiments, the sildenafil citrate cream contains about 3.6% sildenafil citrate by weight.

[0180] In some embodiments, about 2 grams to about 5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 2 grams to about 5 grams. In some embodiments, about 2 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 2 grams.

[0181] In some embodiments, about 0.5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 1 gram of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 1.5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 2 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 2.5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 3 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 3.5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 4 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 4.5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 0.5 grams to about 3 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 1 gram to about 4 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 2 grams to about 5 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 3 grams to about 6 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject. In some embodiments, about 4 grams to about 7 grams of the composition, e.g., sildenafil citrate cream, is administered to the subject.

[0182] In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 1 gram. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 1.5 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 2 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 2.5 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 3 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 3.5 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 4 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 4.5 grams. In some embodiments, a single unit dose of the composition, e.g., sildenafil citrate cream, is about 5 grams.

[0183] In some embodiments, half of a single unit dose of the composition is applied to the external vaginal tissue, hi some embodiments, half of a single unit dose of the composition is applied intravaginally.

[0184] In some embodiments, at least about 10% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 20% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 30% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 40% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 50% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 60% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 70% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 80% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 90% of the composition is applied to the external vaginal tissue. In some embodiments, at least about 100% of the composition is applied to the external vaginal tissue.

[0185] External vaginal tissues (e.g., vulva) include, but are not limited to, the anterior labial commissure, clitoral prepuce, glans penis, frenulum, vaginal vestibule, labia majora, and labia minora. In some embodiments, about 50% of the composition is applied to the external vaginal tissue. In some embodiments, about 50% of the composition is applied to the clitoris, vestibule, vulva, and / or vagina of a subject. In some embodiments, about 50% of the composition is applied to the clitoris, glans penis, and / or frenulum of a subject's genital area. In some embodiments, about 50% of the composition is applied to the clitoris, glans penis, frenulum, and / or vestibule of a subject's genital area. In some embodiments, about 50% of the composition is applied to the clitoris, glans penis, frenulum, vestibule, and / or labia minora of a subject's genital area.

[0186] In some embodiments, at least about 10% of the composition is applied intravaginally. In some embodiments, at least about 20% of the composition is applied intravaginally. In some embodiments, at least about 30% of the composition is applied intravaginally. In some embodiments, at least about 40% of the composition is applied intravaginally. In some embodiments, at least about 50% of the composition is applied intravaginally. In some embodiments, at least about 60% of the composition is applied intravaginally. In some embodiments, at least about 70% of the composition is applied intravaginally. In some embodiments, at least about 80% of the composition is applied intravaginally. In some embodiments, at least about 90% of the composition is applied intravaginally. In some embodiments, at least about 100% of the composition is applied intravaginally.

[0187] In some embodiments, about 50% of the composition is applied intravaginally. In some embodiments, about 50% of the composition is applied to the external vaginal tissue and about 50% of the composition is applied intravaginally.

[0188] In some embodiments, about 10% of the composition is applied to the external vaginal tissue and about 90% of the composition is applied intravaginally. In some embodiments, about 20% of the composition is applied to the external vaginal tissue and about 80% of the composition is applied intravaginally. In some embodiments, about 30% of the composition is applied to the external vaginal tissue and about 70% of the composition is applied intravaginally. In some embodiments, about 40% of the composition is applied to the external vaginal tissue and about 60% of the composition is applied intravaginally. In some embodiments, about 60% of the composition is applied to the external vaginal tissue and about 40% of the composition is applied intravaginally. In some embodiments, about 70% of the composition is applied to the external vaginal tissue and about 30% of the composition is applied intravaginally. In some embodiments, about 80% of the composition is applied to the external vaginal tissue and about 20% of the composition is applied intravaginally. In some embodiments, about 90% of the composition is applied to the external vaginal tissue and about 10% of the composition is applied intravaginally. In some embodiments, about 100% of the composition is applied to the external vaginal tissue and about 0% of the composition is applied intravaginally. In some embodiments, about 0% of the composition is applied externally to the external vaginal tissue and about 100% of the composition is applied intravaginally.

[0189] In some embodiments, the composition is not applied to the subject's labia majora or the dermis bearing pubic hair.

[0190] In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 3 cm of the vagina. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 1 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 1.5 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 2 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 2.5 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 3 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 4 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 5 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 6 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 7 cm. In some embodiments, the composition is applied intravaginally to the distal anterior vagina at a depth of about 0 cm to about 8 cm.

[0191] In some embodiments, the composition is administered about 1 minute to about 2 hours before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 2 hours before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 1 hour before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 50 minutes before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 40 minutes before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 30 minutes before sexual activity. In some embodiments, the composition is administered about 10 minutes to about 20 minutes before sexual activity. In some embodiments, the composition is administered about 1 minute before sexual activity. In some embodiments, the composition is administered about 2 minutes before sexual activity. In some embodiments, the composition is administered about 5 minutes before sexual activity. In some embodiments, the composition is administered about 10 minutes before sexual activity. In some embodiments, the composition is administered about 15 minutes before sexual activity. In some embodiments, the composition is administered about 20 minutes before sexual activity. In some embodiments, the composition is administered about 25 minutes before sexual activity. In some embodiments, the composition is administered about 30 minutes before sexual activity. In some embodiments, the composition is administered about 35 minutes before sexual activity. In some embodiments, the composition is administered about 40 minutes before sexual activity. In some embodiments, the composition is administered about 45 minutes before sexual activity. In some embodiments, the composition is administered about 50 minutes before sexual activity. In some embodiments, the composition is administered about 55 minutes before sexual activity. In some embodiments, the composition is administered about 60 minutes before sexual activity.

[0192] In some embodiments, the composition is administered in up to about 9 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 20 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 19 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 18 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 15 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 12 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 10 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 8 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 7 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 6 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 5 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 4 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 3 doses in about 4 weeks. In some embodiments, the composition is administered in up to about 2 doses in about 4 weeks. In some embodiments, the composition is administered at least about 24 hours before the second dose of the composition.

[0193] In some embodiments, the first dose of the composition is administered at least about 5, at least about 10 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 12 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 15 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 20 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 24 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 36 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 40 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 48 hours before the second dose of the composition. In some embodiments, the first dose of the composition is administered at least about 60 hours before the second dose of the composition.

[0194] In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least two times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least three times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least four times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least five times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least six times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least seven times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least eight times over a period of time. In embodiments, the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least ten times over a period of time.

[0195] In an embodiment, the period is from about 1 week to about 12 weeks. In an embodiment, the period is from about 1 week to about 10 weeks. In an embodiment, the period is from about 1 week to about 8 weeks. In an embodiment, the period is from about 1 week to about 6 weeks. In an embodiment, the period is from about 1 week to about 4 weeks. In an embodiment, the period is from about 2 weeks to about 12 weeks. In an embodiment, the period is from about 2 weeks to about 10 weeks. In an embodiment, the period is from about 2 weeks to about 8 weeks. In an embodiment, the period is from about 2 weeks to about 6 weeks. In an embodiment, the period is from about 2 weeks to about 4 weeks. In an embodiment, the period is about 1 week. In an embodiment, the period is about 2 weeks. In an embodiment, the period is about 3 weeks. In an embodiment, the period is about 4 weeks. In an embodiment, the period is about 5 weeks. In an embodiment, the period is about 6 weeks. In an embodiment, the period is about 7 weeks. In an embodiment, the period is about 8 weeks. In embodiments, the period is about 9 weeks. In embodiments, the period is about 10 weeks. In embodiments, the period is about 11 weeks. In embodiments, the period is about 12 weeks. In embodiments, the period is greater than about 12 weeks.

[0196] In embodiments, the one or more symptoms improve within about 1 week to about 12 weeks after the first administration. In embodiments, the one or more symptoms improve within about 1 week to about 10 weeks after the first administration. In embodiments, the one or more symptoms improve within about 1 week to about 8 weeks after the first administration. In embodiments, the one or more symptoms improve within about 1 week to about 6 weeks after the first administration. In embodiments, the one or more symptoms improve within about 1 week to about 4 weeks after the first administration. In embodiments, the one or more symptoms improve within about 1 week after the first administration. In embodiments, the one or more symptoms improve within about 2 weeks after the first administration. In embodiments, the one or more symptoms improve within about 3 weeks after the first administration. In embodiments, the one or more symptoms improve within about 4 weeks after the first administration. In embodiments, the one or more symptoms improve within about 5 weeks after the first administration. In embodiments, the one or more symptoms improve within about 6 weeks after the first administration. In embodiments, the one or more symptoms improve within about 7 weeks after the first administration. In embodiments, one or more symptoms improve within about 8 weeks of the first administration. In embodiments, one or more symptoms improve within about 10 weeks of the first administration. In embodiments, one or more symptoms improve within about 12 weeks of the first administration.

[0197] In embodiments, the one or more symptoms include arousal lubrication. In embodiments, the one or more symptoms include sexual desire. In embodiments, the one or more symptoms include achieving orgasm. In embodiments, the one or more symptoms include orgasmic pleasure.

[0198] In some embodiments, the female subject exhibiting one or more symptoms of FSAD has not been administered at least one of a guanylate cyclase stimulator, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha blocker within about 28 days prior to administering the first dose of the composition. In some embodiments, the female subject exhibiting one or more symptoms of FSAD has not been administered at least one of a guanylate cyclase stimulator, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha blocker within about 5, 10, 15, 20, 25, 28, 29, 30, 31, 32, 35, 40, 45, or 50 days prior to administering the first dose of the composition.

[0199] In embodiments, the subject does not have a history of active peptic ulcer disease. In embodiments, the subject does not have a history of a clinically significant bleeding disorder. In embodiments, the subject does not have a history of clitoral priapism. In embodiments, the subject does not have a history of a condition that may predispose to clitoral priapism (such as sickle cell anemia, multiple myeloma, or leukemia). In embodiments, the subject does not have a history of myocardial infarction. In embodiments, the subject does not have a history of stroke. In embodiments, the subject does not have a history of life-threatening arrhythmia. In embodiments, the subject does not have resting hypotension (BP<90 / 50 mmHg). In embodiments, the subject does not have a history of coronary artery disease causing angina. In embodiments, the subject does not have a history of congestive heart failure requiring medical intervention. In embodiments, the subject does not have a history of an underlying disease that may be particularly susceptible to the effects of a vasodilator, such as left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) or impaired autonomic control of blood pressure. In embodiments, the subject does not have a history of hearing loss. In embodiments, the subject does not have retinitis pigmentosa, and in embodiments, the subject does not have orthostatic hypotension or a history of orthostatic hypotension (e.g., a drop in systolic blood pressure of 20 mmHg or more, a drop in diastolic blood pressure of 10 mmHg or more, an increase in pulse rate of 20 beats per minute, or lightheadedness or dizziness, one or three minutes after changing position from supine to standing).

[0200] In embodiments, the subject's sexual partner has no history of a disease or disorder that may contraindicate the use of the composition. In embodiments, the subject's sexual partner has no history of myocardial infarction. In embodiments, the subject's sexual partner has no history of stroke. In embodiments, the subject's sexual partner has no history of life-threatening arrhythmia. In embodiments, the subject's sexual partner has no history of resting hypotension (BP<90 / 50 mmHg). In embodiments, the subject's sexual partner has no history of coronary artery disease that causes angina pectoris. In embodiments, the subject's sexual partner has no history of congestive heart failure requiring medical intervention, and in embodiments, the subject's sexual partner has no history of underlying diseases that may be particularly sensitive to the effects of vasodilators, such as left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis). In embodiments, the subject's sexual partner has no history of impaired autonomic control of blood pressure. In embodiments, the subject's sexual partner does not have a history of orthostatic hypotension (e.g., a drop in systolic blood pressure of 20 mmHg or more, a drop in diastolic blood pressure of 10 mmHg or more, an increase in pulse rate of 20 beats per minute, or lightheadedness or dizziness, one or three minutes after changing position from supine to standing). In embodiments, the subject's sexual partner does not have a history of priapism or a condition that may predispose to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). In embodiments, the subject's sexual partner does not have a history of non-arteritic ischemic optic neuropathy (NAION) or any underlying risk factors for NAION.

[0201] definition While several embodiments of the present disclosure have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining one or more of the results and / or advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present disclosure. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present disclosure are used. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the disclosure described herein. Accordingly, the foregoing embodiments are presented by way of example only, and it should be understood that, within the scope of the appended claims and their equivalents, the present disclosure may be practiced otherwise than as specifically described and claimed. The present disclosure relates 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, if such features, systems, articles, materials, kits and / or methods are not mutually inconsistent, is included within the scope of the present disclosure.

[0202] If the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. If two or more documents incorporated by reference include conflicting and / or inconsistent disclosure with respect to each other, the document having the later effective date shall control.

[0203] It should be understood that all definitions defined and used herein take precedence over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0204] The terms "treat," "treatment," "treating," and the like, particularly in their explicit forms, include therapeutic treatment of a subject who already has a disease or disorder. Therapeutic treatment can be symptomatic treatment to alleviate the signs and / or symptoms of the disease or disorder, or causal treatment to reverse, partially reverse, stop, or slow the progression of the disease or disorder. Thus, the compositions and methods of the present disclosure can be used, for example, as therapeutic treatment (e.g., for acute or chronic therapy).

[0205] Furthermore, terms such as "prevent," "preventing," or "prevention" generally refer to reducing, in a statistically significant manner, the occurrence of a disease or disorder and / or its signs and / or symptoms in a treated sample compared to an untreated control sample, or delaying the onset of one or more signs and / or symptoms of a disease or disorder compared to an untreated control sample. Preventing a disease or disorder and / or its signs and / or symptoms includes preventing or delaying the onset of the disease, disorder, signs and / or symptoms. Prevention also includes preventing the recurrence of a disease, disorder, signs and / or symptoms.

[0206] In certain aspects, the composition can be applied to a subject, for example, to the subject's 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, for example, 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 the subject or by another person.

[0207] The subject may be, but is not limited to, a human.

[0208] As used herein, the phrase "genital area of ​​a female subject" refers to the internal and external female reproductive organs, including, but not limited to, the vulva and vagina.

[0209] The term "vulva" includes all structures that form the female external genitalia, including the mons pubis, labia majora, labia minora, clitoris, vestibular bulbs, vulvar vestibule, Bartholin's glands, Skene's glands, urethra, and vaginal opening.

[0210] The term "vagina" refers to the elastic, muscular part of the female reproductive tract. In humans, the vagina extends from the vestibule to the cervix.

[0211] In one set of embodiments, as discussed, the composition is applied to treat a subject with a therapeutically effective amount of an active ingredient, such as any of the active ingredients described herein. A therapeutically effective amount, when administered to a subject to treat or prevent a disease or disorder, can be an amount sufficient to achieve such treatment or prevention for the disease or disorder, such as any of the diseases or disorders described herein. A therapeutically effective amount can also be an amount sufficient to induce a desired biological response, i.e., to alleviate symptoms. A therapeutically effective amount can vary depending on factors such as the desired biological endpoint, the mode of administration, and / or the age and health of the subject.

[0212] The indefinite articles "a" and "an," as used in the specification and claims, unless expressly indicated otherwise, should be understood to mean "at least one."

[0213] The term "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements, related or unrelated to those specifically identified elements, may optionally be present other than the elements specifically identified by the "and / or" clause. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer in one embodiment to A only (optionally including elements other than B); in another embodiment to B only (optionally including elements other than A); in yet another embodiment to both A and B (optionally including elements), etc.

[0214] As used herein and in the 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" shall be interpreted as being inclusive, i.e., including at least one of a number or list of elements, but also including two or more and, optionally, additional unlisted items. Conversely, expressly stated limiting terms, such as "only one of" or "exactly one of," or "consisting of," when used in the claims, refer to the inclusion of exactly one element of a number or list of elements. Generally, the term "or" as used herein shall only be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of."

[0215] As used herein and in the claims, the phrase "at least one" in connection with a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, and not excluding 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 to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "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") can refer, in one embodiment, to at least one, optionally more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally more than one, A, and at least one, optionally more than one, B (and and optionally including other elements); etc.

[0216] The term "about," when used before numerical designations such as temperature, time, amount, concentration, and such others, including ranges, indicates an approximation that may vary by (+) or (-) 10%, 5%, 1%, or any subrange or subvalue therebetween. Preferably, the term "about," when used in reference to an amount, means that the amount may vary by + / - 10%. When the word "about" is used in reference to a number herein, it should be understood that further embodiments of the present disclosure include that number unmodified by the presence of the word "about."

[0217] When a range is given by specifying a lower endpoint separately from the upper endpoint, it will be understood that the range can be defined by selectively combining any one of the upper endpoint variables with any one of the lower endpoint variables, as mathematically possible. When a range is listed, it will be understood that any subrange or value within the listed range, inclusive of the endpoints, is contemplated.

[0218] Also, unless expressly indicated to the contrary, it should be understood that any method claimed herein includes more than one step or action, and that the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0219] In the claims and in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the U.S. Patent Office Manual of Patent Examining Procedure, Section 2111.03. List of Abbreviations Abbreviation definition AE Adverse Event CD Cognitive Debriefing CE concept elicitation COS Clinical Outcomes Solutions DHIF Demographic Health Information Form FDA Food and Drug Administration FSAD Female Sexual Arousal Disorder FSDS-DAO Female Sexual Distress Scale - Desire, Arousal, and Orgasm FSDS-R Female Sexual Distress Scale-Revised FSEP Female Sexual Encounter Profile FSFI Female Sexual Function Index GAS Genital Arousal Screener GSM Genitourinary syndrome associated with menopause HRQL Health-related quality of life HSDD Hypoactive Sexual Desire Disorder ICF Informed Consent Form IRB Institutional Review Board MHF Medical History Form N number (uppercase letters are the total population, lowercase letters are the subgroup population) PRO Patient-reported outcomes SAE serious adverse event SAS Statistical Analysis System SD standard deviation SFQ-28 Sexual Function Questionnaire-28 SOP Standard Operating Procedure API Active Pharmaceutical Ingredient BMI Body Mass Index BP blood pressure CFR Code of Federal Regulations cGMP cyclic guanosine monophosphate CRO Contract Research Organization CSR Clinical Trial Report eCRF Electronic Case Report Form ECG electrocardiogram ED (erectile dysfunction) FSD Female sexual dysfunction GCP Good Clinical Practice GLP Good Laboratory Practice HBsAg hepatitis B virus surface antigen HCV Hepatitis C virus HDPE High Density Polyethylene HED Human Equivalent Dose HIPAA Health Insurance Portability and Accountability Act HIV human immunodeficiency virus HPV human papillomavirus ICF Informed Consent Form ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IND Investigational Drug IP Investigational Products IRB Institutional Review Board IRT Interactive Response Technology MedDRA Drug Regulatory Glossary NF National Formulary NO Nitric oxide NOAEL No Adverse Effect Level OTC (over-the-counter) drugs PANAS Positive and Negative Affect Schedule PDE5 phosphodiesterase type 5 PI Principal Investigator PK Pharmacokinetics QA Quality Assurance QC quality control SAE serious adverse event SHBG Sex hormone binding globulin SOC major classification by organ TEAE Treatment-emergent adverse events TMF Clinical Trial Master File USP United States Pharmacopoeia VPA vaginal pulse amplitude VPP vaginal photoplethysmograph WHODDE WHO Drug Dictionary Expanded Edition [Example]

[0220] The following examples are intended to illustrate certain embodiments of the present disclosure, but do not exemplify the full scope of the disclosure.

[0221] Example 1: Content validation of a patient-reported outcome (PRO) scale for use in female sexual arousal disorder Test Design Given the need to gather evidence of content validity for the Arousal Diary, SFQ-28, and FSDS-DAO, qualitative interviews were conducted with individuals with clinically diagnosed FSAD.

[0222] Prior to Visit 1, initial eligibility was assessed. If participants were determined to be potentially eligible, informed consent was collected. After consent, inclusion / exclusion criteria were confirmed and a clinical interview was conducted. The clinical interview was used to collect additional information and confirm the diagnosis of primary FSAD (N = 35; premenopausal women, n = 20; postmenopausal women, n = 15). At Visit 2, participants underwent an in-depth, qualitative, one-on-one interview consisting of a CE discussion and a CD discussion, which lasted a total of approximately 90 minutes. The CE and CD interview at Visit 2 consisted of three components: 1. The first part of the interview will involve a CE discussion to explore the participant's experience with FSAD and is expected to last approximately 45 minutes. 2. The second part involved participants completing three questionnaires; and 3. After completing each questionnaire, participants completed a debriefing of some of the questionnaire items, which was expected to last approximately 45 minutes.

[0223] No drug interventions or treatments were administered as part of this study.

[0224] Study population Up to 50 in-depth, one-on-one, face-to-face qualitative interviews, involving CE and CD discussion, were conducted with at least 20 premenopausal women and at least 15 postmenopausal women. A maximum of 50 women were enrolled to account for the possibility that some women could be excluded from the final analysis based on answers to the interview questions at Visit 2 indicating that they did not meet the diagnostic criteria for FSAD. However, qualitative interviews were conducted to saturation, meaning that no new concepts were emerging. This was assessed for both premenopausal women in the 7-interview group, the 7-interview group, and the 6-interview group, and postmenopausal women in the 5-interview group. A saturation matrix was developed and recorded. If new concepts were still being discussed after 20 interviews in the premenopausal group and 15 interviews in the postmenopausal cohort, further interviews could be recommended for that cohort.

[0225] Inclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study: 1. Patients must be between 21 and 70 years old. 2. Patients understand and are able to follow the protocol and agree to sign the informed consent document. 3. The patient has been sexually active (in the past 4 weeks). Sexual activity may include any activity that can result in sexual stimulation or sexual pleasure, such as intercourse, fondling, foreplay, masturbation, and oral sex. 4. Based on clinical interview, the patient has previously experienced "normal" sexual function (i.e., normal sexual desire, arousal, orgasm, and absence of pain) for at least 2 years. 5. Postmenopausal women (surgically induced or naturally occurring) must meet one of the following criteria: Self-reported bilateral oophorectomy with or without hysterectomy at least 1 year prior to screening. b. 12 months of spontaneous amenorrhea c. Six months of spontaneous amenorrhea with a serum FSH level greater than 40 mIU / mL (excluding women receiving hormone replacement therapy) 6. Patients must have a body mass index (BMI) of 18-33 kg / m 2 is. 7. The patient is fluent in English. 8. Patient agrees not to use cannabinoid-containing products within 24 hours of Visit 1 and Visit 2.

[0226] Exclusion criteria Any potential participant who met any of the following criteria was excluded from participation in the study: 1. The patient has any disorder, or a history of any disorder, that, in the opinion of the investigator, may prevent successful completion of the study. 2. Patient has self-reported or currently diagnosed with an uncontrolled medical condition (e.g., cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, dermatological, hematological, neurological, genitourinary, or psychiatric condition). 3. Patient reports a history of sexual trauma or sexual abuse contributing to any sexual dysfunction problems (e.g., desire, arousal, orgasm, pain) as determined by clinical interview. 4. Patients have 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 causing angina pectoris; or congestive heart failure requiring medical intervention. 5. Patient has a chief complaint of anorgasmia, pain, vaginismus, low desire, or any other sexual complaint apart from problems with genital arousal as determined by clinical interview. 6. Patients have symptoms of or are currently diagnosed with dyspareunia, vulvovaginal infection or inflammation, vulvar or vaginal inflammatory disorder, vestibulodynia, clitorodynia, or vulvovaginal atrophy (patients who present with painless vaginal dryness as the only symptom of vulvovaginal atrophy remain eligible), or symptoms of any other vulvar or vaginal disorder as determined by clinical interview. a. Patients with bacterial vaginosis or yeast infections can be rescreened after the infection has been treated and resolved. 7. Patient has undergone major pelvic surgery that may cause nerve injury, including but not limited to vulvectomy, colostomy, cystostomy, or bladder abnormalities (including those for incontinence), rectal surgery, or abdominal surgery. 8. Patient reports or has been diagnosed with a neurological disorder due to conditions such as diabetes, stroke, pelvic nerve injury secondary to trauma, cancer treatment, myasthenia gravis, multiple sclerosis, or spinal cord injury. a. Patients with symptoms of peripheral neuropathy, including patients who report "numbness" or "no feeling" in the genitals during sexual activity, are excluded. 9. With the exception of anxiety and depression, participants have any current and / or previously reported diagnosis of a DSM-IV-TR axis I disorder, including organic psychiatric syndromes and disorders. a. Patients diagnosed with anxiety or depression will be managed as determined by the investigator and, if on medication, will be on a stable medication and dosage for at least 6 months prior to the clinical interview. b. Patients have a total score of less than 10 on the Patient Health Questionnaire-8 (a screening and assessment instrument for depression), indicating minimal or mild depression. c. The patient has a total score of less than 6 on the Generalized Anxiety Disorder (GAD)-7 (an anxiety screening and assessment instrument), indicating mild anxiety. 10. Patients have a history of gynecological cancer or are undergoing active treatment for any cancer that would interfere with their ability to successfully complete the study. Patients previously treated for dysplasia (precancerous changes) may be enrolled as long as they have undergone local treatment (e.g., cryosurgery or laser). 11. Patient has a history of substance abuse within 1 year prior to Visit 1. Patients who report a history of substance abuse in the past must have been in remission or abstinent for at least 1 year prior to the clinical interview. 12. Patient has a history of alcoholism within 1 year prior to Visit 1. Patients who previously reported a history of alcoholism must have been in remission or abstinence for at least 1 year prior to the clinical interview. 13. Patients are currently receiving or have received within the past 3 months treatment for FSAD symptoms (pharmacological or non-pharmacological). 14. Patient has a positive finding from a urine drug screen (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, methadone, and opiates), except in the case of a known disorder (e.g., ADHD) that does not interfere with the patient's ability to successfully complete the study. 15. Patient has symptoms of or has been diagnosed with chlamydia, gonorrhea, or syphilis within the past 3 months. 16. Patients report having a genital or anal HPV or HSV outbreak (blisters, warts, or vesicles) at any time in the past month. Patients may be rescreened after the outbreak has been treated and resolved. Patients who report genital skin breakouts, irritation, skin disease or lesions, or other abnormal vulvovaginal findings will also be excluded. 17. Patient has participated in any clinical trial evaluating another investigational drug or treatment within 3 months prior to Visit 1. 18. Patients had been exposed to any of the measures under investigation, including the Arousal Diary, Sexual Function Questionnaire (SFQ), Female Sexual Distress Scale-Desire, and Arousal, Orgasm (FSDS-DAO) or other sexual dysfunction questionnaires (e.g., FSFI, FSDS-R, FSEP), in the past 6 months prior to the clinical interview. 19. Patient has symptoms of or is currently diagnosed with a pelvic or urinary tract infection. Patients may be re-screened after the infection has been treated and resolved. 20. Patients self-report that they are currently breastfeeding or pregnant, plan to start breastfeeding during the study, or have been pregnant or breastfeeding within 6 months prior to Visit 1.

[0227] Clinical Diagnosis of FSAD Patients who met all of the above inclusion and exclusion criteria underwent a formal semi-structured clinical interview at Visit 1 to confirm a diagnosis of primary FSAD as defined by DSM-IV-TR.

[0228] Primary FSAD, as defined by the DSM-IV-TR, is acquired (i.e., not present at birth), generalized (i.e., present across situations), and present for at least 6 months prior to the clinical interview. Eligible patients had a primary complaint of lack of genital arousal during sexual activity and considered their genital response meaningful to their overall sexual experience. Eligible patients also experienced distress due to difficulties with sexual arousal. Patients with secondary complaints related to low desire due to lack of genital arousal (hypoactive sexual desire disorder) were considered eligible as long as the problems related to low genital arousal were considered the most bothersome symptom and occurred before low desire. Patients who exhibited cognitive arousal problems (i.e., not feeling mentally aroused during sexual activity) were also considered eligible as long as the problems related to low genital arousal were considered the most bothersome symptom and occurred before the cognitive arousal problems.

[0229] Because FSAD is a diagnosis of exclusion, the clinical interview also focused on excluding patients with symptoms of vulvovaginal disorders, including but not limited to vulvovaginal infection or inflammation, dyspareunia, genitourinary syndrome of menopause (GSM) or vulvovaginal atrophy, vulvar or vaginal inflammatory disorders (lichen sclerosus, lichen planus, plasma cell vulvitis, mucous membrane pemphigoid, exfoliative inflammatory vaginitis, Sjogren's syndrome, contact dermatitis, allergic vaginitis, vestibulodynia, and clitoral pain).

[0230] Recruitment and Screening Recruitment Strategy Clinics were women's sexual health specialty centers or medical facilities. Recruitment remained open until the study enrollment goal (N = 35; n = 20 premenopausal women, n = 15 postmenopausal women) was met. Screening failures were not counted against total site enrollment.

[0231] All recruitment procedures followed Institutional Review Board (IRB) approved protocols. Potential participants were scheduled for a screening appointment at Visit 1.

[0232] Participants are free to withdraw from the study for any reason and may revoke / revoke permission / withdraw from participation at any time without penalty or repercussion by providing written notice. If required by the participant's clinical condition, the participant's involvement may be terminated at any time during the study.

[0233] The specific objectives are as follows: ● Phase 1: Concept Elicitation (CE) Interview: To explore the relative importance of FSAD symptoms, including the experience of disease-related symptoms and their severity and bothersomeness, as well as their impact on patients' health-related quality of life (HRQL). ● Phase 2: Cognitive Debriefing (CD) Interview: To explore the relevance of selected PRO measures based on patients' own experiences To determine patient understanding of selected PRO instrument items, instructions, and response options To evaluate the appropriateness of the specified recall periods of selected PRO measures, focusing on a 24-hour recall period versus a 4-week period.

[0234] Screening Procedure (Visit 1) Participants were also asked to complete a semi-structured clinical interview to confirm the diagnosis of primary FSAD. After eligibility was confirmed, participants were scheduled for Visit 2, the CE and CD interview.

[0235] Sampling stratification Interview procedure (visit 2) The interview at Visit 2 was conducted in person or by telephone if in person was not possible. The CE portion of the interview came first and lasted approximately 45 minutes. Participants were then asked to complete the Arousal Diary, SFQ-28, and FSDS-DAO, which took approximately 10 minutes. Following this, the CD portion of the interview began and lasted approximately 45 minutes.

[0236] concept derivation The in-person qualitative interviews began with a series of brief CE questions with each participant. This took the form of an open discussion in which each participant discussed their individual experiences of sexual arousal issues and related impacts. This was used to obtain a complete, individually driven picture of the impact of FSAD, ensuring that significant arousal issues and their impacts were fully covered. Participants then discussed the severity of the symptoms elicited, ranked the most bothersome symptoms, and identified those symptoms they perceived as most important for treatment. Participants also discussed the emotional impact of FSAD to determine the words women spontaneously used to describe it, such as bothersome, distressing, and frustrating.

[0237] Cognitive Debriefing Following the CE portion, each participant then completed each questionnaire. The purpose of the CD interview was to explore participants' understanding and relevance of the scales. Participants first completed each scale as they would in a clinical trial (i.e., without interruption from the interviewer). Participants were asked questions regarding the relevance and their experience with the concepts assessed by each item. For items with concepts that participants described as relevant and / or had experienced, additional questions were asked to further debrief the item, assessing the item's content, response options, and scoring. To test for order effects on women's item preferences based on exposure (i.e., preference for questions exposed first), the order of the questionnaires was varied. Half of the premenopausal women and the first eight postmenopausal women completed the questionnaires in the following order: SFQ-28, FSDS-DAO, and wakefulness diary. The remaining half of the premenopausal women and seven postmenopausal women completed the questionnaires in the following order: wakefulness diary, SFQ-28, and FSDS-DAO.

[0238] The interviews also discussed any "new" issues not captured in the scale that were mentioned during the CE portion of the interview to explore whether participants felt these "new" concepts should be added or whether the content of the scale allowed participants to adequately describe these experiences.

[0239] analysis Participant characteristics Participant characteristics were summarized to characterize the enrolled population and provide context for qualitative data. Continuous data were summarized as number (n), mean, and standard deviation (SD). Categorical data were summarized in terms of the number of participants providing data at the relevant time point (n), frequency counts, and percentages. Percentages were based on participants with non-missing parameters. Percentages were reported to two decimal places. Analyses were performed using Statistical Analysis System (SAS) v9.4.

[0240] Qualitative Data Analysis Analysis of CE data The transcribed data were entered into NVivo v.12, a software package designed to facilitate the storage, coding, and analysis of qualitative data. This software allows themes, concepts, or domains to be grouped by different variables (e.g., ethnicity, age). Analysis of the CE interview data was guided by the study's objectives and key concepts of interest and coded thematically. A preliminary codebook based on the study's objectives and key concepts of interest was developed. Using this codebook, interview transcripts were coded, and emerging new codes were identified in subsequent interviews. Revisions to the coding structure were monitored to ensure all codes were clearly defined and consistently applied.

[0241] Saturation analysis To support the validity of the selected PRO measures, it was important to demonstrate that all key concepts emerged in the interview sample; this was referred to as a "saturation analysis." Concept saturation was assessed in the CE interviews, and no new themes or concept explanations were introduced by the final interview. Concept elicitation interviews were conducted until saturation (no new concepts emerged from subsequent interviews); therefore, additional interviews could be conducted until this was achieved.

[0242] Because CD is confirmatory in nature, saturation analyses were conducted only on the CE portion of the interviews. Saturation analyses are only appropriate when the interviews are exploratory by design (i.e., CE interviews). To determine this, CE interview transcripts (N = 35) were divided into premenopausal and postmenopausal women. Premenopausal interview transcripts were grouped into three sets (n = 7, n = 7, n = 6 in each set), and postmenopausal interview transcripts were grouped into three sets of n = 5 in the order in which they were conducted. The derived concepts were then compared between the sets in each group. The process for determining whether concept saturation was achieved among adult participants was as follows. • The thematically derived concepts were converted into two ordinal groups: “not discussed” equals 0 and “discussed” equals 1. • Concepts that emerged in the first series of interviews were compared with concepts that emerged from the second series of interviews. • The concepts that emerged from these first two sets of interviews were then compared with those that emerged from the third set of interviews. • Saturation is considered to have been achieved when no new concepts emerge.

[0243] If saturation was not achieved after all interviews had been analyzed, recommendations were made regarding the usefulness of conducting additional interviews.

[0244] Analysis of CD data Analysis of the CD data focused on quotations related to the primary research question, including relevance, understanding, and any paraphrasing suggestions. The first two CD transcripts were coded to develop a preliminary codebook for the CD interviews. Using this codebook, the remaining interview transcripts were coded to identify any new codes that emerged in subsequent interviews. Revisions to the coding structure were monitored to ensure all codes were clearly defined and consistently applied.

[0245] Example 2: A Phase 2b, Multicenter, Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 3.6% Sildenafil Cream in Premenopausal Patients with Female Sexual Arousal Disorder (FSAD) Currently, there are no approved treatments for female sexual arousal disorder (FSAD). The purpose of this study was to test the systemic and local genital safety of 3.6% topical sildenafil cream in healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period.

[0246] To evaluate patient-reported outcomes (PROs) in women with FSAD, a double-blind, placebo-controlled, phase 2b study assessed changes in female sexual function after administration of 3.6% sildenafil cream using several PRO measures, including the Sexual Function Questionnaire (SFQ28), Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO), Patient Global Impression of Severity (PGI-S), Patient Global Impression of Change (PGI-C), Patient Global Impression of Frequency (PGI-F), Patient Global Impression of Change in Concerns about Sexual Difficulties (PGI-C Concern), Patient Global Impression of Change in Satisfying Sexual Events (PGI-C SSE), and an arousal diary.

[0247] Female sexual arousal disorder (FSAD) is defined in the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (DSM-IV-TR) as the persistent or recurrent inability to achieve or maintain an adequate lubrication-swelling response to sexual arousal until the end of sexual activity, causing significant distress or interpersonal difficulties. FSAD is estimated to adversely affect approximately 20% of women in the United States (US), and furthermore, the disruption of sexual arousal affects other aspects of the sexual response. Orgasm is unlikely without arousal, and FSAD generally results in a lack of desire because sexual activity is not pleasurable or reinforcing. Despite the high prevalence of FSAD in women and its potential impact on other aspects of sexual function, to date, there are no pharmacologic treatments for FSAD approved by the US Food and Drug Administration (FDA). Most commonly, treatment involves the administration of topical lubricants, which help mask the lack of vaginal lubrication associated with FSAD, but are ineffective in enhancing genital / clitoral blood flow or alleviating the reduced genital sensation associated with FSAD.

[0248] Published placebo-controlled trials of oral sildenafil citrate administered to premenopausal and postmenopausal women with a wide range of FSDs (e.g., hypoactive sexual desire disorder (HSDD), FSAD, female orgasmic disorder (FOD), dyspareunia) unrelated to comorbid illness or medication use have shown marginal efficacy versus placebo.

[0249] The present disclosure provides a 3.6% topical sildenafil cream for the treatment of FSAD. Local delivery of sildenafil specifically targeted to genital anatomical structures central to the vasoarousal response results in less systemic exposure and subsequent systemic side effects, leading to a more favorable safety profile. The co-primary objective of this study was to evaluate the safety and efficacy of 3.6% sildenafil cream in healthy premenopausal women with FSAD.

[0250] Patient evaluation Healthy premenopausal women aged 18 years or older and their sexual partners were screened. Applicants and their sexual partners provided written informed consent before any study-related procedures were performed. Women at risk of pregnancy used effective contraception throughout the study. Women or their partners were excluded if they had uncontrolled hypertension, a history of serious cardiac events (e.g., myocardial infarction, stroke), orthostatic hypotension, or other serious medical comorbidities. A one-on-one, individual clinical interview with each potential participant was conducted using an interviewer who was a recognized expert in the field and not an employee of the sponsor to establish the diagnosis of FSAD and to confirm that FSAD was the woman's primary sexual dysfunction concern in the presence of other secondary FSDs. Table 2 outlines the assessment schedule.

[0251] Applicants and their sexual partners underwent informed consent and screening safety procedures at Visit 1. Approximately 1 year after the start of the study, many applicants were unwilling to disclose their FSAD symptoms to their sexual partners, so the protocol was amended to allow participation from women whose recruitment barriers were the requirement that their sexual partners consent and be involved in adverse event (AE) reporting. Specifically, protocol amendment 3 allowed women to enroll in the trial if they did not have a sexual partner or if their sexual partner did not want to participate in the informed consent and safety monitoring process. In the latter case, the investigational product (IP) was to be used only for unpartnered, solo sexual encounters; if the subject had a sexual partner, no partnered sexual events could occur within 72 hours of IP application. If a partnered sexual encounter was recorded with a non-consenting partner, the participant was discontinued from the study.

[0252] The study included a 28-day drug-free period followed by a 28-day single-blind placebo run-in period. If participants failed to record sexual experiences and AEs in the electronic diary (eDiary) or had a predefined placebo response (total score ≤18) on the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) during the single-blind placebo run-in period, their partners failed during these 2-month screening periods. At Visit 4, eligible participants were randomized 1:1 to 3.6% sildenafil cream versus placebo cream.

[0253] The double-blind treatment period lasted 12 weeks, from Visit 4 to Visit 7. During this period, participants were seen monthly, and the investigator assessed treatment-emergent adverse events (TEAEs), as well as the severity of the TEAEs and their relationship to the study product or procedures. Between visits, participants recorded TEAEs using an eDiary.

[0254] Patients and Partners - Study Participation and Safety Assessment Eligible patients and their respective partners completed a separate informed consent form (ICF) at Visit 1 before participating in the study. Both patients and their partners also met all respective inclusion and exclusion criteria required for study participation, which were assessed at Visit 1. Both patients and their partners completed assessments as needed and recorded any adverse events at home using a separate eDiary. In addition, patient-administered PRO assessments (SFQ28, FSDS-DAO, PGI-S, PGI-C, and PBE) were completed at scheduled visits using the eDiary.

[0255] The eDiary prompted patients to complete the eDiary within 24 hours of each sexual event and at any time during the course of the study if an AE occurred. If a sexual event occurred, patients used the eDiary to record the application of IP, record any adverse events, and complete an arousal diary. The eDiary also prompted partners to assess every 24 hours whether they had had a partnered sexual event for the purpose of capturing any adverse events.

[0256] If a sexual event occurred, the eDiary prompted the patient and partner: "Have you had any complaints since your sexual event?" If the patient or partner answered "yes," the eDiary further prompted them about some of the more common side effects associated with oral phosphodiesterase type 5 (PDE5) inhibitors. Assuming wireless connectivity, responses from patients or partners reporting complaints after sexual activity were electronically transmitted to the site for evaluation and triage within 24 hours of receiving the information. Additionally, patients and their partners who answered "yes" to any complaints were reminded to contact the study site.

[0257] Patient population, demographics and baseline characteristics Enrollees (n = 833) and their sexual partners (n = 605) provided informed consent. Of those who consented, 277 eligible participants participated in the drug-free run-in period, and 252 participated in the single-blind placebo run-in period. Two hundred participants were randomized to either 3.6% sildenafil cream (n = 101) or placebo cream (n = 99). During the double-blind treatment period, 99 women assigned to 3.6% sildenafil cream and 94 women assigned to placebo cream received at least one dose of their assigned IP. There were no allocation errors. An additional 40 women exposed to at least one dose of placebo cream during the single-blind run-in period were also included in the safety analysis population, bringing the total number of placebo-exposed participants to 134. Table 1A shows the demographics and baseline characteristics of subjects included in the safety analysis population. [Table 1] Main purpose: SFQ28(AS)-28-Day Recall: To evaluate the efficacy of 3.6% sildenafil cream versus placebo cream in patients with FSAD, as measured by the change from baseline to the end of the study (i.e., the end of the 12-week double-blind dosing period) in the arousal-sensation domain of the Sexual Function Questionnaire (SFQ28). Using the SFQ28(AS) score at the end of the single-blind placebo run-in as the baseline, the results of the 3.6% sildenafil cream arm will be compared to those of the placebo cream arm.

[0258] The SFQ28 is a 28-item PRO questionnaire that covers most aspects of the sexual response cycle (desire, arousal, orgasm) and pain or discomfort. Specifically, the SFQ28 has eight domains (desire, arousal sensation, arousal-lubrication, arousal-cognition, orgasm, pain, enjoyment, and partner) that ask about a woman's sexual activity and her sex life with her partner over the past four weeks. The SFQ28 defines sexual life as both physical sexual activity and the emotional sexual relationship a person had with their partner. To evaluate the efficacy of 3.6% sildenafil cream versus placebo cream in patients with FSDS-DAO (Q14)-28-day recall: To evaluate the efficacy of 3.6% sildenafil cream versus placebo cream in patients with FSAD, as measured by the change from baseline to end of study in score on the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) Concerns Due to Difficulties in Sexual Arousal-Item #14 only. Using the FSDS-DAO (Q14) score at the end of single-blind placebo run-in as the baseline, the results of the 3.6% sildenafil cream arm will be compared to those of the placebo cream arm.

[0259] The FSDS-DAO is a 15-item PRO questionnaire that includes a list of feelings and problems women may have regarding their sexuality. Specifically, women are asked to rate each item in terms of frequency, from 0 (never) to 4 (always), that best describes "how often you have been bothered or distressed by the problem during the past 30 days, including today." To calculate a total score for this scale, items are summed to produce a total ranging from 0 to 60, with higher scores indicating greater sexual-related distress. In this study, item 14 is scored using the value associated with the selected response option. Secondary Objectives: Stimulation Diary (SSE): To evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD as measured by the change from baseline to the end of the study (i.e., the last 4 weeks of the double-blind dosing period) in the number of satisfying sexual events completed by daily prompt within 24 hours after each sexual event (Stimulation Diary Question #11). Using the SSE score at the end of the single-blind placebo run-in as the baseline, the results of the 3.6% sildenafil cream arm will be compared to those of the placebo cream arm.

[0260] Exploratory purpose: The eDiary is completed (using daily prompts) within 24 hours after each sexual event. Arousal Diary (AS): To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) in the Arousal-Sensation domain of the adapted SFQ28 (Arousal Diary Questions #1-5) completed within 24 hours after each sexual event.

[0261] Arousal diary questions include: "During sexual activity, how much pleasurable sensation did you feel in your vaginal / genital area?" (item 1), "During sexual activity, how much 'warmth' (e.g., a feeling of increased temperature) did you feel in your vaginal / genital area?" (item 2), "During sexual activity, how much 'pulsation' or 'tingling' did you feel in your vaginal / genital area?" (item 3), "During sexual activity, how much 'numbness' did you feel in your vaginal / genital area?" (item 4), "During sexual activity, how much "How much 'engorgement' or 'fullness' did you feel in your vaginal / genital area?" (Item 5). Responses range on a five-point scale from 1 (no pleasant sensation / no 'warmth' sensation / no 'pulsating' or 'tingling' sensation / no 'numbness' sensation / no 'engorgement' or 'fullness' sensation) to 5 (very pleasant sensation / extremely 'warmth' / very strong 'pulsating' or 'tingling' sensation / very strong 'numbness' sensation / very strong 'engorgement' or 'fullness' sensation). Arousal Diary (AL): To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) in the Arousal-Lubrication domain of the adapted SFQ28 (Arousal Diary Question #6) completed within 24 hours after each sexual event. Arousal Diary (GA): To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) in genital arousal questions (#7-9 on the Arousal Diary) completed within 24 hours of each sexual event. Arousal Diary (SSE): In addition to the above secondary objectives, to evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by the change from baseline to Week 4 (Visit 5) and Week 8 (Visit 6) in the number of satisfying sexual events completed by daily prompt (Arousal Diary Question #11). It was completed at the end of drug run-in, single-blind placebo run-in, and after each month during the double-blind medication period. ● SFQ28(AS)-28-day recall: In addition to the above secondary objectives, to evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in the Alertness-Sensation domain at Week 4 (Visit 5) and Week 8 (Visit 6). ●FSDS-DAO (Q14) - 28-Day Recall: In addition to the above secondary objectives, to evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in item 14 of the FSDS-DAO at Week 4 (Visit 5) and Week 8 (Visit 6). SFQ28(AL)-28-Day Recall: To evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in the Alertness-Lubrication domain at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7). ● SFQ28 (Orgasm) - 28-Day Recall: To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in the orgasm domain at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7). SFQ28 (Wake Cognition)-28-Day Recall: To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in the wake cognition domain at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7). ● SFQ28 (Cravings) - 28-Day Recall: To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in the craving domain at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7). ● FSDS-DAO-28-Day Recall: To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by change from baseline in total score at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7). PGI-S: To evaluate the effectiveness of 3.6% sildenafil cream in patients with FSAD as measured by Patient Global Impression of Severity at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7). PGI-C: To evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD as measured by Patient Global Impression of Change at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) of the double-blind dosing period. To be completed at the end of the double-blind medication period. ● PBE (Patient Benefit Assessment): To evaluate the efficacy of 3.6% sildenafil cream in patients with FSAD, as measured by PBE, assessed with a yes / no question at the end of double-blind treatment.

[0262] Table 1B provides an overview of the PRO instruments and assessments used in the trial for the clinical diagnosis of FSAD, the inclusion criteria for FSAD, and the primary, secondary, and exploratory endpoints. [Table 2] Note: At Visit 2, no PRO measures will be administered or PRO assessments will be conducted. (a) An arousal diary to be completed (via daily prompts) within 24 hours after the completion of each sexual activity. (b) Responses and scores after 4 weeks of single-blind placebo run-in were used to establish a baseline. Additional notes regarding Table 1B Primary endpoint SFQ28(AS): Change in the SFQ28 Alertness-Sensation (AS) domain score from baseline to the end of the study FSDS-DAO (Q14): Change from baseline to end of study in scores regarding concerns about difficulties in sexual arousal (item 14 of the FSDS-DAO) Secondary endpoints Arousal Diary (SSE): Change in number of satisfying sexual events (SSE) from baseline to end of study Exploratory Endpoints • Awakening Diary (AS): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • Awakening Diary (AL): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • Awakening Diary (GA): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • Sneaky Sentence Examination (SSE): In addition to the secondary endpoint analyses above, change from baseline to week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period. ● SFQ28(AL): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ●SFQ28 (AC): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • SFQ28 (craving): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ● SFQ28 (Orgasm): Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ●SFQ28 (AS): In addition to the primary endpoint analysis above, change from baseline to week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period. • FSDS-DAO: Change from baseline in FSDS-DAO total score obtained from Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ●FSDS-DAO (Q14): In addition to the primary endpoint analyses above, the change from baseline in item 14 of the FSDS-DAO obtained from week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period. ● PGI-S: Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ● PGI-C: Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ● PGI-F: Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • PGI-C Concerns: Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. • PGI-C SSE: Change from baseline to Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) of the double-blind dosing period. ●PBE: Patient Benefit Evaluation [Table 3] Both the patient and their partner (all partners must attend Visits 1 and 2; same-sex partners of childbearing potential will also attend Visit 7). Partners will be allowed to conduct vital signs from home using a blood pressure cuff assigned to the study. If self-assessment is selected, partners will be examined remotely via a telehealth visit. b. A vulvo-vaginal examination will be performed using vulvoscopy (using a speculum) to determine the level of sensitivity at each visit. c. Following successful completion of Visit 1, perform laboratory evaluation (including chemistries, hematology, thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), albumin, sex hormone binding globulin (SHBG), total testosterone, estradiol, prothrombin time, urinalysis), urine drug screen, serum pregnancy test, serology (including HIV antibodies), nucleic acid amplification tests (NAAT) for sexually transmitted diseases (gonorrhea, chlamydia, trichomoniasis), bacterial vaginosis, and yeast. d. Perform a Pap smear unless the patient has had a Pap smear within 3 years of Visit 1 and can provide documentation. e. If the patient's partner is a woman of childbearing potential, a urine pregnancy test will be administered to her at the Screening Visit and at Visit 7 (or upon early termination). f. At Visit 1, a single standard 12-lead ECG will be collected for medical screening purposes. g. Patient adverse events will be captured initially using the eDiary and assessed by the PI or designee after Visit 2. Any adverse events reported by the partner will be captured in source documents and eCRFs by study site staff. h. At Visit 3, all patients will be given a placebo cream.

[0263] Investigational Product (IP), Dose and Mode of Administration: 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 was a placebo cream. The double-blind IPs were either 3.6% sildenafil cream or placebo cream. The IPs were provided in 30-gram tubes. Patients were randomized 1:1 via Interactive Response Technology (IRT) for participation in the double-blind dosing period and provided with corresponding tubes. There were no allocation errors. A dosing card was provided to ensure accurate measurement of the administered dose. Patients were instructed to apply approximately 50% of the IP externally to the vulva (i.e., clitoris, vestibule, and labia minora) and approximately 50% intravaginally. Patients were instructed to use the dosing card to measure out the appropriate amount of cream for intravaginal and vulvar application. Patients were instructed to gently apply the cream internally and externally as directed.

[0264] Study design and methodology: Described herein is a Phase 2b, multicenter, multiple-dose, double-blind, placebo-controlled study to evaluate the efficacy and safety of 3.6% sildenafil cream in premenopausal patients with FSAD.

[0265] The study consisted of four periods: a medical screening period, a drug-free period, a single-blind placebo run-in period, and a double-blind medication period. All patients were contacted (by telephone) after completing the final visit for a safety follow-up period. Table 2 provides a schedule of events and visit requests for the study, as well as a summary of the instruments and assessments utilized: (i) diagnoses, (ii) inclusion and exclusion criteria, and (iii) primary, secondary, and exploratory endpoints.

[0266] Medical Screening Period: (Visit 1) After completion of telephone screening (less than 28 days prior to Visit 1) or in-person discussion, eligible participants were scheduled for Visit 1 and completed the following five steps to confirm eligibility to proceed to the drug-free period (Visit 2). Table 1B provides a complete list of required assessments.

[0267] Step 1 - FSAD Screening Tool for Inclusion and to Establish Baseline Sexual Function After patients provided written informed consent, baseline levels of FSAD symptoms (including genital hyposensitivity and distress related to sexual problems) and sexual function were assessed by two patient-reported outcome (PRO) measures: 1. Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) a. A total score of 18 or greater is required to confirm distress related to sexual dysfunction 2. Sexual Function Questionnaire-SFQ28 Step 2 - Additional Inclusion Criteria - Patients may enter the study if they meet all of the following criteria: 1. Patients must be premenopausal women aged 21 years or older. 2. The patient is fluent in English. 3. Patients understand and are able to follow the protocol and agree to sign the informed consent document. 4. Patients are in a secure, communicative, stable, single-partner relationship for at least 6 months prior to Visit 1. This relationship is with one sexual partner who is psychologically, physically, and sexually functional. The partner is consistent and available throughout the duration of the study. 5. Based on a clinical interview, the patient has experienced "normal" sexual function for at least two years. The patient has engaged in sexual activity at least twice a month for the past six months and agrees to engage in sexual activity at least twice a month during the study period. Sexual activity may include any activity that can produce sexual stimulation or sexual pleasure, such as intercourse, fondling, foreplay, masturbation, and oral sex. a. Patients will be excluded if they have experienced recent major life stress (e.g., loss of income, death of a family member) or relationship discord (excluding distress related to FSAD) that may interfere with sexual activity. 6. Females of childbearing potential agree to continue using an acceptable form of birth control for the duration of the study and must be on a stable dose or have an insert / implant for at least 6 months without complications prior to Visit 1 and agree to remain on their birth control dose throughout the entire study period. a. Acceptable forms of birth control include the following: intrauterine systems [IUS], progestin- and / or estrogen-containing hormonal oral contraceptives, contraceptive patches, contraceptive implants, contraceptive injections, or copper-containing intrauterine devices (IUDs). b. Vaginal forms of contraception, such as contraceptive foams / gels, diaphragms, penile or vaginal condoms, contraceptive vaginal rings, and sponges, are not considered acceptable methods of birth control for this study. c. Latex and polyisoprene condoms are not acceptable forms of contraception but may be used to prevent sexually transmitted diseases. 7. Patients must have a body mass index (BMI) between 18 and 35 kg / m 2 is. 8. Patient has had a Pap smear performed within 3 years prior to Visit 1 and can provide documentation of normal test results (based on current guidelines published by the US Preventive Services Task Force). If the patient is unable to provide documentation, a Pap smear will be performed at Visit 1. Patients with abnormal findings will be excluded from study participation and referred for follow-up care as appropriate. 9. Patients are medically healthy and have no clinically significant medical history, physical exam, gynecological history and exam, laboratory profile (e.g., hematology, urinalysis), vital signs (e.g., uncontrolled hypertension) or ECG. a. Patients with clinically significant ECG abnormalities at Visit 1 will be excluded. b. Patients with controlled treated hypertension (i.e., <140 / 90 mmHg, on stable doses for the past 6 months, on no more than two antihypertensive medications excluding alpha blockers and nitrates) are considered eligible. c. Patients with thyroid disease under controlled treatment with stable medication and dose for the past six months will be considered eligible. TSH must be within the normal range (confirmed by laboratory testing). 10. Participants agree not to use vaginal hormone therapy (e.g., vaginal estrogen, vaginal prasterone), vaginal or vulvar lubricants, spermicides, creams or gels, contraceptive foams, or vaginal douche products throughout the study period. a. Women who self-report abnormal physiologic vaginal discharge are excluded until the abnormal physiologic discharge symptoms have resolved. b. Patients using systemic (transdermal or oral) therapy will be on a stable dose for at least 6 months prior to Visit 1. Step 3 - Exclusion Criteria - Patients who meet any of the following criteria will not participate in the study. 1. Patients were lactating or pregnant (based on a positive serum pregnancy test), would become pregnant or wish to initiate lactation during the study period, or had been pregnant or lactating within 6 months prior to Visit 1. 2. The patient has two or more sexual partners. 3. Patients are postmenopausal (surgically induced or naturally occurring) meeting any of the following criteria: a. Underwent bilateral oophorectomy with or without hysterectomy; b. 12 months of spontaneous amenorrhea; c. Six months of spontaneous amenorrhea with a serum FSH level >40 mIU / mL (excluding women receiving hormone replacement therapy). 4. Patient has any disorder or history of any disorder that may prevent successful completion of the study. 5. Patient has a significant cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, dermatological, hematological, neurological, genitourinary, or other unstable medical condition that contraindicates administration of study medication, interferes with study assessments, limits study participation, or confounds interpretation of study results. 6. Patient has a history of unresolved sexual trauma or sexual abuse contributing to any sexual dysfunction problems (desire, arousal, orgasm, etc.) as determined by clinical interview. 7. Patients with any history of active peptic ulcer or clinically significant bleeding disorder. 8. Patients with a history of clitoral priapism or conditions that may predispose to clitoral priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). 9. Patients with a history of myocardial infarction, stroke, or life-threatening arrhythmia within 6 months prior to Visit 1; any history of coronary artery disease causing resting hypotension (BP < 90 / 50 mmHg) or angina pectoris, or congestive heart failure requiring medical intervention; patients with underlying conditions that may be particularly sensitive to the effects of vasodilators, including patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and patients with impaired autonomic control of blood pressure, or whose underlying cardiovascular condition makes sexual activity inadvisable. 10. Patients with a history of hearing loss. 11. Patients have retinitis pigmentosa even though they feel clinically well at Visit 1. Patients with retinitis pigmentosa will be identified by specifically asking whether they have the condition, whether they have visual signs and symptoms of the condition (including asking patients about whether they have difficulty seeing at night or in low light and whether they have any visual field defects indicating loss of peripheral or central vision), or whether they have a family history. 12. Patient has a history of orthostatic hypotension, defined as a decrease in systolic blood pressure of 20 mmHg or more, a decrease in diastolic blood pressure of 10 mmHg or more, an increase in pulse rate of 20 beats per minute, or experiencing lightheadedness or dizziness 1 or 3 minutes after a supine to standing position change, or orthostatic hypotension noted at Visit 1. 13. Patient has a chief complaint of anorgasmia, vaginismus, low desire, or any other sexual complaint apart from problems with genital arousal as determined by clinical interview. 14. Patients have untreated dyspareunia, vulvovaginal infection or inflammation, vulvar or vaginal inflammatory disorders, vestibulodynia, clitorodynia, or symptomatic vulvovaginal atrophy (defined as women with 5% or less superficial cells on a vaginal smear, a vaginal pH greater than 5, and patient-perceived moderate or severe symptoms of vulvovaginal atrophy at baseline). 15. The patient had undergone major pelvic or abdominal surgery that could cause nerve injury, including vulvectomy, colostomy, cystostomy, hysterectomy, and bladder neck suspension. 16. Patients with comorbid conditions that may cause an underlying neurological disorder (i.e., type 1 or type 2 diabetes, metabolic syndrome, stroke, myasthenia gravis, multiple sclerosis, or spinal cord injury). a. Patients with symptoms of peripheral neuropathy will be excluded. 17. Patients with pelvic nerve injury secondary to trauma will be excluded. 18. Patient has any current and / or previously reported diagnosis of a DSM-IV-TR axis I disorder (e.g., schizophrenia, bipolar disorder), including delirium, dementia, and amnesia, excluding anxiety and depression. a. Patients diagnosed with anxiety or depression must be on a stable and controlled dose of medication (i.e., SSRIs, SNRIs, buspirone, bupropion, and benzodiazepines) for at least the past 6 months, as determined by the investigator. b. Patients must have a total score of less than 10 on the Patient Health Questionnaire-8 (PHQ-8, Appendix G), a screening and assessment instrument for depression, indicating mild depression. c. Patients must have a total score of less than 6 on the Generalized Anxiety Disorder (GAD-7, Appendix H) (Anxiety Screening and Assessment Instrument) indicating mild anxiety. d. Patients with any history of antipsychotic therapy within the past year will be excluded. 19. Patients will be excluded if they have a history of gynecological cancer or are undergoing active treatment for any cancer (or have completed treatment within the last 6 months) that would interfere with their ability to successfully complete the study. a. Patients previously treated for dysplasia (precancerous changes) may be included as long as the patient underwent local treatment (e.g., cryosurgery or laser). b. Patients with a history of pelvic radiation are excluded. 20. Patient has any surgical or medical condition that may interfere with the absorption, distribution, metabolism, or excretion of the test article. 21. Patient self-reports a history of substance abuse in the 2 years prior to Visit 1 or currently exhibits symptoms of substance abuse. 22. Patient self-reports a history of alcohol abuse in the 2 years prior to Visit 1 or currently exhibits symptoms of alcohol abuse. 23. Patient has a history of non-arteritic ischemic optic neuropathy (NAION) or any underlying risk factors for NAION. 24. Subjects whose sexual function was affected (enhanced or worsened) by any medication within the 28 days prior to Visit 1 and any time prior to the drug-free period of the study. 25. Patients are currently receiving or have received within 1 month (28 days) prior to Visit 1 any of the following medications: guanylate cyclase stimulators (e.g., riociguat), clonidine, strong CYP3A4 inhibitors, nitric oxide donors such as organic nitrates or organic nitrites, and alpha-blockers. a. Patients who are currently receiving, or have received in the past 3 months, any treatment for FSAD symptoms, pharmacological treatment (e.g., any form of PDE5 inhibitor other than 3.6% sildenafil cream or other experimental treatments used to enhance arousal response) or non-pharmacological treatment (e.g., sex therapy) will also be excluded. 26. Patient has a positive urine drug screen (e.g., amphetamines, barbiturates, cocaine, methadone, and opiates) or alcohol breath test. 27. The patient has positive tests for sexually transmitted diseases (trichomoniasis, gonorrhea, chlamydia) and human immunodeficiency virus (HIV) antibodies. 28. The patient reports having an outbreak (blister, wart, or vesicle) due to either of the following sexually transmitted diseases at any time in the past 3 months: genital herpes or HPV. 29. The patient had been diagnosed with chlamydia, trichomoniasis, or gonorrhea within the past 3 months. 30. Patient has participated in any clinical trial evaluating another investigational drug or investigational therapy within 30 days (or 6 half-lives of the investigational drug, whichever is longer) prior to Visit 1 and agrees not to participate in another clinical trial throughout the study period. 31. The patient has any clinically significant abnormal findings (e.g., genital skin breaks, irritation, skin disease or lesions) on the vulvo-vaginal examination performed during the physical and gynecological examination at Visit 1. 32. The patient currently has moderate to severe vaginitis, vaginal infection including bacterial vaginosis, yeast infection or the presence of yeast based on nucleic acid amplification testing (NAAT). a. If the patient has a vaginal infection or a positive yeast test during the screening visit, they will be treated and the screening visit may be rescheduled. b. If a patient develops a vaginal infection after enrollment in the study, study medication will be withheld and the patient will be treated for the infection. If the infection does not resolve within two weeks, the patient will be withdrawn from the study. Treatment for vaginal infection will be permitted two times after enrollment. If the patient develops a third vaginal infection, the patient will be withdrawn from the study. 33. The patient has a pelvic or urinary tract infection. 34. Patient self-reports known hypersensitivity or adverse reaction to any component in the IP.

[0268] Step 4 - Laboratory Evaluation All patients who remained eligible for the study (successfully completed steps 1-3 above) had blood, urine, and vaginal samples collected. Patients who continued to meet the inclusion criteria after review of laboratory results were scheduled for a clinical diagnosis of FSAD.

[0269] Step 5 – Clinical diagnosis of FSAD Patients who met all of the above inclusion and exclusion criteria underwent a formal clinical interview to diagnose primary FSAD, which was acquired (i.e., not present at birth), generalized (i.e., present regardless of situation), and had symptoms present for at least the past 6 months prior to Visit 1. Eligible patients had a chief complaint of lack of genital responsiveness during sexual activity and considered their genital responsiveness meaningful to their overall sexual experience. Eligible patients also had to experience distress due to difficulty with sexual arousal.

[0270] Patients with secondary complaints related to low desire due to lack of genital arousal (hypoactive sexual desire disorder) are considered eligible as long as the problems related to low genital arousal are considered to be the most bothersome symptom.

[0271] After completion of the clinical interview, FSAD diagnosis will be confirmed by DSMIV-TR criteria. Eligible patients will be scheduled for Visit 2 within 14 days of Visit 1.

[0272] Drug-free period - 4 weeks (Visit 2) After successfully completing all medical screening, including laboratory evaluations, and confirming the inclusion and exclusion criteria, eligible patients and their partners were enrolled in a 4-week drug-free period. Visit 2 was the first day of the 4-week drug-free period. During this 4-week period, patients were not permitted to use oral or topical products (e.g., Dream Cream, Zestra®, OTC lubricants, PDE-5 inhibitors, etc.) for arousal problems or receive non-pharmacological interventions (i.e., sexual treatments). Both patients and their partners were provided with separate eDiary devices and associated instructions for their use. During the drug-free period, adverse events were recorded by both patients and their partners using separate eDiary devices. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete the eDiary daily within 24 hours after completing each sexual activity. Furthermore, if a sexual event occurred, patients were prompted to identify the sexual activity with their partner on the eDiary and complete the arousal diary. Eligible patients were scheduled for Visit 3 in 4 weeks.

[0273] Single-blind placebo run-in period - 4 weeks (Visit 3) After completing the 4-week drug-free run-in period, eligible patients participated in a 4-week single-blind placebo run-in period. Visit 3 was the first day of the 4-week single-blind placebo run-in period. At the start of the single-blind placebo run-in period, study inclusion and exclusion criteria were confirmed, and patients' compliance with completing the eDiary was assessed.

[0274] At Visit 3, eligible patients completed the following instruments and assessments using an eDiary in the clinic: 1. Sexual Function Questionnaire (SFQ28) 2. Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) a. The total score must remain >18 to confirm sexual dysfunction-related distress. 3. Patient Global Impression of Severity (PGI-S) 4. Patient Global Impression of Change (PGI-C)

[0275] Patients were provided with a single 30g tube of single-blind IP and instructed to apply the cream 10-20 minutes before each sexual activity. Patients and partners were also instructed to wash off any remaining treatment cream after all sexual activity had concluded. During the single-blind placebo run-in period, adverse events were recorded by both patients and their partners using separate eDiary devices. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete the daily eDiary within 24 hours after the completion of each sexual activity.

[0276] Additionally, if a sexual event occurred, patients were encouraged to record IP application in the eDiary, identify partnered sexual activity, and complete an arousal diary. Baseline was established using eDiary responses, including arousal diary, SFQ28, and FSDS-DAO scores, after a 4-week single-blind placebo run-in period (Visit 4). Eligible patients were scheduled for Visit 4 at 4 weeks.

[0277] Double-blind treatment period - 12 weeks (visits 4-7) After completing the 4-week single-blind placebo run-in period, eligible patients entered the double-blind dosing period. Visit 4 was 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 patients' compliance with completing the eDiary and using the study product was assessed.

[0278] At Visit 4, eligible patients completed the following instruments and assessments using an eDiary in the clinic: 1. Sexual Function Questionnaire (SFQ28) 2. Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) a. The total score must remain >18 to confirm sexual dysfunction-related distress. 3. Patient Global Impression of Severity (PGI-S) 4. Patient Global Impression of Change (PGI-C)

[0279] Baseline was established using eDiary responses including wakefulness diary, SQF28 and FSDS-DAO scores after 4 weeks of single-blind placebo run-in (Visit 4).

[0280] During the double-blind dosing period, patients returned to the clinic every 4 weeks for efficacy and safety assessments. Visit 4 was the first day of the double-blind dosing period, and Visit 7 was the completion of the 12-week double-blind dosing period.

[0281] At Visits 4–6, patients were provided with a single 30 g tube of double-blind IP according to the randomization schedule. Patients returned the tube at subsequent visits (i.e., Visits 5–7) and received a new tube the following month of 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, adverse events were recorded by both patients and their partners using separate eDiary devices. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete the eDiary daily within 24 hours after the completion of each sexual activity. Furthermore, if a sexual event occurred, patients were prompted to record the application of the IP on the eDiary, identify the sexual activity with their partner, and complete the arousal diary.

[0282] At visits 5-7, patients completed the following measures and assessments in the clinic using an eDiary: 1. Sexual Function Questionnaire (SFQ28) 2. Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) 3. Patient Global Impression of Severity (PGI-S) 4. Patient Global Impression of Change (PGI-C)

[0283] At Visit 7, patients completed a Patient Benefit Assessment (PBE) in the clinic. During the double-blind treatment period, adverse events were recorded by both patients and their partners using separate eDiary devices. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete the daily eDiary within 24 hours of completing each sexual activity. Additionally, if a sexual event occurred, patients were prompted to record the application of IP on the eDiary, confirm the sexual activity with their partner, and complete the arousal diary.

[0284] At the end of the study (Visit 7) or after study withdrawal, a selected number of patients were interviewed by telephone in semi-structured exit interviews to provide a more detailed qualitative description of their symptoms, response to treatment, what and why constituted meaningful change on both the PGI-S and PGI-C, and treatment satisfaction, to augment the quantitative assessments captured in the PRO instruments.

[0285] Safety Assessment Follow-Up (Phone Call): Seven ± 3 days after the last visit in the double-blind dosing period, each patient and their partner were contacted by telephone to record any changes in concomitant medications and any potential adverse events that may have occurred after the final study visit (Visit 7). The maximum study duration was approximately 6 months.

[0286] Recall period evaluation At the end of the single-blind placebo run-in, and at weeks 4, 8, and 12 of the double-blind treatment period, the correlation between the 24-hour recall period and the 4-week recall period was assessed for all patients who completed both the wakefulness diary and the SFQ28. Additionally, at the same intervals, a randomly selected subset of patients (n=30) who completed the SFQ28 but not the wakefulness diary was evaluated via Interactive Response Technology (IRT) to investigate whether completing the diary questions affected patients' scores on the wakefulness (sensation) domain of the SFQ28.

[0287] Patient withdrawal Patients who signed the informed consent form at Visit 1 and those who received at least one IP dose and dropped out of the study early were instructed to complete the relevant PRO instrument (SFQ28, FSDS-DAO, etc.). These patients were also tabulated by reason for discontinuation in final study tables, lists, and figures.

[0288] Withdrawal criteria Patients may choose to withdraw from the study at any time for any reason. Additionally, patients may withdraw from the study for any of the following reasons: the patient or their partner is unwilling or unable to adhere to the protocol; During the course of the study, the patient develops a symptom or condition listed in the exclusion criteria; During the course of the study, the patient experiences any of the following: visual adverse effects, severe skin reactions, symptomatic orthostatic tachycardia, symptomatic hypotension, asymptomatic hypotension, or asymptomatic orthostatic hypotension; Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness or other medical condition where continued participation is not in the patient's best interest, as determined by the investigator; or • Other medical reasons.

[0289] Stopping criteria If more than 1% of patients or partners treated with the active cream report serious post-administration symptoms related to loss of consciousness (fainting) and serious injurious hypotension (dizziness, lightheadedness, nausea), the study will be discontinued.

[0290] Inclusion criteria - Eligibility of patients' partners Patients' partners may participate in the study if they meet all of the following criteria at Visit 1: 1. Partners must be 21 years of age or older. 2. Partners must be fluent in English. 3. The partner understands and is able to follow the protocol and agrees to sign the informed consent document. 4. The partner has been in a secure, communicative, stable, single-partner relationship with the patient for at least 6 months prior to Visit 1. The partner is sexually functional, both psychologically and physically. The partner is consistent and available throughout the duration of the study.

[0291] Exclusion criteria - regarding the eligibility of the patient's partner Partners who meet any of the following criteria at Visit 1 will not participate in the study: 1. Partner is breastfeeding or pregnant (based on a positive urine pregnancy test) or hoping to become pregnant during the study period. 2. Partner has any disability or history of any disability that may prevent successful completion of the study. 3. Partners currently receiving, or within 1 month (28 days) prior to Visit 1, any of the following treatments will be excluded: vaginal hormone products (e.g., estrogen or prasterone), guanylate cyclase stimulators (e.g., riociguat), phosphodiesterase (PDE) type 5 inhibitors, or nitric oxide donors such as organic nitrates or organic nitrites. 4. Partner has a significant cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, dermatological, hematological, neurological, genitourinary, or psychiatric disease, or other unstable medical condition or any concomitant medication that contraindicates administration of study medication, interferes with study assessments, limits study participation, or confounds interpretation of study results. 5. Partners with a history of myocardial infarction, stroke, or life-threatening arrhythmia within 6 months prior to Visit 1; patients with any history of coronary artery disease causing resting hypotension (BP < 90 / 50 mmHg) or angina, or congestive heart failure requiring medical intervention; patients with underlying conditions that may be particularly sensitive to the effects of vasodilators, including patients with left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and partners with impaired autonomic control of blood pressure, or partners whose underlying cardiovascular condition makes sexual activity inadvisable. 6. Partner has a history of orthostatic hypotension, defined as a decrease in systolic blood pressure of 20 mmHg or more, a decrease in diastolic blood pressure of 10 mmHg or more, an increase in pulse rate of 20 beats per minute, or experiencing lightheadedness or dizziness 1 or 3 minutes after a supine to standing position change, or orthostatic hypotension noted at Visit 1. 7. Partner has a history of priapism or a condition that may predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). 8. Your partner currently has a pelvic or urinary tract infection. 9. Partner self-reports having had any sexually transmitted disease (including gonorrhea, trichomoniasis, and chlamydia) in the past three months. 10. Partner self-reports a diagnosis of human immunodeficiency virus (HIV). 11. Partner self-reports having had an outbreak (blisters, warts, or vesicles) of one of the following sexually transmitted diseases at any time in the past three months: genital herpes or HPV. 12. Partner has a history of non-arteritic ischemic optic neuropathy (NAION) or any underlying risk factors for NAION. 13. Partner has participated in any clinical trial evaluating another investigational drug or investigational therapy within 30 days (or 6 half-lives of the investigational drug, whichever is longer) prior to Visit 1. Partner also agrees not to participate in any other clinical trials during the study period. 14. Partner self-reports any known hypersensitivity or adverse reaction to any ingredient in the investigational product (IP).

[0292] Investigational Product (IP) Throughout the protocol, the single-blind IP and double-blind IP are collectively referred to as investigational products (IPs). Depending on the randomization scheme, the single-blind IP was a placebo cream, and the double-blind IP was either a placebo cream or a 3.6% sildenafil cream. The single-blind IP and double-blind IP were provided in 30-gram white aluminum tubes. A single 30-gram tube allows for nine 2-gram applications. A medication card was also provided for patient use to ensure dosing accuracy. The creams were water-based and white to off-white in appearance, with the color, odor, and consistency identical between the sildenafil and placebo creams.

[0293] The 3.6% sildenafil cream is a white to off-white cream containing 5% (w / w) sildenafil citrate, salts, and excipients listed in Table 3, resulting in a sildenafil concentration of 3.6%. Packaging and labeling of the IP complied with all applicable regulatory requirements. The IP was stored at room temperature (20-25°C) in a secure, temperature- and humidity-monitored area. [Table 4]

[0294] The placebo cream contains the same ingredients as the 3.6% sildenafil cream, except that it does not contain the active ingredient, sildenafil citrate. The appearance, odor, consistency, and color are identical to those of the 3.6% sildenafil cream. A complete list of ingredients is provided in Table 4 below. [Table 5]

[0295] Single-blind placebo run-in period One 30-gram tube of placebo cream for the single-blind run-in period was distributed to patients at Visit 3, allowing for nine 2-gram applications of the cream. Patients were instructed to apply 2 grams of cream 10 to 20 minutes before each sexual activity. Specific dosing instructions were provided to patients separately. Double-blind treatment period Each month, participants were given 30-gram tubes of IP along with nine 2-gram dosing cards. Participants were instructed to apply 2 grams of product no more than once per 24-hour period and no more than nine applications per month. After receiving the 2-gram portion on the dosing card, participants applied 2 grams of IP using their index finger approximately 10 to 20 minutes before sexual activity. One gram was applied externally to the anterior labial commissure, clitoral hood, glans penis, frenulum, vestibule, and labia minora. The other gram was applied to the distal anterior vaginal area, targeting the distal lower third of the vagina, approximately 0 to 3 cm deep, or approximately midway between the distal and proximal interphalangeal joints. Participants were instructed to wash off the cream after sexual activity and, if applicable, have their partner wash off the cream. Use of more than nine applications per month was recorded as a protocol violation. IP Dosage Application Procedure

[0296] During both the single-blind placebo run-in period and the double-blind dosing period, the exact amount of cream to be applied will be measured using the medication card according to the following instructions: Patients were instructed to measure the exact amount of cream as follows: "To measure the correct amount of cream, place the medication card on a flat surface. Squeeze the cream onto the card by evenly filling the rectangle drawn on the medication card. Make sure that the cream covers the entire area of ​​the rectangle drawn on the medication card."

[0297] The rectangle on the dosing card (sized to deliver 2 grams of cream) was divided into two equal portions and used to apply the cream externally to the designated vulvar area and internally into the vagina, respectively.

[0298] Approximately 50% of the cream was to be applied externally to the vulva (i.e., clitoris, vestibule, labia minora) and approximately 50% was to be applied intravaginally. Patients were instructed to indicate application times on their eDiary and, using the medication card, to administer the appropriate amount of cream for intravaginal and vulvar application as follows:

[0299] External cream application:

[0300] Patients were instructed to apply approximately half of the cream externally from the medication card with their index finger as described below.

[0301] Step 1. Starting at the anterior labial commissure, gently apply the cream to the clitoral prepuce, glans and frenulum.

[0302] Step 2. Continue to gently apply the cream to the vestibule.

[0303] Step 3. Continue to gently apply the cream to the labia minora.

[0304] (Note: Avoid application to the labia majora and avoid applying product to pubic hair)

[0305] Internal cream application:

[0306] Step 4. Using your index finger, take the remaining half of the cream and gently apply it in a stroking motion to the anterior distal vagina (targeting the distal lower third of the vagina, approximately 0-3cm deep, or approximately midway between the distal and proximal interphalangeal joints).

[0307] Prior to the single-blind placebo run-in period, patients underwent thorough on-site training to ensure they understood the product usage instructions. Patients were instructed to wash their hands and to avoid wiping or rinsing 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 had concluded.

[0308] IP dosing frequency The IP was distributed to allow for a total of nine 2-gram applications of cream during monthly intervals (a 30-gram tube reliably delivers nine 2-gram doses). Patients were instructed to apply the cream 10-20 minutes before each sexual activity, but not to exceed a maximum of nine doses in each 4-week period. Patients were further instructed not to apply the cream within 24 hours of a previous application.

[0309] Medication schedule Single-blind placebo run-in period (visit 3) After completing a 4-week drug-free period, eligible patients participated in a 4-week single-blind placebo run-in period. During this 4-week study period, patients received single-blind IP in a single 30-gram tube, distributed to patients in a single-blind manner to provide a monthly supply. Patients were instructed to apply 2 grams of cream 10 to 20 minutes before each sexual activity.

[0310] Double-blind medication period (visits 4-7) After completing a 4-week single-blind placebo run-in period, eligible patients entered a 12-week double-blind treatment period. During this 12-week study, patients received the same double-blind IP in a 30-gram tube at each visit based on their randomization schedule. Patients received a single 30-gram tube at Visits 4, 5, and 6 to provide a monthly supply. Patients were instructed to apply 2 grams of cream 10 to 20 minutes before each sexual activity.

[0311] Medication history and concomitant medications Permitted Concomitant Medications Patients and their respective partners were permitted to receive concomitant medications as needed, with guidance from medical surveillance, except for the medications listed below.

[0312] All concomitant medications were recorded for patients enrolled in the study and their respective partners from 28 days before Visit 1 until completion of Visit 7.

[0313] Changes in concomitant medications were captured in the eDiary for patients and their partners.

[0314] Prohibited Concomitant Medications - Patients and Their Partners Patients with positive findings from urine drug screens (e.g., amphetamines, barbiturates, cocaine, methadone, and opiates) or alcohol breath tests will be excluded from further study participation. Patients will be excluded from study participation if they are currently taking, or have been treated within the last 28 days prior to Visit 1 with, any of the following medications: guanylate cyclase stimulators (e.g., riociguat), clonidine, strong CYP3A4 inhibitors, nitric oxide donors such as organic nitrates or organic nitrites, or alpha-blockers. Patients will also be excluded if they are currently receiving, or have received within the past 3 months, treatment for FSAD symptoms, pharmacological treatment (e.g., any form of PDE5 inhibitor except 3.6% sildenafil cream or other experimental therapeutics used to enhance arousal responses), or non-pharmacological treatment (i.e., sex therapy).

[0315] Patients are prohibited from using vaginal hormone products (e.g., vaginal estrogen, vaginal prasterone), vaginal or vulvar lubricants, spermicides, creams or gels, contraceptive foams, or vaginal douche products throughout the study period. Partners who are currently taking, or have taken within the 1 month (28 days) prior to Visit 1, nitric oxide donors such as guanylate cyclase stimulators (e.g., riociguat), clonidine, strong CYP3A4 inhibitors, phosphodiesterase (PDE) type 5 inhibitors, or organic nitrates or organic nitrites are excluded. Patients using contraceptive vaginal sponges are excluded. Patients or their partners are excluded from study participation if they are currently receiving or have been treated with any prohibited medications, as outlined in the study's respective inclusion and exclusion criteria.

[0316] Patient and partner safety assessment Adverse events (AEs) Adverse events were collected for patients and their respective partners at each visit, starting with signing the informed consent. AEs reported before the first application of IP were recorded in the AE eCRF but were not included in the summary of treatment-emergent AEs (TEAEs). AEs reported after the first application of IP were recorded in the AE eCRF. AEs occurring after the completion of the last visit were recorded 7 ± 3 days after the end of the double-blind dosing period (Visit 7).

[0317] Adverse Event Reporting Patients and their partners were instructed to immediately notify any serious medical problems that occurred during the course of the study. Patients and their partners were instructed to call 911 in the event of a life-threatening emergency. Patients recorded all AEs in the eDiary according to the instructions provided. Patients completed the eDiary within 24 hours of each sexual event and at any time during the study when an AE could occur. Partners recorded all AEs in a separate eDiary according to the instructions provided. Partners completed the eDiary within 24 hours of each sexual event and at any time during the study when an AE could occur. The eDiary prompted both patients and partners to assess every 24 hours whether a sexual event had occurred. If a sexual event had occurred, the eDiary prompted patients and partners with the following prompt: "Have you had any complaints since your sexual event?" If the participant or partner answered "yes," the eDiary further prompted the participant or partner for some of the more common side effects associated with oral sildenafil cream or genital cream, such as (1) "Did you experience any local sensitivity or discomfort?", (2) "Did you feel dizzy or lightheaded?", and (3) "Are there any other complaints you would like to report?" Responses from participants who reported complaints after sexual activity were electronically sent to the site for evaluation and triage within 24 hours. Additionally, participants who answered "yes" to a complaint were reminded to contact the study site. Subjects were instructed to call the investigator's emergency number if they did not receive a response within 24 hours of submitting their complaint electronically. Participants were also instructed to promptly report any complaints of local sensitivity or discomfort to the investigator for follow-up.

[0318] If participants confirmed via the eDiary that a sexual event had occurred with their partner, study site staff were asked to contact their partner within 72 hours of the event to determine if they had any complaints. If so, the partner was further questioned about common side effects associated with oral sildenafil (e.g., lightheadedness) or genital cream exposure (e.g., genital hypersensitivity). Partners were instructed to contact the investigator if they did not receive a phone call within 72 hours of sexual activity with the participant.

[0319] Participants recorded TEAEs in their eDiary. Participants and sexual partners were invited to an unscheduled clinic visit if they had a TEAE complaint that they wanted to undergo a physical examination to evaluate, or at the investigator's discretion based on the reported AE.

[0320] At each visit, participants were given standing vital signs, and heart rate and blood pressure were measured in the supine position and 1 and 3 minutes after standing. The same standing vital signs were measured in participating sexual partners in the clinic or via telehealth at each visit.

[0321] Adverse events An adverse event is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related. An AE (also called an adverse experience) can be any untoward, unintended sign (e.g., abnormal laboratory finding), symptom, or disease that is temporally related to the use of the drug and does not imply any determination of causality. AEs can occur with any use of a drug (e.g., off-label use, concomitant use with another drug) and with any route of administration, formulation, or dose (including overdoses).

[0322] Suspected adverse reactions A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug caused the AE. For the purposes of investigational new drug (IND) safety reporting, "reasonable possibility" means that there is evidence suggesting a causal relationship between the drug and the AE. A suspected adverse reaction means there is less certainty regarding the causal relationship than an adverse reaction, which means any AE caused by the drug.

[0323] Life-threatening or suspected life-threatening adverse reaction An AE or suspected adverse reaction is considered "life-threatening" if its occurrence poses an imminent risk of death to the patient or their partner. It does not include an AE or suspected adverse reaction that could have caused death if it occurred in a more severe form.

[0324] Serious AE or serious suspected adverse reaction An AE or suspected adverse reaction is considered "serious" if it results in any of the following outcomes: ●Death, life-threatening AEs (see definition above); • hospitalization of an inpatient or extension of an existing hospitalization; A persistent or significant inability or substantial disruption of the ability to perform normal life functions; and ●Congenital abnormalities / birth defects.

[0325] A serious medical event that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based on sound medical judgment, it may place the patient or their partner at risk and 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 care in an emergency room or at home, a blood disorder or seizure that does not result in inpatient hospitalization, or the development of drug dependence or drug abuse.

[0326] Relationship with investigational drugs A causality assessment will be provided for all AEs (serious and non-serious). The causality assessment is a determination of whether there is a reasonable possibility that the investigational product (IP) caused or contributed to the AE.

[0327] None: There is no relationship between the experience and the administration of the study drug, but rather related to other etiologies such as concomitant medications or the patient's clinical condition.

[0328] Unlikely: Current knowledge indicates that a relationship is unlikely.

[0329] Possible: A reaction that follows a plausible timeline from administration of the study drug and that follows a known pattern of response to the suspected study drug. The reaction may have been caused by the patient's clinical condition or other treatment modalities administered to the patient, but this is not known with certainty.

[0330] Probable: A response that follows a plausible temporal sequence from administration of the study drug and that follows the known pattern of response to the suspected study drug. The response cannot be reasonably explained by known features of the patient's clinical condition or other treatment modalities administered to the patient.

[0331] Unequivocal: A response that follows a reasonable temporal sequence from administration of the test drug, follows a known pattern of response to the suspected test drug, and can be confirmed by a positive repeat challenge test or supporting laboratory data.

[0332] severity For the Adverse Event eCRF, the terms mild, moderate, severe, or life-threatening are used to describe the maximum intensity of the AE. For consistency, these intensity grades are defined as shown below.

[0333] Mild: Signs or symptoms are noticeable but are well tolerated

[0334] Moderate: Discomfort that interferes with normal daily activities

[0335] Severe: Inability to carry out normal daily activities

[0336] Life-threatening: Imminent risk of death from a reaction if it occurs

[0337] Screening Laboratory Evaluation The following laboratory evaluations were performed after successful completion of Visit 1. Serum chemistry: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, (total) bilirubin, blood urea nitrogen, creatinine, potassium, (total) protein, sodium, chloride and bicarbonate Hematology: Hematocrit, hemoglobin, platelets, red blood cell count, white blood cell count, and total white blood cell (WBC) count differential only if WBC count is abnormal. Prothrombin time TSH FSH Estradiol Total testosterone, SHBG and albumin Urine tests: bilirubin, blood, glucose, ketones, nitrites, pH, protein, specific gravity, urobilinogen and leukocyte esterase HBsAg, HCV HIV and antibodies ●NAAT (Nucleic Acid Amplification Test): Bacterial vaginosis, yeast (Candida species) and sexually transmitted diseases (gonorrhea, chlamydia, trichomoniasis) Urine drug screen for the following drugs of abuse: amphetamines, barbiturates, cocaine, methadone, and opiates.

[0338] Women were required to undergo a urine pregnancy test at every visit during the course of the study, except for Visit 1, where a serum pregnancy test was administered. Women with a positive test were immediately discontinued from the study. electro-cardiogram

[0339] A single standard 12-lead ECG was collected at Visit 1 before participation in the drug-free period of the study. The screening ECG was obtained after patients rested in the supine position for a minimum of 5 minutes. ECGs were classified as normal, with clinically insignificant abnormalities, or with clinically significant abnormalities. Patients with clinically significant ECG abnormalities at Visit 1 were excluded.

[0340] Vulvovaginal clinical examination At each visit, a clinical vulvo-vaginal examination was performed using vulvoscopy to determine the level of irritation (using the following scale): Additionally, patients reporting local irritation or discomfort during the study were instructed to contact the investigator immediately for follow-up. This examination included a visual examination of the vagina, including observation of the mucosa for pinpoint hemorrhage, pallor, friability, dryness, and redness. Observations were graded on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe) as described in Table 5A. [Table 6]

[0341] statistical analysis A formal statistical analysis plan (SAP) was developed and finalized before data unblinding. The SAP defined the population to be analyzed, outlined all data processing rules, and specified all statistical methods to be used in analyzing the data. Generally, safety and efficacy variables were presented by treatment arm and time point, where applicable, with descriptive statistics and figures, as appropriate. Continuous variables were summarized using the number of nonmissing observations, mean, standard deviation (SD), median, first and third quartiles, and minimum and maximum values. Categorical variables were presented using number of patients and percentages. For ordinal categorical variables, cumulative percentages may also be presented. An unblinded intention-to-treat interim analysis was performed after at least 50 patients each had been assessed for the primary endpoint in the placebo and sildenafil cream groups. The interim analysis included all patients who successfully completed Visit 7 and those who dropped out by the time of the interim analysis. Because this interim analysis did not intend to terminate the trial early for efficacy reasons, a conservative gamma-based spending function with a parameter of -40 was applied to each endpoint to compare the sildenafil 2 gram group with the corresponding placebo group at a one-sided 0.025 alpha level. The final study sample sizes for the placebo and sildenafil cream groups were determined based on the observed intermediate conditional power for the coprimary endpoints. For re-estimation of sample size for the placebo and sildenafil cream groups, the sample size was not increased unless the intermediate conditional power for both coprimary endpoints reached at least 50%, in which case it was increased to the maximum of the two sample sizes calculated for each endpoint.

[0342] The sample size for this study was based on the coprimary product efficacy endpoint. The safety analysis set consisted of all women who applied IP at least once during the study. The frequency of TEAEs was described according to product group, association with IP use or study procedures, and severity. TEAE frequencies were compared by treatment group using chi-square statistics or Fisher's exact test based on expected cell size. Vital sign data were normally distributed and therefore compared between the 3.6% sildenafil cream group and the placebo cream group by visit and timing / position of measurement (e.g., supine position) using independent samples t-tests. A P value of <0.05 was considered significant.

[0343] Measures of effectiveness The primary objective of this study was to demonstrate the efficacy of 3.6% sildenafil cream 2 grams compared with a matching placebo cream based on the co-primary endpoints, SFQ-AS and FSDS-DAO item 14, as described below. Patient scores after the single-blind placebo run-in period served as each patient's baseline.

[0344] Efficacy was assessed using the following: Co-primary endpoints SFQ28(AS): Change in the SFQ28 Alertness-Sensation (AS) domain score from baseline to the end of the study FSDS-DAO (Q14): Change from baseline to end of study in scores regarding concerns about difficulties in sexual arousal (item 14 of the FSDS-DAO) Secondary endpoints: Arousal Diary (SSE): Change in number of satisfying sexual events (SSE) from baseline to end of study Exploratory endpoints: Sneezing diary (SSE): In addition to the secondary endpoint analyses above, changes from baseline at week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period Arousal Diary (AS): Change from baseline in genital arousal sensations (AS) reported by patients after each sexual event and captured by the eDiary at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) Arousal Diary (AL): Change from baseline in lubrication (AL) reported by the patient after each sexual event and captured by the eDiary at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) Arousal Diary (GA): Change from baseline in sexual arousal (AE) reported by the patient after each sexual event and captured by the eDiary at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) ●SFQ28 (AS): In addition to the primary endpoint analyses above, change from baseline at week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period. SFQ28(AL): Change from baseline in the Alertness-Lubrication (AL) domain of the SFQ28 at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) SFQ28 (AC): Change from baseline in the SFQ28 Vigilance-Cognition (AC) domain at Weeks 4 (Visit 5), 8 (Visit 6), and 12 (Visit 7) SFQ28 (Crazy): Change from baseline in the Craving domain of the SFQ28 at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) SFQ28 (Orgasm): Change from baseline in the orgasm domain of the SFQ28 at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) FSDS-DAO: Change from baseline in FSDS-DAO total score at Week 4 (Visit 5), Week 8 (Visit 6), and Week 12 (Visit 7) FSDS-DAO (Q14): In addition to the primary endpoint analyses above, the change from baseline in item 14 of the FSDS-DAO obtained from week 4 (visit 5) and week 8 (visit 6) of the double-blind dosing period. PGI-S: Percentage of patients who improved in at least one severity category from baseline to the end of the study • PGI-C: The proportion of patients who reported at least a significant improvement related to sexual arousal problems from baseline to the end of the study. PBE: The percentage of patients who reported experiencing a meaningful benefit from the study drug at the end of the study, assessed with a yes / no question.

[0345] Unless otherwise stated, efficacy analyses were performed as randomized, i.e., patients were assigned to their originally assigned treatment regardless of the treatment actually administered. Summary statistics were presented for each efficacy measure by treatment and time point (where applicable).

[0346] The primary objective was evaluated by testing the following hypotheses for the 3.6% sildenafil cream treatment group (2 grams) versus the matching placebo cream for the SFQ28 (AS) endpoint, and the corresponding hypotheses for the FSDS-DAO co-primary endpoint: Null hypothesis (H0): There is no difference in the mean change from baseline to week 12 in SFQ28(AS) for the 3.6% sildenafil cream treatment group compared to the corresponding placebo cream group. H0: μ(sildenafil) = μ(placebo) Alternative hypothesis (H1): There is a difference in the mean change from baseline to week 12 in SFQ28(AS) for the 3.6% sildenafil cream treatment group compared to the corresponding placebo cream group. H1: μ(sildenafil) ≠ μ(placebo)

[0347] The comparisons were performed using a fixed-order fallback procedure at a one-sided 0.025% (or two-sided 0.05) statistical significance level. Analyses of 3.6% sildenafil cream versus matched placebo cream included baseline (as a continuous covariate), treatment group, visit (as a categorical variable), and visit duration (as a variable). *Analysis was performed using a mixed-model repeated measures (MMRM) model, including a term with treatment interaction as a fixed effect and subject as a random effect. An "unstructured" covariance structure was used to model within-subject error. The Kenward-Roger approximation was used to estimate the denominator degrees of freedom and adjust standard errors. Estimated treatment means and differences (3.6% sildenafil cream vs. matched placebo cream) at the last visit (visit 7 of the double-blind dosing period) compared to baseline were reported as part of this analysis. The analysis was performed on the intention-to-treat (ITT) dataset. Analysis was also performed on the PP set.

[0348] result Of the 252 participants who participated in the 28-day single-blind placebo run-in period, 227 received at least one dose of IP, of which 219 completed the single-blind placebo run-in period. During this period, participants received a mean of four doses of placebo cream for a mean of 2.5 (1.3) weeks. Median compliance with IP during the single-blind placebo run-in period was reported as 75%. During the single-blind period, 51 of the 227 placebo-exposed participants (22.5%) reported 94 TEAEs. All subjects who reported TEAEs during the single-blind placebo run-in period were graded as mild or moderate in severity. Of these 94 TEAEs, 73 TEAEs reported by 37 subjects were graded as treatment-related. Six treatment-related TEAEs reported by four participants led to discontinuation of IP during the single-blind placebo run-in period. All six of these TEAEs occurred immediately after application of the IP and included genital discomfort, burning, stinging, folliculitis, and erythema.During the single-blind placebo run-in period, the most common TEAE reported by 32 participants was genital application site discomfort, and COVID-19 infection was the second most common TEAE reported by 12 participants.

[0349] During the single-blind placebo run-in period, 7 of 197 placebo-exposed sexual partners reported 8 TEAEs, all of which were mild to moderate in intensity. Four sexual partners reported 5 TEAEs considered treatment-related (headache, penile burning, penile irritability, and perineal irritability). No partner-reported TEAEs led to IP or study discontinuation during the single-blind placebo run-in period.

[0350] During the double-blind dosing period, the mean (standard deviation, SD) duration of IP use was 10.3 (2.5) weeks and 9.7 (3.1) weeks for sildenafil and placebo users, respectively. The cumulative doses of sildenafil and placebo cream received during this period were 23.5 (14.0) grams and 22.9 (14.5) grams, respectively. Median reported compliance, defined as IP use 10 to 20 minutes before sexual encounter, ranged from 78.8 to 98% for 3.6% sildenafil cream users versus 85 to 95% for placebo cream users. The highest median compliance rate (98%) for 3.6% sildenafil cream users was reported at 3 months of use, whereas the highest median compliance rate for placebo cream users was 95%, reported at 1 month of use. During the double-blind dosing period, 1,357 and 1,160 sexual experiences were recorded when 3.6% sildenafil cream or placebo cream was used, respectively. The majority of sexual experiences were partnered (76% of sildenafil cream-exposed events and 80% of placebo cream-exposed events). No episodes of sexual activity with non-consenting partners were found in the eDiary, and therefore, no participants discontinued the study due to this protocol violation.

[0351] Table 5B shows the number of participants and sexual partners who reported at least one TEAE, as well as the total number of TEAEs, broken down by severity and relatedness. During the double-blind dosing period, there were no significant differences in the frequency of various TEAEs reported by 3.6% sildenafil cream users compared with placebo cream users (all p values ​​>0.50, Table 5B). The mean (SD) time to onset of the first TEAE reported during the double-blind dosing period was 21 (11) days and 20 (8) days for participants assigned to sildenafil and placebo cream, respectively. All TEAEs reported by participants or sexual partners during the double-blind dosing period were graded as mild or moderate. During the dosing period, two participants assigned to sildenafil reported three TEAEs (burning sensation 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 led to discontinuation of IP. There were two TEAEs reported by placebo cream users during the double-blind treatment period that were not related to IP use (dyspareunia and vulvar laceration) but nevertheless led to IP discontinuation.

[0352] Table 5B also shows that during the double-blind dosing period, seven partners exposed to the 3.6% sildenafil cream reported nine TEAEs, while four partners exposed to the placebo cream reported four TEAEs. There were no statistically significant differences in the frequency of reports of various TEAEs by sexual partners exposed to either the active or placebo IP (all p values ​​> 0.25). One TEAE, a burning sensation in the genitals upon contact with the IP during intercourse, was considered treatment-related and led to IP discontinuation in the sexual partner exposed to the 3.6% sildenafil cream. [Table 7]

[0353] Post hoc analyses (Table 5C) demonstrated that the number of participants assigned to 3.6% sildenafil cream who reported at least one type of TEAE was similar when subclassified based on quartiles of the total number of sexual events reported during the double-blind treatment period (all p values ​​> 0.19). [Table 8] * For participants with ≥2 TEAEs, the highest severity, association, and behavior were recorded.

[0354] Table 5D shows the most common treatment-related (possibly, likely, or definitely) TEAEs by system organ class reported by subjects or their sexual partners during the double-blind dosing period. As shown in Table 5D, there were no significant differences in the system organ classes of treatment-related TEAEs reported by sildenafil cream users compared to placebo cream users (all p-values ​​>0.11) or compared to the sexual partners of sildenafil cream users (all p-values ​​>0.25). [Table 9]

[0355] Because oral sildenafil use may be associated with orthostatic hypotension, especially in users taking nitrates for angina pectoris, orthostatic vital signs were obtained from participants (Table 6) and their sexual partners at baseline and then monthly during the double-blind dosing period. As shown in Table 6, there were no differences in vital signs obtained in various positions between participants assigned to 3.6% sildenafil cream or placebo at any time during the study (all p values ​​>0.10). Consistent with a normal physiological response, mean pulse rate increased from that recorded in the supine position 1 and 3 minutes after standing. The median change from baseline in pulse rate increased by 1 to 4 beats / min in the 3.6% sildenafil cream and placebo groups, with no outliers. Median changes from baseline in systolic blood pressure in both treatment groups ranged from -3.5 mmHg to +3.0 mmHg, indicating no clinically significant changes. Finally, diastolic blood pressure showed a median change from baseline of -2.0 to +1.0 during the double-blind dosing period.

[0356] During the double-blind dosing period, one placebo-randomized subject reported palpitations that were mild in severity and considered unrelated to the study IP. No other cardiovascular or nervous system disorders were reported by subjects during the double-blind dosing period. Regarding sexual partners, one partner exposed to 3.6% sildenafil cream during the double-blind dosing period reported a headache that was graded as mild but considered related to study IP exposure. No other cardiovascular or nervous system TEAEs were reported by sexual partners during the double-blind dosing period.

[0357] Finally, baseline laboratory tests and electrocardiograms were not repeated at the end of the study, although there were no TEAEs that required repeating these baseline screening assessments. [Table 10]

[0358] conclusion This study demonstrated that topical 3.6% sildenafil cream was safe and well tolerated in healthy premenopausal women and their sexual partners, with 1,357 recorded genital exposures to 3.6% sildenafil cream during the double-blind treatment period. Previous clinical trials of oral sildenafil citrate in women have used doses typically administered to men for erectile dysfunction (25 mg to 100 mg) and have shown high rates of side effects.

[0359] The most common side effects of oral sildenafil use are headache, flushing, indigestion, visual disturbances, nasal congestion, back pain, muscle pain, nausea, dizziness, and rash.

[0360] The safety data presented herein confirm that adverse events associated with topical 3.6% sildenafil cream use were primarily related to local genital hypersensitivity. Post-hoc analysis found that the frequency of TEAEs was similar based on quartiles of total genital exposure reported during the double-blind treatment period, supporting the lack of cumulative toxicity from multiple exposures. Many users of 3.6% sildenafil cream used the product more than the protocol-specified nine times per month, and these protocol violations did not result in increased TEAEs. While the sample size was not powered to detect differences in TEAEs, no significant differences in the types of TEAEs reported by participants using 3.6% sildenafil cream compared to placebo were found using rigorous statistical methods. In this study, TEAEs were documented in sexual partners; TEAEs were reported directly by sexual partners, rather than by study participants on their behalf, as is common in clinical trials of products used during sexual activity.

[0361] Strengths of this study include detailed reporting of TEAEs by participants via an eDiary with daily prompts as described above, and direct reporting of TEAEs to sexual partners. Based on the reluctance of some potential participants to include sexual partners in the trial, a modified protocol allowed for the enrollment of women without partners or women whose partners did not wish to participate in the informed consent or safety monitoring process. Consistent with Good Clinical Practice (GCP), participants with non-consenting sexual partners were instructed not to have partnered sexual experiences within 72 hours of IP application. Given that TEAEs in sexual partners were rare and all were mild or moderate in severity, the potential benefits of topical sildenafil outweigh the risks to users and their sexual partners.

[0362] Postural vital signs were monitored in the clinic and / or via telemedicine for sexual partners, but postural vital signs could not be measured immediately after IP use. Data from the earlier safety study in men discussed above support the finding that orthostatic heart rate changes were likely a benign, normal physiologic response to standing, and the extensive vital sign and TEAE data collected in this study indicate that systemic effects of oral sildenafil citrate were not seen with topical application.

[0363] In conclusion, these data confirm that topical sildenafil is safe for users and exposed sexual partners. These data support the clinical development of 3.6% sildenafil cream for the treatment of FSAD.

[0364] Example 3: Exit Interview in Female Sexual Arousal Disorder - Phase 2B Study Addendum To evaluate patient-reported outcome measures (PROMs) for use in assessing efficacy in patients with FSAD, interviews were conducted with pre- and postmenopausal women aged 21-70 years with FSAD to corroborate the content of the PROMs.

[0365] The results of the study confirmed that the PROM is fit for purpose and provides support for an instrument that can assess concepts in FSAD and be used as endpoints in clinical trials of patients with FSAD. Exit interviews will be conducted to better understand what might be considered a meaningful change on measures used as primary or secondary endpoints, and to ascertain what patients consider when they rate a change as an improvement on the Patient Global Impression of Change (PGI-C), a one- or two-category improvement in severity on the Patient Global Impression of Severity (PGI-S), or report a meaningful benefit from the study drug on the Patient Benefit Assessment (PBE).

[0366] An exit interview will be conducted with a subset of patients at the end of the study (at Visit 7).

[0367] The overall aim of conducting this study was to further evaluate, according to the perspective of patients with FSAD: What constitutes meaningful change for the following patient-reported outcome measures (PROMs): SFQ-AS domain, ○Item 14 of FSDS-DAO and ○AS Domain of Awakening Diary • What is considered when answering "yes" or "no" to the patient benefit assessment questions?

[0368] Test Design This interview will focus on collecting data from a subset of women participating in the Phase 2b FSAD clinical trial described in Example 2. The study will be designed as a substudy that will be an addendum to the main clinical trial protocol. An exit interview will be conducted via videoconference or telephone at the completion of the clinical trial for each patient who is willing and eligible to participate. The interview will focus on discussing with the patient what constitutes meaningful change on the PROMs of interest (SFQAS domains, AS diary domains, and FSDS-DAO item 14, PBE), as well as improvement on the PGI-C and PGI-S.

[0369] Study population In total, 60 adult (over 21 years of age) women with FSAD will be recruited from the Phase 2b clinical trial of Example 2, which will enroll approximately 400-590 patients (300-400 will complete). Women selected to participate in the exit interview will be those who first complete the study and agree to be part of this subset. Sample size will be determined by the need to observe varying levels of improvement over the course of the clinical trial.

[0370] Exit Interview Procedure Given that the exit interview will occur no later than two weeks after the final clinical trial visit, the interviewer will ascertain (a) whether any changes occurred during the trial, and (b) whether any changes have occurred between the final visit and the present (i.e., the day of the interview). This helps ensure that the discussion focuses on the patient's experience during the trial and not on how the patient has felt since their last visit (if any symptoms have improved or worsened since stopping study treatment).

[0371] Part 1: Overall FSAD Experience Introduction and discussion of the experience of living with FSAD. The purpose of this section is to "warm up" the patient and put them at ease, rather than delving deeply into their experience. Therefore, the questions in this section should be brief, and the discussion should last approximately 10 minutes.

[0372] Part 2: Experiences of FSAD-related problems with sexual arousal or sensation As the interview continues, questions focus on issues related to sexual arousal and sensation and the experience of changes during the study (e.g., whether these improved, stayed the same, or worsened, and whether any of these changes were meaningful).

[0373] Patients are asked whether a change in score on the response scale for each PROM instrument, either higher or lower, would be meaningful and whether each level of score change reflects a change in symptoms or impact. Any changes over time in each response scale due to treatment and the MCT for each response scale will be discussed below. Four items in the SFQ28 AS domain ○FSDS-DAO item 14 ○Five items in the AS domain of the awakening diary ○ PGI-S for one item ○PGI-C for one item One-item PBE (i.e., patient's yes / no response to the question, "Did you experience any meaningful benefit from the study drug?") ●This series of questions will continue for approximately 45 minutes. Part 3: Patients' opinions about topical medications in clinical trials If time permits, discuss the use of the topical medication, e.g., the cream's application process, ease of use, texture, and whether the patient would recommend it to a friend. This discussion should take approximately 5 minutes.

[0374] Example 4: Evaluation of condition-related symptom experience and relative importance of FSAD symptoms the purpose The purpose of this study was to conduct in-depth qualitative interviews with premenopausal (n=20) and postmenopausal (n=15) women who had been clinically diagnosed with FSAD by a trained sexual medicine clinician (N=35). The purpose of the interviews was to assess the experience of condition-related symptoms and the relative importance of FSAD symptoms, including their severity, bothersomeness, and impact on participants' health-related quality of life.

[0375] method Study population This study recruited adult female participants aged 21 to 70 years with a clinical diagnosis of FSAD. Participants were required to be sexually active (within the past 4 weeks) and to have experienced "normal" sexual function for at least 2 years. Participants who met all inclusion and exclusion criteria underwent a formal semi-structured clinical interview to confirm a diagnosis of FSAD, defined by DSM-IV-TR as a primary FSD complaint. FSAD is classified by DSM-IV-TR as acquired vs. present at birth and generalized vs. situational, with symptoms present for at least 6 months prior to the clinical interview. Eligible participants had a primary complaint of lack of genital arousal during sexual activity, and this genital response had a detrimental and distressing impact on the participant's overall sexual experience.

[0376] Recruitment Women were recruited via an internet-based screening questionnaire and clinically diagnosed with FSAD. Prior to Visit 1, initial eligibility was assessed by telephone. If participants were deemed potentially eligible, site staff administered and completed an informed consent form at the first visit to confirm the diagnosis (Visit 1). After consent, inclusion / exclusion criteria were confirmed, and a clinical interview was conducted to confirm the primary diagnosis of FSAD as defined by DSM-IV-TR. Women with secondary complaints related to low desire 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 as long as symptoms related to low genital arousal were considered the most bothersome symptoms and occurred before low desire. If deemed eligible after Visit 1, women were asked to return for a second visit (Visit 2) and participate in an in-depth, qualitative, one-on-one 90-minute interview.

[0377] Visit for exam interview A semi-structured interview combined with concept elicitation (CE) and cognitive debriefing (CD) was identified as the most appropriate approach to address the research objectives (only the CE portion of the interview is reported here). Semi-structured interviews allow for exploration of participants' subjective thoughts, experiences, and details that are not possible in structured interviews. Furthermore, semi-structured interviews allow for evaluation of participants' responses regarding specific symptoms by using appropriate probes when necessary to facilitate discussions that are not possible in unstructured interviews.

[0378] Elicitation interviews examined the symptoms and impacts experienced by women with FSAD. Open-ended questions were used to encourage participants to spontaneously report on their experiences. When necessary, interviewers used more direct questions to elicit further details from participants. Below are examples of the types of questions: ● "Tell me about the typical arousal problems you experience," ● "How long has this been happening?", "How bad could this problem be?", ● "How do you feel when this problem occurs?" ● "How does this issue make you feel about being intimate with your partner?" ● "Can you think about the different types of things you mentioned and rank them from least bothersome to most bothersome?"

[0379] This data collection approach was used to gain participant-led insights and to refine bottom-up thematic data analysis.

[0380] analysis All interviews were audio-recorded and transcribed verbatim into Microsoft Word documents by a professional transcription company (Rev), which were used for analysis. The qualitative software program, Nvivo v12.0, was utilized to assist researchers in coding and analyzing the qualitative data. This software allows researchers to apply codes to sections of text using thematic analysis. Thematic analysis allowed the four expert researchers who coded the data to identify themes or patterns within the data. Symptoms and impacts were coded as "spontaneous" (S) or "probed" (P) at the first point of mention during the interview, providing an assessment of the symptoms and impacts most frequently described by participants without prompting by the interviewer. A codebook was developed to assist coding, and then four expert coders used it to independently code the transcripts.

[0381] All key concepts emerged in the interview sample (called a "saturation analysis"). The researchers assessed whether concept saturation was achieved in that no new themes or conceptual descriptions were introduced in the final set of interviews. To determine this, the transcripts were grouped into three sets for the premenopausal and postmenopausal cohorts in the order in which they were conducted. The concepts derived were then compared between the sets. The point at which no new concepts emerged was considered to be the point at which saturation was achieved.

[0382] result Study population A total of n = 23 premenopausal women and n = 13 postmenopausal women participated in the study. The n = 23 premenopausal women and n = 13 postmenopausal women were primarily Caucasian (60.9% / 69.2%; premenopausal / postmenopausal). Black / African American was the next most common race reported by six women, split evenly between the premenopausal and postmenopausal samples. Four women in the premenopausal group identified as Hispanic / Latino. The overall mean age was 49 years, with an age range of 23-69 years. The majority of 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 commonly reported relationship status in both the premenopausal and postmenopausal samples was married (n = 16), followed by "in a committed relationship" (n = 11). 94.4% of women considered their sexual orientation to be heterosexual, while 5.6% were bisexual.

[0383] Interview results sexual activity At the beginning of the interview, women were asked about the types of sexual activities they regularly engaged in. Women were asked to spontaneously describe and define these activities. The interviewer also probed with a predetermined list of activities, including intercourse, fondling, foreplay, masturbation, and oral sex. All premenopausal women reported participating in sexual activities defined by the terms "penetration," "penetrating," "penetrative intercourse," or "penis-into-vagina" by n=9 participants. Most premenopausal women also reported participating in oral sex (n=18) and masturbation (n=15), with mentions split roughly between spontaneous and probing responses. Anal sex was spontaneously reported by n=2 premenopausal participants.

[0384] Nearly all postmenopausal women participants reported participating in sexual activities defined by n=9 participants using the terms "penetration," "penetrating," "penetrative intercourse," or "penis-into-vagina" (n=11). Most postmenopausal women also reported participating in oral intercourse (n=8) and masturbation (n=10). All postmenopausal participants who mentioned oral intercourse did so spontaneously, but for masturbation, the split between spontaneous and exploratory responses was nearly equal. Anal intercourse was spontaneously reported by all n=3 postmenopausal participants. In both the premenopausal and postmenopausal groups, fondling and foreplay were not spontaneously reported by nearly as many women as intercourse, oral intercourse, and masturbation.

[0385] Frequency of symptoms Following questions about sexual activity, women were asked, "What physical / genital sensations or feelings are you currently experiencing?" to elicit spontaneous responses regarding the types of sexual symptoms they experience as a result of FSAD. Premenopausal women spontaneously mentioned 10 symptoms, eight of which focused on physical / genital arousal, two of which related to a lack of cognitive arousal ("not feeling sexually aroused" or "aroused") and low sexual desire. Postmenopausal women spontaneously mentioned eight symptoms, seven of which focused on physical / genital arousal, one of which related to a lack of sexual desire (Table 7).

[0386] The most frequently reported symptom in the premenopausal (n = 21; n = 11 (spontaneous), n = 10 (probing)) and postmenopausal (n = 13; n = 7 (spontaneous), n = 6 (probing)) groups was "inability or difficulty in reaching orgasm."

[0387] Lack of lubrication or wetness was the next most frequently reported symptom in the premenopausal group (n=19; n=13 (spontaneous), n=6 (probing)), followed by loss of feeling / sensation (n=17; n=13 (spontaneous), n=6 (probing)). In the postmenopausal group, lack of lubrication or wetness and loss of feeling / sensation were the next most frequently reported symptoms (loss of lubrication / wetness n=12; n=7 (spontaneous), n=5 (probing); loss of feeling / sensation n=12; n=11 (spontaneous), n=1 (probing)).

[0388] Although inability or difficulty in reaching orgasm was the most common symptom reported overall, lack of lubrication or wetness and loss of feeling / sensation in the premenopausal group (spontaneously reported by n=13) and loss of feeling / sensation in the postmenopausal group (spontaneously reported by n=11) were spontaneously mentioned by more participants than those who endorsed inability or difficulty in reaching orgasm.

[0389] Women also discussed some of the consequences of decreased physical / genital arousal during sexual activity, namely, low desire and cognitive arousal ("not feeling aroused"). Specifically, the impact of cognitive arousal and sexual desire was discussed as a consequence of genital arousal symptoms: Desire: Premenopausal women: n = 12 (n = 11 spontaneous, n = 1 probed); Postmenopausal women: n = 7, all spontaneously reported; Cognitive-Arousal Problems: Premenopausal women: n = 12 (n = 5 spontaneous, n = 7 probed); Postmenopausal women: n = 4, all probed. Due to the fact that none of the postmenopausal participants reported "not feeling aroused" as a symptom, the concept "not feeling aroused / aroused" included in the premenopausal cohort is listed only as "not feeling aroused" in the postmenopausal cohort. [Table 11] * For the postmenopausal group, this concept is "not sexually arousable."

[0390] The most problematic symptom Participants in the premenopausal and postmenopausal cohorts were asked to rank their FSAD symptoms from most to least bothersome to identify those that presented the most problems (Table 8). In the premenopausal group, the most frequently reported symptom in the top three was lack of lubrication or wetness (n = 17), followed by loss of feeling / sensation (n = 12), and then inability to reach orgasm (n = 8). Lack of lubrication was ranked as the most bothersome symptom by n = 6 participants, and loss of feeling / sensation was ranked as the top symptom by n = 5 participants. Lack of lubrication and loss of feeling / sensation were followed by difficulty or inability to reach orgasm, with 8 women placing this in their top three symptoms. Lack of numbness (n = 6) and inability to feel sexually aroused / aroused were reported in the top three by n = 7 and n = 8 participants, respectively. In the postmenopausal group, the top three most frequently reported symptoms were loss of feeling / sensation (n=10), followed by lack of lubrication or wetness (n=9), and then both inability to reach orgasm and lack of desire (both n=6). Inability to feel sexually aroused was only identified as the top most bothersome symptom by n=2 women. Specific descriptors of loss of sensation, such as numbness and tingling, were each mentioned by one woman, and together they reported this as the third most bothersome symptom. [Table 12] * Pulsation was not reported as the most troublesome FSAD symptom by any of the participants. ** Not all participants listed three symptoms as most problematic; some participants listed / ranked only two. One woman in the postmenopausal group listed the same problem as both number one and number three. *** One postmenopausal woman stated that difficulty achieving orgasm and low desire were both her number one biggest problems. †Because premenopausal participants used the terms "sexual arousal" and "arousal," these two concepts were combined into one concept for that group. For postmenopausal participants who did not report "not aroused" as a symptom, this concept was "not aroused."

[0391] Symptoms that are most important to treat Following the question about the most bothersome symptom, participants were asked which symptom would be most important to treat if there were a treatment product on the market. Similar to the ranking of the most bothersome FSAD symptoms in Table 8, in the premenopausal group, lack of lubrication and wetness was the symptom listed as most desired for treatment, with 17 women ranking it in their top three (Table 9). Twelve women cited loss of feeling / sensation, followed by difficulty or inability to reach orgasm and lack of numbness (both n = 7). These numbers correspond with the ranking women gave to their most bothersome problems, particularly for the two symptoms most important to treat. Overall, a total of n = 22 premenopausal women reported wanting treatment for at least one genital arousal sensation problem, including loss of feeling / sensation (n = 12), lack of numbness (n = 7), and loss of fullness / engorgement (n = 1). This is higher than the number of participants who reported lack of lubrication or wetness as the most important FSAD symptom to treat (n = 17).

[0392] In the postmenopausal group, loss of feeling / sensation and lack of lubrication / wetness were both identified as the top two symptoms for which treatment was most desired (n = 9) (Table 9). This was followed by difficulty or inability to reach orgasm (n = 7), and then low desire (i.e., lack of interest in sexual activity) (n = 5). Lack of sexual arousal when participating in sexual activity (cognitive arousal) was listed by n = 2 women as the most important symptom to treat, while the specific sensory issues of lack of tingling and lack of warmth were each reported by n = 1 woman. Although the ranking of the most problematic symptoms (Table 8) and the ranking of the symptoms for which treatment was most desired differ slightly (i.e., difficulty / inability to reach orgasm was listed as the most problematic and third most problematic), the results from these two questions suggest a match between the FSAD symptoms that postmenopausal women view as troublesome and those for which treatment was most desired. Overall, a total of n=11 women reported wanting treatment for at least one genital arousal sensation problem, including loss of feeling / sensation (n=9), lack of numbness (n=1), and lack of tingling (n=1). This is higher than the number of participants who reported lack of lubrication or wetness as the most important FSAD symptom to treat (n=9). [Table 13] * Pulsation was not reported as the most important FSAD symptom to treat by any participant. ** One premenopausal participant listed treating both symptoms, namely warmth and numbness, as the second most important symptom. *** One postmenopausal participant listed orgasm and low desire as the two symptoms most important to treat. † Not all participants listed three symptoms as most important to treat; some participants listed / ranked only two. ††Because premenopausal participants used the terms "sexual arousal" and "arousal," these two concepts were combined into one concept for that group. For the postmenopausal group who did not report "not aroused" as a symptom, this concept was "not aroused."

[0393] Frequency of impact from FSAD When describing their experiences with FSAD, participants also discussed the impact the disorder had on their lives. Both impacts reported in the premenopausal and postmenopausal cohorts were spontaneously reported by participants. Participants described the impact of FSAD on their HRQoL in vague terms, and in some cases explained how it related to specific symptoms they experienced. The impacts reported by women fell into five major themes: 1) psychological problems, 2) emotional problems, 3) relational problems, 4) cognitive problems, and 5) physical problems. The most frequently reported impacts in both cohorts were related to psychological, emotional, and relational problems.

[0394] Decreased trust was the most commonly reported effect, reported by nearly all premenopausal (n = 21) and postmenopausal (n = 12) women. Participants' descriptions of decreased trust included discussions of feeling awkward, inferior, inadequate, anxious, "not normal," bad about themselves and about themselves, unattractive, like a failure, ignored, and "less feminine."

[0395] In the premenopausal group, the next two most frequently reported impacts were related to relationship problems: the impact of FSAD on partners (n = 18) and the difficulties it poses to relationships (n = 16) (Table 10). Participants described the impact of FSAD on their partners' moods, including feelings of sadness, disappointment, and irritability. Additionally, participants noted that FSAD can cause partners to question themselves, their sexual abilities, and the relationship in general. Following these impacts, the next two most frequently discussed were emotional problems of dissatisfaction and depression, both reported by n = 15 women. Over half of the women in this cohort reported experiencing anxiety as an impact of FSAD (n = 12). Anger was also described by nearly half of the women in this cohort (n = 10).

[0396] In the postmenopausal group, the next two most commonly reported impacts were related to emotional problems: feeling dissatisfied and disappointed (n = 10 each) (Table 10). Women also noted feeling "discouraged" and "demotivated." The next most commonly reported impacts (n = 9 each) were emotional problems, including depression, and relationship problems, such as relationship difficulties and changes, and lack of interest in sexual activity. Eight postmenopausal women reported "feeling old" as a result of their FSAD problems. Women (n = 7) described feeling bad for their partner, the impact of FSAD on their partner, being unable to connect with their partner, and feeling angry. Participants' descriptions of the impact of FSAD on their partner included feeling sad, disappointed, frustrated, and a vague sense of something being lost. Additionally, n = 7 women noted that they sometimes had difficulty approaching or connecting with their partner due to the lack of sexual intimacy. [Table 14]

[0397] Women were given a choice between the phrases "feel bothered," "feel concerned," "feel dissatisfied," and "feel distressed" and asked to choose a preferred term to describe their feelings about FSAD. The majority of premenopausal women (n = 19) and postmenopausal women (n = 7) selected "feel dissatisfied." Two premenopausal women selected "feel concerned," two selected "feel distressed," while none selected "feel bothered." Four postmenopausal women selected "feel distressed," and two selected "feel bothered," while none selected "feel concerned." Descriptions of similarities and differences between these phrases revealed that women perceived the phrases to be related and on a continuum of intensity, with "feel bothered" being the least intense, followed by "feel concerned," then "feel dissatisfied," and then "feel distressed."

[0398] Saturation analysis For the premenopausal cohort, saturation analysis based on reported FSAD symptom concepts demonstrated that only one concept, "pulsation," was introduced in the final series of interviews. All other concepts were introduced in the first series of interviews, and all, except for tingling, were mentioned across all three series of interviews. Pulsation was not mentioned until the final series of interviews, where it was only mentioned as a symptom by one participant in this cohort. Therefore, further interviews were not recommended. The saturation analysis also revealed that no participants spontaneously reported "not feeling aroused," although, based on the descriptions given by participants, this concept appears to be similar to "not feeling sexually aroused." Saturation was considered to have been met across the sample for all concepts.

[0399] For the postmenopausal cohort, saturation analysis based on reported FSAD symptom concepts demonstrated that no concepts were introduced in the final series of interviews. Four concepts—lack of lubrication / wetness, loss of feeling / sensation, difficulty or inability to reach orgasm, and low desire—were spontaneously mentioned by participants in all three series of interviews. Lack of warmth was not introduced in the first series of interviews but appeared in both the second and third series. All other concepts were introduced in the first series of interviews, except for discomfort, which was only discussed by participants in the second series. Given this data, saturation was considered to have been met. Therefore, because no new concepts emerged in the third series of interviews, no additional interviews were recommended for this sample.

[0400] During the interviews, women described a variety of symptoms they experienced related to their FSAD. Premenopausal women described a total of 10 symptoms, all of which were spontaneous. Of these, 8 were physical arousal / genital arousal symptoms and 2 were cognitive arousal / desire-related. Postmenopausal women described a total of 11 symptoms, 8 of which were spontaneous. Of these, 9 were physical arousal / genital arousal symptoms and 2 were cognitive arousal / desire-related. In contrast to premenopausal women, postmenopausal women did not spontaneously endorse feeling pulsating, tingling, or sexually aroused or aroused. The most frequently reported symptom in both the premenopausal (n = 21) and postmenopausal (n = 13) cohorts was "inability or difficulty achieving orgasm." The high number of reports of difficulty or inability to achieve orgasm is perhaps not surprising, given that this population lacks a healthy genital arousal response (e.g., the ability to feel sensation, become moist / lubricated), a necessary component of the sexual response cycle that precedes orgasm. Many women in both groups attributed their orgasmic problems specifically to a lack of their genital arousal, demonstrating that orgasmic dysfunction is a secondary effect of FSAD.

[0401] The most and second most bothersome symptoms for premenopausal and postmenopausal women were reversed between groups: premenopausal women stated that lubrication and wetness were the most problematic symptom (n = 17), while postmenopausal women stated that it was loss of feeling / sensation (n = 10). The second most problematic symptom for premenopausal women was loss of feeling / sensation (n = 12), while for postmenopausal women, it was lubrication and wetness (n = 9). Orgasm was the third most problematic symptom for both groups (premenopausal, n = 8; postmenopausal, n = 6). The symptom women most wanted treated was lubrication for premenopausal women, while for postmenopausal women, lack of lubrication or wetness was tied with loss of feeling and sensation (both n = 9). Despite the availability of over-the-counter (OTC) lubricants (and postmenopausal women reporting the need to use lubricants for sexual comfort), women in both groups expressed interest in FSAD treatments that addressed lack of lubrication. This suggests that OTC lubricants do not address the needs of women with FSAD, who reported a desire for treatment options to help them provide their own lubrication.

[0402] Although "loss of feeling / sensation" was the second most bothersome symptom and second most desired for treatment in premenopausal women, along with lubrication and wetness in postmenopausal women, both groups of women in this sample used a variety of terms to describe loss of feeling / sensation in the genitals (e.g., lack of warmth, lack of numbness, lack of throbbing, lack of tingling, lack of tingling heat, lack of feeling of fullness / engorgement (both in the clitoris and nipples), lack of feeling or sensation in the genitals, "numbness," feeling that the genitals are "dead," "lack of blood flow or arousal to the genitals," and decreased skin sensitivity (including the nipples and elsewhere on the body)). These descriptions in both groups of women demonstrate a significant overlap between specific genital arousal-sensation descriptors and the broad term "loss of feeling / sensation." Furthermore, a total of 21 of the 23 premenopausal women and all of the postmenopausal women (n=13) reported sensation or lack of sensation in the genitals, indicating that "sensation" was the most relevant and important concept for women with FSAD.

[0403] Postmenopausal women endorsed an additional physical / genital arousal symptom that did not appear in the premenopausal sample: discomfort. The study investigators were careful to separate discussions of pain and discomfort related to lack of lubrication and wetness as a secondary effect of this symptom from those discussed in unrelated terms. Thus, the "discomfort" described by the postmenopausal sample encompasses descriptions by women of "pain and cramping" and "vaginal pressure that was uncomfortable" that were separate from lack of lubrication and wetness. Furthermore, no postmenopausal women endorsed "not feeling aroused," and the only postmenopausal woman who endorsed "not feeling sexually aroused" did so upon probing by the interviewer.

[0404] Women in the premenopausal and postmenopausal cohorts also described a wide variety of ways in which FSAD affected their HRQoL. The most frequently reported impact in both groups was decreased trust. In the premenopausal group, the second most frequently reported impact was the impact on the woman's partner and the difficulties FSAD caused in their relationship. In the postmenopausal group, this was followed by feelings of dissatisfaction, disappointment, and depression, and the difficulties it caused in their relationship. Premenopausal women also described a number of emotional impacts, the most frequently reported of which were dissatisfaction and depression. Anxiety and anger were also frequently reported in this population. Postmenopausal women also described feeling angry at their partner and feeling bad for them.

[0405] In both the premenopausal and postmenopausal samples, "feeling dissatisfied" was spontaneously offered as the term that best described their feelings about FSAD (n = 5 and n = 7, respectively). Given a choice between four phrases (bothersome, concerned, frustrated, distressed), women in both groups again selected "feeling dissatisfied" (n = 19 and n = 7, respectively). Data from both cohorts suggest that participants understood these phrases as being on a continuum, with bothersome and concerned at one end and frustrated and distressed at the other. Distressed was perceived as the "extreme" or "strong" end of these phrases. Women in the postmenopausal group were more willing to endorse or use the phrase "feeling distressed" than premenopausal women. This phrase is often associated with a feeling that the dissatisfaction has continued for some time, at which point these women felt unavoidable or would never change, and thus distressed by the situation.

[0406] One finding from this study is that women in both cohorts consistently distinguished symptoms of reduced arousal that were unrelated to desire (i.e., desire was present but the desire was not translated into a desired genital arousal response). The emphasis on lack of genital sensation and orgasmic dysfunction, as well as the reported distress related to these issues, demonstrates the importance of maintaining arousal as a separate domain. This calls into question the DSM-5's merging of FSAD and HSDD into FSIAD, especially given women's justifications for their inability to distinguish between desire and arousal. In this study, women cited desire problems in addition to arousal problems but were able to distinguish between the two. Merging desire and arousal into a single diagnostic entity could potentially exclude women who previously met criteria for either FSAD or HSDD from treatment for these conditions. The symptoms reported in this study support the idea that desire and arousal are not the same underlying construct and, therefore, the separate criteria outlined in DSM-IV are more appropriate for diagnosing these conditions. This is consistent with the ISSWSH nomenclature, which delineates and defines HSDD and FSAD as separate conditions, and distinguishes and defines cognitive and genital arousal disorders. The ISSWSH nomenclature is intended for use by clinicians across specialties who treat women with FSD.

[0407] The results from the study suggest that there are no major differences in how premenopausal and postmenopausal women experience FSAD. Both groups, despite spanning a wide age range, not only reported similar symptoms but also used similar words to describe them.

[0408] conclusion Analysis of qualitative data from the interviews revealed the physical and emotional burden of FSAD. Results from the premenopausal and postmenopausal cohorts suggest that the manifestations of FSAD are similar in these two populations.

[0409] Example 5: Topline Data from an Exploratory Phase 2b Study Topline results from the study outlined in Example 2 demonstrated that patients treated with sildenafil cream experienced meaningful improvements in the co-primary endpoint, which assessed change from baseline in the arousal-sensation domain of the Sexual Function Questionnaire. Patients treated with sildenafil cream also experienced improvements in secondary endpoints and pre-specified exploratory endpoints assessing sexual satisfaction, arousal lubrication, and orgasmic achievement and pleasure. These data support the continued development of sildenafil cream and the selection of the proposed primary endpoint assessment for the Phase 3 trial.

[0410] The exploratory study was designed to test the sensitivity of several patient-reported outcome (PRO) efficacy endpoints and their ability to determine the treatment effect of sildenafil cream compared with placebo to inform ongoing sildenafil cream development. The study also served as a validation study of exploratory endpoints that could serve as candidate endpoints in Phase 3 trials of sildenafil cream. Because there are currently no FDA-approved treatments for FSAD, no potential treatments for FSAD have had efficacy endpoints tested in pivotal Phase 3 trials to date.

[0411] FSAD is the inability to achieve or maintain an adequate physical response to sexual stimulation. Of the various types of female sexual dysfunction disorder, FSAD most closely resembles male erectile dysfunction (ED). Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, is the active ingredient in the oral tablet currently marketed under the trade name Viagra® for the treatment of male ED. Sildenafil cream is an investigational, proprietary topical sildenafil cream formulation specifically designed to increase blood flow to female genital tissues. If successfully developed, sildenafil cream has the potential to become the first FDA-approved treatment for FSAD. Market research suggests that 16% of U.S. women aged 21 to 60, or approximately 10 million women, suffer from symptoms associated with FSAD, including lack or reduced sexual arousal, and actively seek solutions to improve their condition. In comparison, the prevalence of complete ED in men is estimated to be approximately 5% of men aged 40, increasing to approximately 15% by age 70.

[0412] FSAD is characterized primarily by a lack of sexual desire and is distinct from female hypoactive sexual desire disorder (HSDD). FSAD is a condition characterized primarily by a persistent or recurring inability to achieve or maintain sufficient genital arousal (sufficient lubrication-swelling response) during sexual activity, often resulting in distress or interpersonal difficulties. Like male ED, FSAD is associated with insufficient blood flow to the genitals.

[0413] 3.6% sildenafil cream is an investigational, proprietary cream formulation of the PDE-5 inhibitor sildenafil designed for topical administration to vulvo-vaginal tissues to increase genital blood flow and improve female genital arousal responses while avoiding the systemic side effects observed with oral formulations of sildenafil. Sildenafil cream has been evaluated in Phase 1 and Phase 2a clinical trials. In a Phase 1 clinical trial in 20 healthy postmenopausal women, topical sildenafil cream was safe and well tolerated at clinically relevant doses, and study subjects reported favorable product attributes, including ease of application and easy absorption. In a Phase 2a study in women with FSAD (15 premenopausal and 16 postmenopausal), sildenafil cream increased measurable blood flow to genital tissues compared with placebo cream. Furthermore, data from thermographic studies in six healthy women demonstrated a significantly greater increase in genital temperature after administration of sildenafil cream compared with placebo cream, indicating a positive effect on genital blood flow during the 30-minute test session, with statistical separation from placebo within the first 15 minutes of dosing.

[0414] The exploratory Phase 2b RESPOND trial was a multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of sildenafil cream in premenopausal patients with FSAD (see Example 2). The study included a PRO instrument to screen eligible women with FSAD and was the first of its kind in a Phase 2b clinical trial to include two co-primary endpoints, secondary endpoints, and several exploratory endpoints to measure, among other things, improvement in local genital arousal sensation, reduction in distress experienced by women with FSAD, and satisfying sexual events. There are no FDA-approved treatments for FSAD, and therefore, no potential treatments for FSAD have previously had efficacy endpoints approved for use in pivotal Phase 3 trials.

[0415] The FDA required that any PROs used to assess efficacy in Phase 3 trials be fully validated. Part of that validation included an exit interview conducted as part of the Phase 2b RESPOND trial to qualitatively better understand what constituted meaningful change for the subjects (see Example 3). These qualitative assessments of meaningful change were used to determine the endpoints that achieved meaningful improvement in the sildenafil cream group.

[0416] Exam Overview The Phase 2b RESPOND trial began with 99 subjects in the sildenafil cream intent-to-treat population and 93 subjects in the placebo intent-to-treat population, and completed with 70 subjects in the sildenafil cream intent-to-treat population and 60 subjects in the placebo intent-to-treat population, thus lacking statistical power to assess statistical significance. During the study, participants used sildenafil cream and placebo cream in their home environment and recorded their experiences using a PRO instrument. The study evaluated sildenafil cream compared to placebo cream over 12 weeks of medication, following both a drug-free run-in period and a placebo run-in period.

[0417] Study efficacy results and safety Summary of top-line data The co-primary endpoint of the Phase 2b RESPOND trial was to evaluate the efficacy of sildenafil cream compared with placebo, as measured by the change from baseline to the end of the study in the arousal-sensation domain of the 28-item Sexual Function Questionnaire (SFQ28). The endpoint did not achieve statistical significance. However, the change at the end of the study in the sildenafil cream-treated group was consistent with the extent to which women reported meaningful improvement in the end-of-study exit interview.

[0418] Another co-primary endpoint was to assess the efficacy of sildenafil cream compared with placebo, as measured by the change from baseline to the end of the study in scores regarding perceived concern due to difficulties with sexual arousal. Changes were assessed using the previously validated Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) survey. This assessment did not distinguish sildenafil cream from placebo.

[0419] A secondary endpoint of the study was to evaluate the efficacy of sildenafil cream compared with placebo, measured by the change from baseline to the end of the study in the number of satisfying sexual events, based on subjects' responses to questions answered and recorded via an electronic diary within 24 hours after each sexual event. This endpoint was selected because it could serve as the primary endpoint in a phase 3 trial based on the FDA 2016 Draft Guidance Document for Female Sexual Dysfunction. When measured at weeks 4 and 8 after randomization, subjects treated with sildenafil cream had a higher proportion of satisfying sexual events during the previous month (68.6% and 74.1% at weeks 4 and 8, respectively) compared with placebo-treated subjects (47.9% and 67.9% at weeks 4 and 8, respectively) (p-value for week 4 = 0.04).

[0420] Exploratory endpoints (selected based on content validity testing, see Examples 1 and 4) included endpoints related to genital arousal, genital blood flow, lubrication, orgasm, concerns about difficulties with sexual arousal, and other assessments, including questions about satisfying sexual events. Exploratory endpoints were assessed via electronic diaries at multiple time points over the course of the study. The exploratory endpoint regarding concerns about difficulties with sexual arousal showed differences between sildenafil cream and placebo. Specifically, when asked about their overall impression of change regarding concerns about difficulties with sexual arousal, women treated with sildenafil cream were more likely to report an overall improvement. Based on responses to questions at weeks 4, 8, and 12 after randomization, 44% to 49% of subjects treated with sildenafil cream reported an overall improvement compared with 37% to 44% of subjects treated with placebo (P<0.01). Exploratory endpoints related to arousal lubrication and orgasmic achievement and pleasure, as measured by change from baseline to week 8 after randomization, also showed significant differences between subjects treated with sildenafil cream compared to placebo, with P values ​​of 0.059 and 0.066, respectively (these estimates trend toward significance despite the small number of subjects in each group: n=73 in the sildenafil cream intention-to-treat group and n=64 in the placebo intention-to-treat group). 48.7% of subjects treated with sildenafil cream reported increased satisfaction with overall sexual activity as measured at the end of the study, compared with 42.6% of subjects treated with placebo.

[0421] Table 11 presents selected data regarding the co-primary endpoints, secondary endpoints, and selected exploratory endpoints. The exploratory Phase 2b RESPOND trial was underpowered to assess statistical significance, but statistical significance was achieved for selected assessments. [Table 15] (1) The numbers in this column represent the number of subjects included in the evaluation at the time point indicated. (2) This exploratory endpoint was measured beginning 4 weeks after randomization and periodically until the end of the study.

[0422] safety Sildenafil cream was generally safe and well tolerated. There were no treatment-related serious adverse events, and most treatment-related adverse events were mild in severity. Further test results [Table 16] * Approximately n=30 patients were included in an analysis to investigate whether completing the wakefulness diary questions affected patients' scores on the SFQ28 sense of wakefulness domain and FSDS-DAO question 14. These approximately 30 patients completed the entire trial but did not complete the wakefulness diary throughout the trial. These patients were not included in the analysis of the co-primary endpoints. [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0423] The data in Table 18 were derived from the desire domain of the SFQ (range 5–31).

[0424] (Q1) How often do you have pleasant thoughts and feelings related to sexual activity?

[0425] (Q2) How often did you want to be touched and caressed sensually by your partner?

[0426] (Q3) How often did you desire to participate in sexual activity?

[0427] (Q4) How often did you initiate sexual activity with your partner?

[0428] (Q14) How often have you participated in sexual activity involving penetration (e.g., vaginal penetration and intercourse)?

[0429] (Q26) How often did you expect sexual activity?

[0430] Patients treated with sildenafil cream experienced meaningful improvements in the coprimary endpoint, which assessed change from baseline in the arousal-sensation domain of the Sexual Function Questionnaire, although the endpoint did not achieve statistical significance. Patients treated with sildenafil cream also experienced improvements in secondary and prespecified exploratory endpoints that assessed various aspects of the sexual experience, including sexual satisfaction, arousal lubrication, orgasmic achievement and pleasure, and sexual desire.

[0431] summary: 1. Increased sexual satisfaction Women treated with sildenafil cream had a higher rate of satisfying sexual events. Sildenafil cream resulted in 68.6% and 74.1% of women at weeks 4 and 8, respectively (P=0.04 at week 4), compared with placebo-treated women (47.9% and 67.9%, respectively).

[0432] 2. Improvement in overall impression of change regarding concerns about difficulties in sexual arousal; Women treated with sildenafil cream were more likely to report an overall improvement. Based on responses to questionnaires at 4, 8, and 12 ...

Claims

1. A method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a female subject.

2. 10. The method of claim 1, wherein treating FSAD comprises increasing satisfying sexual events, improving arousal sensations, increasing arousal lubrication, increasing orgasm, reducing sexual arousal apprehension, reducing pain or discomfort during sexual activity, reducing pain or discomfort after sexual activity, and / or improving satisfaction with sexual activity.

3. 3. The method of claim 2, wherein treating FSAD comprises increasing satisfying sexual events.

4. 3. The method of claim 2, wherein treating FSAD comprises improving a sense of wakefulness.

5. 3. The method of claim 2, wherein treating FSAD comprises increasing wakefulness lubrication.

6. 3. The method of claim 2, wherein treating FSAD comprises increasing orgasm.

7. 3. The method of claim 2, wherein treating FSAD comprises reducing concerns about sexual arousal.

8. 3. The method of claim 2, wherein treating FSAD comprises reducing pain or discomfort during sexual activity.

9. 3. The method of claim 2, wherein treating FSAD comprises reducing pain or discomfort after sexual activity.

10. 3. The method of claim 2, wherein treating FSAD comprises improving satisfaction with sexual activity.

11. 11. The method of any one of claims 1-10, wherein treating FSAD comprises increasing sensation in the genital area.

12. 12. The method of claim 11, wherein the genital sensations include one or more of numbness, pleasure, warmth, throbbing, tingling, congestion, or fullness in the genital area.

13. A method for increasing satisfying sexual events in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

14. A method for improving the sense of arousal in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

15. A method for increasing arousal lubrication in a sexually active female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

16. A method for increasing orgasm in a sexually active female subject comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

17. A method for reducing concerns about sexual arousal or improving satisfaction with sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

18. A method for alleviating pain or discomfort during sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

19. A method for alleviating pain or discomfort following sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

20. A method for treating female sexual dysfunction (FSD) or symptoms thereof, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​a female subject.

21. 1. A method for increasing sexual desire in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

22. A method for increasing response to physical or psychological sexual stimulation in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​the female subject.

23. 23. The method of claim 22, wherein response to physical sexual stimulation is increased.

24. 23. The method of claim 22, wherein response to psychological sexual stimuli is increased.

25. 23. The method of claim 22, wherein the response to physical and psychological sexual stimuli is increased.

26. 26. The method of any one of claims 1 to 25, wherein the phosphodiesterase type 5 inhibitor and / or salt thereof is administered at least twice over a period of time.

27. 27. The method of claim 26, wherein the period is from about 1 week to about 8 weeks.

28. 28. The method of claim 26 or 27, wherein one or more symptoms are improved within about 1 week to about 8 weeks after the initial administration.

29. 29. The method of claim 28, wherein one or more symptoms are improved within about 1 week to about 4 weeks after said initial administration.

30. 30. The method of claim 28 or 29, wherein the one or more symptoms include arousal lubrication.

31. 30. The method of claim 28 or 29, wherein the one or more symptoms include sexual desire.

32. 30. The method of claim 28 or 29, wherein the one or more symptoms include orgasmic achievement and / or pleasure.

33. 33. The method of any one of claims 1 to 32, wherein the phosphodiesterase type 5 inhibitor is sildenafil, avanafil, lodenafil, mirodenafil, tadalafil, vardenafil, udenafil, acetyldenafil, or thiomethisosildenafil.

34. 33. The method of claim 32, wherein the phosphodiesterase type 5 inhibitor is sildenafil.

35. The topical composition comprises: a. a stabilizing polymer; and b. propylene glycol; c. a polysorbate surfactant; d. L-arginine or an L-arginine salt; e. an ionic salt.

36. The method of any one of claims 1 to 35, wherein the composition is a cream, gel or lotion.

37. 36. The method of claim 34 or 35, wherein the composition comprises an L-arginine salt.

38. 38. The method of any one of claims 34 to 37, wherein the composition comprises L-arginine HCl.

39. 39. The method of any one of claims 34 to 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. 40. The method of any one of claims 34 to 39, wherein the ionic salt is capable of driving the phosphodiesterase type 5 inhibitor and / or salt thereof through the stratum corneum of a subject.

41. 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. 42. The method of any one of claims 34 to 41, wherein the ionic salt comprises potassium chloride.

43. 43. The method of any one of claims 34 to 42, wherein the stabilizing polymer comprises xanthan gum.

44. 44. The method of any one of claims 34 to 43, wherein the stabilizing polymer is present at a concentration of at least about 0.8% by weight of the composition.

45. 45. The method of any one of claims 34 to 44, wherein the propylene glycol is present at a concentration of at least about 8% by weight of the composition.

46. 46. ​​The method of any one of claims 34 to 45, wherein the polysorbate surfactant comprises polysorbate 20.

47. 47. The method of any one of claims 34 to 46, wherein the polysorbate surfactant is present at a concentration of at least about 2% by weight of the composition.

48. 48. The method of any one of claims 1 to 47, wherein the phosphodiesterase type 5 inhibitor is sildenafil.

49. 49. The method of any one of claims 1 to 48, wherein the phosphodiesterase type 5 inhibitor and / or salt thereof is present in a concentration of at least about 1% to about 10% by weight of the composition.

50. 50. The method of any one of claims 1 to 49, wherein the composition comprises glyceryl stearate, cetyl alcohol, squalane, isopropyl myristate, oleic acid, trisodium citrate dihydrate, sodium benzoate, and / or gluconolactone.

51. 51. The method of any one of claims 1 to 50, wherein purified water is present at a concentration of at least about 40% by weight of the composition.

52. The method of any one of claims 1 to 51, wherein the subject is a human.

53. The composition comprises: a. purified water; b. potassium chloride; c. L-arginine HCl; d. glyceryl stearate, and e. cetyl alcohol, f. squalane, g. xanthan gum, h. isopropyl myristate, i. oleic acid; j. propylene glycol; k. Polysorbate 20, and l. sildenafil citrate.

54. The composition contains each of the following compounds at concentrations not exceeding ±20% of the stated concentrations: a. purified water at a concentration of about 35% to about 55% by weight; b. potassium chloride at a concentration of about 2.5% to about 15% by weight; c. L-arginine HCl 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. cetyl 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 at 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; l. sildenafil citrate at a concentration of about 1% to about 10% by weight.

55. 55. The method of any one of claims 1 to 54, wherein the subject has Female Sexual Arousal Disorder (FSAD).

56. 56. The method of any one of claims 1-55, wherein the subject is at risk for Female Sexual Arousal Disorder (FSAD).

57. The composition comprises: a. purified water at a concentration of about 40% by weight; b. potassium chloride at a concentration of about 5% by weight; c. L-arginine HCl at a concentration of about 7.5% by weight; d. glyceryl stearate at a concentration of about 7% by weight; e. cetyl alcohol at a concentration of about 7% by weight; f. squalane at a concentration of about 4% by weight; g. xanthan gum at a concentration of about 0.8% by weight; h. isopropyl myristate at a concentration of about 1% by weight; i. oleic acid at a concentration of about 1% by weight; j. propylene glycol at a concentration of about 8.5% by weight; k. Polysorbate 20 at a concentration of about 2% by weight; l. trisodium citrate dihydrate at a concentration of about 10% by weight; m. sodium benzoate at a concentration of about 0.2% by weight; n. gluconolactone at a concentration of about 0.25% by weight; o. sildenafil citrate at a concentration of about 5%.

58. 1. A method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising: a. selecting a female subject exhibiting one or more symptoms of FSAD; b. administering to the subject's genital area a composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, a stabilizing polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt, and an ionic salt.

59. 59. The method of claim 58, wherein the one or more symptoms are selected from: decreased genital sensitivity, lack of genital responsiveness during sexual activity, decreased genital arousal, pain and / or discomfort during sexual activity, pain and / or discomfort after sexual activity, and / or distress related to sexual arousal difficulties.

60. 60. The method of 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 intravaginally.

61. externally administering about 50% of the composition; applying said composition to the anterior labial commissure, the clitoral prepuce, the glans penis and the frenulum; b. applying said composition to the vestibule of the vagina; c. applying the composition to the labia minora.

62. 62. The method of claim 60 or 61, wherein the composition is not applied to the labia majora or pubic hair.

63. 63. The method of any one of claims 60-62, wherein administering about 50% of the composition intravaginally comprises applying the composition to the anterior distal vagina at a depth of about 0 cm to about 3 cm within the vagina.

64. 64. The method of any one of claims 1 to 63, wherein the composition is administered about 10 to about 20 minutes before sexual activity.

65. 65. The method of any one of claims 1-64, wherein the composition is administered in up to about 9 doses over about 4 weeks.

66. 66. The method of any one of claims 1-65, wherein the composition is administered at least about 24 hours before the second dose of the composition.

67. 67. The method of any one of claims 1 to 66, wherein the subject has not been administered at least one of a guanylate cyclase stimulator, clonidine, a CYP3A4 inhibitor, a nitric oxide donor, an organic nitrate, an organic nitrite, or an alpha blocker within 28 days prior to administration of the first dose of the composition.

68. 68. The method of any one of claims 1-67, wherein the subject avoids wiping or washing any of the genital areas to which the composition has been applied.

69. 69. The method of any one of claims 1 to 68, wherein any remaining composition is washed off after sexual activity has concluded.

70. 70. The method of any one of claims 1 to 69, wherein sexual arousal is increased.

71. 71. The method of any one of claims 1 to 70, wherein sexual arousal is increased.

72. 72. The method of any one of claims 1 to 71, wherein administering results in a satisfying sexual event.

73. 73. The method of any one of claims 1-72, wherein administering results in increased genital arousal sensations.

74. 74. The method of any one of claims 1-73, wherein administering results in increased lubrication in the genital area during sexual activity.

75. 75. The method of any one of claims 1 to 74, wherein cognitive sexual arousal is increased.

76. 76. The method of any one of claims 1 to 75, wherein sexual desire is increased.

77. 77. The method of any one of claims 1-76, wherein administering results in increased orgasm during sexual activity.

78. 78. The method of any one of claims 1-77, wherein administering results in a reduction in the difficulty or inability to reach orgasm during sexual activity.

79. 79. The method of any one of claims 1-78, wherein administering results in increased sensitivity or sensation in the genital area during sexual activity.

80. 80. The method of any one of claims 1-79, wherein administering results in increased numbness in the genital area during sexual activity.

81. 81. The method of any one of claims 1-80, wherein administering results in increased engorgement in the genital area during sexual activity.

82. 82. The method of any one of claims 1-81, wherein administering results in increased warmth, tingling or throbbing in the genital area during sexual activity.

83. 83. The method of any one of claims 1-82, wherein administering results in relief of pain and / or discomfort during sexual activity.

84. 84. The method of any one of claims 1 to 83, wherein administering results in relief of pain and / or discomfort following sexual activity.

85. 85. The method of any one of claims 1 to 84, wherein sexual arousal is increased.

86. 86. The method of any one of claims 58 to 85, wherein the one or more symptoms include a decreased response to physical sexual stimulation.

87. 86. The method of any one of claims 58 to 85, wherein the female subject's primary complaint is decreased response to physical sexual stimulation.

88. After administration, the subject: a. an improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28); b. an improvement of at least 1 in the wakefulness and lubrication domain score of the SFQ28; c. an improvement of at least 1.5 in the SFQ28 sense of alertness domain score; d. An improvement of at least 2 in the craving domain score of the SFQ28; e. an improvement of at least 1.20 in the orgasm domain score of the SFQ28; f. an improvement of at least 1 in the pain domain score of the SFQ28; g. An improvement of at least -7 in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score; h. An improvement in the sense of wakefulness score of at least 1.45; i. an improvement in genital arousal score of at least 1.13; j. an improvement in genital arousal concern score of at least 1.49; k. A wakefulness diary item 12-SSE rate improvement of at least 0.25; 1. Entry 12 of the wakefulness diary - an improvement of at least 1.41 in the number of SSEs.

89. 89. The method of any one of claims 1-88, wherein the subject comprises a primary diagnosis of FSAD as defined by the Diagnostic and Statistical Manual of Mental Disorders Text Revision Fourth Edition (DSM-IV-TR).

90. 90. The method of any one of claims 1 to 89, wherein the topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof does not cause one or more of the following: orthostatic hypotension, headache, flushing, dyspepsia, lightheadedness, visual disturbances, nasal congestion, back pain, muscle pain, nausea, dizziness, and rash.

91. 91. The method of any one of claims 1 to 90, wherein the subject's primary complaint is FSAD.

92. 92. The method of any one of claims 1 to 91, wherein the subject's primary complaint is FSAD and the subject exhibits symptoms of secondary HSDD.

93. 1. A method for treating female sexual arousal disorder (FSAD) or a symptom thereof, comprising: a. Selecting a female subject with a primary complaint of FSAD; b. applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof to the genital area of ​​said subject.

94. 94. The method of claim 93, wherein the subject exhibits symptoms of secondary HSDD.

95. 1. A method for determining the efficacy of a treatment for FSAD, comprising: Obtaining a baseline score on one or more of the following: the Sexual Function Questionnaire (SFQ28) Arousal Cognition Domain score, the SFQ28 Arousal Lubrication Domain score, the SFQ28 Arousal Sensory Domain score, the SFQ28 Desire Domain score, the SFQ28 Orgasm Domain score, the SFQ28 Pain Domain score, the Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) score, the Arousal Sensory score, the Genital Arousal score, the Genital Arousal Concerns, the Arousal Diary Item 12 - Percentage of SSEs, and the Arousal Diary Item 12 - Number of SSEs; b. administering said FSAD treatment to a female subject; c. determining an improvement in one or more of said scores of step a.

96. The following: a. an improvement of at least 1 in the arousal cognition domain score of the Sexual Function Questionnaire (SFQ28); b. an improvement of at least 1 in the wakefulness and lubrication domain score of the SFQ28; c. an improvement of at least 1.5 in the SFQ28 sense of alertness domain score; d. An improvement of at least 2 in the craving domain score of the SFQ28; e. an improvement of at least 1.20 in the orgasm domain score of the SFQ28; f. an improvement of at least 1 in the pain domain score of the SFQ28; g. An improvement of at least -7 in the Female Sexual Distress Scale-Desire, Arousal, and Orgasm (FSDS-DAO) score; h. an improvement in sense of alertness of at least 1.45; i. an improvement in genital arousal of at least 1.13; j. an improvement of at least 1.49 in genital arousal concerns; k. An improvement of at least 0.25 in the Wakefulness Diary Item 12-SSE percentage; and l. an improvement of at least 1.41 in wakefulness diary item 12 - number of SSEs, indicates that the FSAD treatment is effective.

97. 97. The method of claim 95 or 96, further comprising applying one or more additional doses of the topical composition to the subject.

98. 98. The method of any one of claims 1-97, wherein the subject's primary complaint is FSAD and the subject does not exhibit symptoms of female orgasmic disorder (FOD).

Images