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

Abstract

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

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480023900.X (22) Application Date 2024.02.14 (30) Priority Data 63 / 484,812 2023.02.14 US 63 / 506,302 2023.06.05 US 63 / 513,082 2023.07.11 US 63 / 595,279 2023.11.01 US (85) PCT International Application Entering National Phase Date 2025.09.30 (86) PCT International Application Application Data PCT / US2024 / 015721 2024.02.14 (87) PCT International Application Publication Data WO2024 / 173493 EN 2024.08.22 (71) Applicant: Dell Biosciences, Inc. Address: California, USA (72) Inventor: D. Freund (74) Patent Agency: Beijing Jikai Intellectual Property Agency Co., Ltd. 11245 Patent Attorney: Zhang Quanxin (51) Int.Cl. A61K 31 / 519 (2006.01) A61K 31 / 4985 (2006.01) A61K 9 / 00 (2006.01) A61K 31 / 506 (2006.01) A61K 31 / 53 (2006.01) A61K 45 / 06 (2006.01) A61P 15 / 00 (2006.01) A61P 15 / 02 (2006.01) (54) Title of Invention Compositions and Methods for Treating Female Sexual Dysfunction and Female Sexual Arousal Disorder (57) Abstract This disclosure generally relates to compositions and techniques for treating female sexual dysfunction (FSD), including female sexual arousal disorder (FSAD). In some embodiments, a composition such as a cream may be applied to the genitals of a subject. The composition may also contain an active ingredient for treating FSD and / or FSAD, such as sildenafil and / or a pharmaceutically acceptable salt thereof. Furthermore, some embodiments described herein generally relate to techniques for using such compositions, kits including such compositions, etc. Claims 7 pages Description 109 pages CN 120981235 A 2025.11.18 CN 1 20 98 12 35 A 1. A method for treating female sexual arousal disorder (FSAD) or its symptoms, 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. The method of claim 1, wherein treating FSAD comprises increasing satisfactory sexual events and improving arousal.1. The method of claim 2, wherein treating FSAD includes increasing arousal lubrication, increasing orgasm, reducing anxiety about sexual arousal, reducing pain or discomfort during sexual activity, reducing pain or discomfort after sexual activity, and / or increasing satisfaction with sexual activity. 2. The method of claim 2, wherein treating FSAD includes increasing satisfying sexual events. 3. The method of claim 2, wherein treating FSAD includes improving arousal sensation. 4. The method of claim 2, wherein treating FSAD includes improving arousal sensation. 5. The method of claim 2, wherein treating FSAD includes increasing arousal lubrication. 6. The method of claim 2, wherein treating FSAD includes increasing orgasm. 7. The method of claim 2, wherein treating FSAD includes reducing anxiety about sexual arousal. 8. The method of claim 2, wherein treating FSAD includes reducing pain or discomfort during sexual activity. 9. The method of claim 2, wherein treating FSAD includes reducing pain or discomfort after sexual activity. 10. The method of claim 2, wherein treating FSAD includes increasing satisfaction with sexual activity. 11. The method of any one of claims 1-10, wherein treating FSAD includes increasing sensation in the genital area. 12. The method of claim 11, wherein the sensation at the genital site comprises one or more of the following: tingling, pleasure, warmth, throbbing, palpitation, congestion, or fullness in the genital area. 13. A method for increasing sexual satisfaction in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 14. A method for improving arousal in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 15. A method for increasing arousal lubrication in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 16. A method for increasing orgasm in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 17. A method for reducing anxiety about sexual arousal or increasing satisfaction with sexual activity in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 18. A method for relieving pain or discomfort in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject. 19. A method for relieving pain or discomfort in a female subject after sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.20. A method for treating female sexual dysfunction (FSD) or its symptoms, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject. 21. A method for increasing libido in a female subject, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject. 22. A method for increasing the response of a female subject to physical or psychological stimuli, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject. 23. The method of claim 22, wherein the response to physical stimuli is enhanced. 24. The method of claim 22, wherein the response to psychological stimuli is enhanced. 25. The method of claim 22, wherein the response to both physical and psychological stimuli is enhanced. 26. The method of any one of claims 1-25, wherein the phosphodiesterase type 5 inhibitor and / or its salt are administered at least twice within a time period. 27. The method of claim 26, wherein the time period is from about 1 week to about 8 weeks. 28. The method of claim 26 or 27, wherein one or more symptoms improve within about 1 week to about 8 weeks after initial application. 29. The method of claim 28, wherein one or more symptoms improve within about 1 week to about 4 weeks after initial application. 30. The method of claim 28 or 29, wherein one or more symptoms include arousal and lubrication. 31. The method of claim 28 or 29, wherein one or more symptoms include libido. 32. The method of claim 28 or 29, wherein one or more symptoms include achieving orgasm and / or experiencing orgasmic pleasure. 33. The method of any one of claims 1-32, wherein the phosphodiesterase type 5 inhibitor is sildenafil, avanafil, lodenavir, mirtenafil, tadalafil, vardenafil, urdenafil, serotonin, or thiomethylsildenafil. 34. The method of claim 32, wherein the phosphodiesterase type 5 inhibitor is sildenafil. 35. The method of any one of claims 1-34, wherein the topical composition further comprises: a. a stable polymer; b. propylene glycol; c. a polysorbate surfactant; d. L-arginine or an L-arginine salt; and e. an ionic salt. 36. The method of any one of claims 1-35, wherein the composition is a cream, gel, or lotion. 37. The method of claim 34 or 35, wherein the composition comprises an L-arginine salt. 38. The method of any one of claims 34-37, wherein the composition comprises L-arginine hydrochloride.39. The method of any one of claims 34-38, wherein the L-arginine or L-arginine salt is present at a concentration of at least about 5% by weight of the composition. 40. The method of any one of claims 34-39, wherein the ionic salt is capable of driving the type 5 phosphodiesterase inhibitor and / or its salt through the stratum corneum of the subject. 41. The method of claim 40, wherein the ionic salt is present at a concentration of at least about 5% by weight of the composition. 42. The method of any one of claims 34-41, wherein the ionic salt comprises potassium chloride. 43. The method of any one of claims 34-42, wherein the stabilizing polymer comprises xanthan gum. 44. The method of any one of claims 34-43, wherein the stabilizing polymer is present at a concentration of at least about 0.8% by weight of the composition. 45. The method of any one of claims 34-44, wherein the propylene glycol is present at a concentration of at least about 8% by weight of the composition. 46. ​​The method according to any one of claims 34-45, wherein the polysorbate surfactant comprises polysorbate 20. 47. The method according to any one of claims 34-46, wherein the polysorbate surfactant is present at a concentration of at least about 2% by weight of the composition. 48. The method according to any one of claims 1-47, wherein the phosphodiesterase type 5 inhibitor is sildenafil. 49. The method according to any one of claims 1-48, wherein the phosphodiesterase type 5 inhibitor and / or its salt is present at a concentration of about 1% by weight to about 10% by weight of the composition. 50. The method according to any one of claims 1-49, wherein the composition comprises glyceryl stearate, hexadecyl alcohol, squalane, isopropyl myristate, oleic acid, trisodium citrate dihydrate, sodium benzoate, and / or gluconolactone. 51. The method according to any one of claims 1-50, wherein purified water is present at a concentration of at least about 40% by weight of the composition. 52. The method according to any one of claims 1-51, wherein the subject is a human. 53. The method according to any one of the preceding claims, wherein the composition comprises primarily the following: a. purified water; b. potassium chloride; c. L-arginine hydrochloride; d. glyceryl stearate; e. hexadecyl alcohol; f. squalane; g. xanthan gum; h. isopropyl myristate; i. oleic acid; j. propylene glycol; k. polysorbate 20; and l. sildenafil citrate. 54. The method according to any one of the preceding claims, wherein the composition comprises each of the following compounds at a concentration not exceeding ±20% of the stated concentration:a. purified water 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 hydrochloride at a concentration of about 2.5% to about 15% by weight; d. glyceryl stearate at a concentration of about 4% to about 10% by weight; e. hexadecyl alcohol at a concentration of about 4% to about 10% by weight; f. squalane at a concentration of about 1% to about 8% by weight; g. xanthan gum at a concentration of about 0.1% to about 5% by weight; h. isopropyl myristate at a concentration of about 0.1% to about 5% by weight; i. oleic acid 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; and l. sildenafil citrate at a concentration of about 1% to about 10% by weight. Claims 3 / 7, page 4, CN 120981235 A 55. The method according to any one of claims 1-54, wherein the subject suffers from female sexual arousal disorder (FSAD). 56. The method according to any one of claims 1-55, wherein the subject is at risk of suffering from female sexual arousal disorder (FSAD). 57. The method according to any one of claims 1-56, wherein 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 hydrochloride at a concentration of about 7.5% by weight; d. glyceryl stearate at a concentration of about 7% by weight; e. hexadecyl 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; and o. sildenafil citrate at a concentration of about 5% by weight. 58. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. selecting a female subject exhibiting one or more FSAD symptoms, and b. applying a composition to the genital area of ​​the subject, said composition comprising a phosphodiesterase type 5 inhibitor and / or a salt thereof, a stable polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and an ionic salt. 59. The method of claim 58, wherein said one or more symptoms are selected from decreased genital sensitivity, lack of genital response during sexual activity, reduced genital arousal, pain and / or discomfort during sexual activity, pain and / or discomfort after sexual activity, and / or distress caused by difficulty in sexual arousal.60. The method 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. The method of claim 60, wherein applying about 50% of the composition externally comprises: a. applying the composition to the anterior commissure, clitoral hood, glans clitoris, and frenulum; b. applying the composition to the vaginal vestibule; and c. applying the composition to the labia minora. 62. The method of claim 60 or 61, wherein the composition is not applied to the labia majora or pubic hair. 63. The method of any one of claims 60-62, wherein applying about 50% of the composition intravaginally comprises applying the composition to the distal anterior vagina at a depth of about 0 cm to about 3 cm within the vagina. 64. The method of any one of claims 1-63, wherein the composition is applied about 10 to about 20 minutes before sexual activity. 65. The method of any one of claims 1-64, wherein the composition is administered at most about 9 doses over about 4 weeks. 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. The method of any one of claims 1-66, wherein the subject has not received at least one of guanylate cyclase stimulants, clonidine, CYP3A4 inhibitors, nitric oxide donors, organic nitrates, organic nitrites, or alpha receptor blockers within 28 days prior to the administration of the first dose of the composition. 68. The method of any one of claims 1-67, wherein the subject avoids wiping or washing away any of the genital areas where the composition has been applied. 69. The method of any one of claims 1-68, wherein any remaining composition is washed away after sexual activity. 70. The method of any one of claims 1-69, wherein sexual arousal is increased. 71. The method of any one of claims 1-70, wherein sexual excitement is increased. 72. The method of any one of claims 1-71, wherein application results in a satisfactory sexual event. 73. The method of any one of claims 1-72, wherein application results in increased genital arousal. 74. The method of any one of claims 1-73, wherein application results in increased lubrication of the genital area during sexual activity. 75. The method of any one of claims 1-74, wherein cognitive arousal is increased. 76. The method of any one of claims 1-75, wherein libido is increased. 77. The method of any one of claims 1-76, wherein application results in increased orgasm during sexual activity.78. The method of any one of claims 1-77, wherein the application results in a reduction in the difficulty or inability to achieve orgasm during sexual activity. 79. The method of any one of claims 1-78, wherein the application results in an increase in sensation or feeling in the genital area during sexual activity. 80. The method of any one of claims 1-79, wherein the application results in an increase in tingling sensation in the genital area during sexual activity. 81. The method of any one of claims 1-80, wherein the application results in an increase in blood flow to the genital area during sexual activity. 82. The method of any one of claims 1-81, wherein the application results in an increase in warmth, throbbing, or pulsation in the genital area during sexual activity. 83. The method of any one of claims 1-82, wherein the application results in a reduction in pain and / or discomfort during sexual activity. 84. The method of any one of claims 1-83, wherein the application results in a reduction in pain and / or discomfort after sexual activity. 85. The method of any one of claims 1-84, wherein sexual arousal is increased. 86. The method of any one of claims 58-85, wherein one or more symptoms include a decreased response to bodily sexual stimulation. 87. The method according to any one of claims 58-85, wherein the primary complaint of the female subject is a diminished response to bodily sexual stimulation. 88. The method according to any one of claims 1-87, wherein the subject, after administration, exhibits one or more of the following: a. an improvement of at least 1 point in the arousal cognition category score of the Sexual Function Questionnaire (SFQ28); b. an improvement of at least 1 point in the arousal lubrication category score of the SFQ28; c. an improvement of at least 1.5 points in the arousal sensation category score of the SFQ28; d. an improvement of at least 2 points in the desire category score of the SFQ28; e. an improvement of at least 1.20 points in the orgasm category score of the SFQ28; f. an improvement of at least 1 point in the pain category score of the SFQ28; g. an improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score; h. an improvement of at least 1.45 points in the arousal sensation score; i. an improvement of at least 1.13 points in the genital arousal score; j. an improvement of at least 1.49 points in the genital arousal anxiety score; k. Improvement of at least 0.25 points in the proportion of evoked diary item 12-SSE; and l. Improvement of at least 1.41 points in the number of evoked diary item 12-SSE. 89. The method of any one of claims 1-88, wherein the subject has a preliminary diagnosis of FSAD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revision (DSM-IV-TR). 90. The method of any one of claims 1-89, wherein the method comprises a phosphodiesterase type 5 inhibitor and / or...The topical composition of the salt thereof does not cause one or more of the following: orthostatic hypotension, headache, flushing, indigestion, dizziness, visual disturbances, nasal congestion, back pain, myalgia, nausea, vertigo, and rash. 91. The method of any one of claims 1-90, wherein the primary complaint of the subject is FSAD. 92. The method of any one of claims 1-91, wherein the primary complaint of the subject is FSAD, and wherein the subject exhibits secondary HSDD symptoms. 93. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. selecting a female subject with a primary complaint of FSAD, and b. applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the subject. 94. The method of claim 93, wherein the subject exhibits secondary HSDD symptoms. 95. A method for determining the efficacy of FSAD treatment, comprising: a. obtaining baseline scores for one or more of the following: Sexual Function Questionnaire 28 (SFQ28) scores in the arousal cognition category, SFQ28 scores in the arousal lubrication category, SFQ28 scores in the arousal sensation category, SFQ28 scores in the desire category, SFQ28 scores in the orgasm category, SFQ28 scores in the pain category, Female Sexual Distress Scale-Desire, Arousal, Orgasm (FSDS-DAO) scores, arousal sensation scores, genital arousal scores, genital arousal anxiety, the proportion of arousal diary item 12-SSE, and the number of arousal diary item 12-SSE; b. administering the FSAD treatment to a female subject; and c. determining the improvement in one or more of the scores in step a. 96. The method of claim 95, wherein one or more of the following indicate that the FSAD treatment is effective: a. an improvement of at least 1 point in the arousal cognition category score of the Sexual Function Questionnaire (SFQ28); b. an improvement of at least 1 point in the arousal lubrication category score of the SFQ28; c. an improvement of at least 1.5 points in the arousal sensation category score of the SFQ28; d. an improvement of at least 2 points in the desire category score of the SFQ28; e. an improvement of at least 1.20 points in the orgasm category score of the SFQ28; f. an improvement of at least 1 point in the pain category score of the SFQ28; g. an improvement of at least -7 points in the Female Sexual Distress Scale – Desire, Arousal, and Orgasm (FSDS-DAO) score; h. an improvement of at least 1.45 points in arousal sensation; i. an improvement of at least 1.13 points in genital arousal; j. an improvement of at least 1.49 points in genital arousal anxiety; k. Improvement of at least 0.25 points in the proportion of 12-SSE evocation diary items; and l. Improvement of at least 1.41 points in the number of 12-SSE evocation diary items. 97. The method of claim 95 or 96, further comprising administering one or more additional doses of the topical composition to the subject.98. The method according to any one of claims 1-97, wherein the primary complaint of the subject is FSAD, and wherein the subject does not exhibit symptoms of female orgasmic disorder (FOD). Claims 7 / 7 pages 8 CN 120981235 A Compositions and methods for treating female sexual dysfunction and female sexual arousal disorder Technical Field

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

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

[0003] Phosphodiesterase type 5 inhibitors are drugs used to block the degradation of cyclic GMP by phosphodiesterase type 5 in the smooth muscle cells of the inner wall of the blood vessels supplying the corpora cavernosa of the penis. These drugs are commonly used to treat erectile dysfunction. Phosphodiesterase type 5 inhibitors are usually delivered orally, and there are currently no FDA-approved transdermal formulations. Previous studies have shown that the most common treatment-oriented adverse events (TEAEs) when using daily oral phosphodiesterase inhibitors (PDEs) to treat pulmonary hypertension are similar to those when using PDEs as needed to treat erectile dysfunction (ED) (headache, hot flashes). Because pulmonary hypertension is more common in women than men, FDA safety data on the use of daily oral PDEs are primarily (75–78%) for women with serious cardiac and respiratory complications due to an underlying diagnosis of pulmonary hypertension. Therefore, women using significantly higher daily systemic doses of oral PDEs to treat pulmonary hypertension do not experience more severe adverse events compared to those using PDEs to treat ED. There are no FDA-approved treatments for febrile stenosis (FSSD), febrile fibroid disease (FSAD), or febrile fibroid-associated disease (FSIAD). Therefore, there is a need for systems that can deliver clinically useful doses of PDEs percutaneously.This disclosure relates generally to compositions and methods for treating female sexual dysfunction (FSD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. This disclosure also relates to compositions and methods for treating female sexual arousal disorder (FSAD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. This disclosure further relates to compositions and methods for treating female sexual interest / arousal disorder (FSIAD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. This disclosure further relates to compositions and methods for treating female sexual interest / arousal disorder (FSIAD) or its symptoms, including applying a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to a genital area. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, a nitric oxide donor, and an ionic salt. In embodiments, the composition further comprises a stabilizing polymer, propylene glycol, a polysorbate surfactant, and an ionic salt. In embodiments, the composition further comprises a moisturizing agent. In embodiments, the composition further comprises L-arginine or an L-arginine salt. In embodiments stating L-arginine or L-arginine salts, any moisturizer may be used in place of L-arginine or L-arginine salts. In some embodiments, the composition is a cream. In some embodiments, the composition is a gel. In some embodiments, the composition is a lotion.

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

[0006] In some 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 close to or connecting with a sexual partner, experiencing pleasure, increasing bodily sensations, arousal, passion, and / or having pleasurable sexual experiences.

[0007] In some embodiments, treating FSAD includes increasing sensation in the genital area. In some embodiments, genital sensations include one or more of the following: tingling, pleasure, warmth, pulsating, palpitations, etc. in the genital area.Throbbing, congestion, or fullness.

[0008] In some aspects, this document describes a method for increasing a female subject's sexual satisfaction during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

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

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

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

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

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

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

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

[0016] (Page 2 / 109, CN 120981235 A)In some aspects, this document describes a method for increasing the libido of a female subject, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

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

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

[0019] In embodiments, one or more symptoms improve within about 1 week to about 8 weeks after the initial application. In embodiments, one or more symptoms improve within about 1 week to about 4 weeks after the initial application. In embodiments, one or more symptoms include arousal and lubrication. In embodiments, one or more symptoms include libido. In embodiments, one or more symptoms include achieving orgasm and / or the pleasure of orgasm.

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

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

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

[0023] In some embodiments, the composition comprises glyceryl stearate. In some embodiments, the composition comprises hexadecyl alcohol. In some embodiments, the composition comprises squalane. In some embodiments, the composition comprises isopropyl myristate. In some embodiments, the composition comprises oleic acid. In some embodiments, the composition comprises trisodium citrate dihydrate. In some embodiments, the composition comprises sodium benzoate. In some embodiments, the composition comprises gluconolactone. In some embodiments, purified water is present at a concentration of at least about 40% by weight of the composition. In some embodiments, the subject is a human. Specification 3 / 109 pages 11 CN 120981235 A

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0043] In some embodiments, the composition comprises: (See specification 4 / 109, page 12, CN 120981235 A)

[0044] a. purified water at a concentration of about 40% by weight;

[0045] b. potassium chloride at a concentration of about 5% by weight;

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

[0047] d. glyceryl stearate at a concentration of about 7% by weight;

[0048] e. hexadecyl alcohol at a concentration of about 7% by weight;

[0049] f. squalane at a concentration of about 4% by weight;

[0050] g. xanthan gum at a concentration of about 0.8% by weight;

[0051] h. isopropyl myristate at a concentration of about 1% by weight;

[0052] i. oleic acid at a concentration of about 1% by weight;

[0053] j. propylene glycol at a concentration of about 8.5% by weight;

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

[0055] l. Trisodium citrate dihydrate at a concentration of about 10% by weight;

[0056] m. Sodium benzoate at a concentration of about 0.2% by weight;

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

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

[0059] This disclosure generally relates to a method of treating female sexual arousal disorder (FSAD) or its symptoms, comprising selecting a female subject exhibiting one or more FSAD symptoms and administering a composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the subject. 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 response during sexual activity, reduced genital arousal, and / or difficulty in sexual arousal. In embodiments, one or more symptoms include a diminished response to physical sexual stimulation. In embodiments, the primary complaint of the female subject is a diminished response to physical sexual stimulation.

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

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

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

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

[0064] In some embodiments, any remaining composition is washed away after sexual activity.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0080] In some embodiments, application of a composition comprising a phosphodiesterase type 5 inhibitor and / or its salts to the genital area of ​​the subject results in an increase in sexual arousal. Specification 6 / 109 pages 14 CN 120981235 A

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

[0082] In some embodiments, the primary complaint of the female subject is diminished responsiveness to physical sexual stimulation.

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

[0084] a. an improvement of at least 1 point in the arousal cognition category of the Sexual Function Questionnaire (SFQ28);

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

[0086] c. an improvement of at least 1.5 points in the arousal sensation category of the SFQ28;

[0087] d. an improvement of at least 2 points in the desire category of the SFQ28;

[0088] e. an improvement of at least 1.20 points in the orgasm category of the SFQ28;

[0089] f. an improvement of at least 1 point in the pain category of the SFQ28;

[0090] g. an improvement of at least 7 points in the Female Sexual Distress Scale – Desire, Arousal, and Orgasm (FSDS-DAO);

[0091] h. an improvement of at least 1.45 points in the arousal sensation score;

[0092] i. an improvement of at least 1.13 points in the genital arousal score;

[0093] j. Improvement of at least 1.49 points in genital arousal concern score;

[0094] k. Improvement of at least 0.25 points in the proportion of arousal diary item 12-SSE; and

[0095] l. Improvement of at least 1.41 points in the number of arousal diary item 12-SSE.

[0096] In some embodiments, the subject exhibits 2 or more of a-1. In some embodiments, the subject exhibits 3 or more of a-1. In some embodiments, the subject exhibits 4 or more of a-1. In some embodiments, the subject exhibits 5 or more of a-1. In some embodiments, the subject exhibits 6 or more of a-1. In some embodiments, the subject exhibits 7 or more of a-1. In some embodiments, the subject exhibits 8 or more of a-1. In some embodiments, the subject exhibits 9 or more of a-1. In some embodiments, the subject exhibits 10 or more of a-1. In some embodiments, the subject exhibits 11 or more of a-1. In some embodiments, the subject exhibits all 12 of a-l.

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

[0098] In some embodiments, the topical composition comprising a type 5 phosphodiesterase inhibitor and / or its salt does not cause orthostatic hypotension, headache, flushing, indigestion, light headedness, visual disturbances, nasal congestion, back pain, muscle weakness, or other adverse reactions.Pain, nausea, dizziness, and rash, or one or more of these.

[0099] In some embodiments, the primary complaint of the subject is FSAD or one or more of these symptoms.

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

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

[0102] a. selecting a female subject with a primary complaint of FSAD, and

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

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

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

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

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

[0108] c) determining improvements in one or more scores in step a.

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

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

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

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

[0113] d. Improvement of at least 2 points in the desire category score of the SFQ28;

[0114] e. Improvement of at least 1.20 points in the orgasm category score of the SFQ28;

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

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

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

[0118] i. Genital arousal improved by at least 1.13 points;

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

[0120] k. Arousal diary item 12-SSE ratio improved by at least 0.25 points; and

[0121] l. Arousal diary item 12-SSE number improved by at least 1.41 points.

[0122] In some embodiments, the presence of two or more of a-l indicates that FSAD treatment is effective. In some embodiments, the presence of three or more of a-l indicates that FSAD treatment is effective. In some embodiments, the presence of four or more of a-l indicates that FSAD treatment is effective. In some embodiments, the presence of 5 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 6 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 7 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 8 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 9 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 10 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of 11 or more of a-1 indicates that FSAD treatment is effective. In some embodiments, the presence of all 12 of a-1 indicates that FSAD treatment is effective.

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

[0124] Other advantages and novel features of this disclosure will become apparent from the following detailed description of various non-limiting embodiments of this disclosure when considered in conjunction with the accompanying drawings. Instruction manual 8 / 109 pages 16 CN 120981235 A Detailed Description

[0125] It is estimated that female sexual dysfunction (FSD) affects approximately 40% of American women at some stage in their lives. The prevalence of FSD increases with age and is associated with vascular risk factors and menopause.

[0126] In DSM IV-TR, FSAD is defined as a persistent or recurrent inability to achieve or maintain adequate lubrication and swelling response before completion of sexual activity, resulting in significant distress or interpersonal difficulties. FSAD is estimated to affect approximately 20% of American women.It has a negative impact on women. In addition, the interruption of sexual arousal affects other aspects of sexual response. Without sexual arousal, orgasm is impossible, and lack of sexual arousal often leads to a lack of desire because sexual activity is unpleasant or compulsive. Sexual dysphagia may be intricately linked to a lack of adequate sexual arousal. Sexual intercourse without lubrication can be painful, and repeated intercourse without arousal can lead to vulvar infections, chronic irritation, and may lead to secondary vaginismus, fear of sex, or complete avoidance of sexual activity.

[0127] In DSM-5, FSIAD is defined as a lack or significant reduction in sexual interest / arousal, measured by three of the following six symptoms: lack or reduction in interest in sexual activity; lack or reduction in sexual thoughts or fantasies; lack or reduction in the initiation of sexual activity, and usually unacceptable to the initiation attempts of a partner; lack or reduction in sexual arousal or pleasure in almost all or all sexual contact; lack or reduction in sexual interest / arousal to any internal or external sexual cues; and loss or reduction in genital or non-genital sensation during sexual activity in all or almost all sexual contact. These symptoms are sure to cause significant clinical distress and last for at least six months.

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

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

[0130] One set of embodiments provides a composition for local delivery comprising a 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, a combination of stabilizing polymers (e.g., xanthan gum, and / or), propylene glycol, and polysorbate surfactants (e.g., polysorbate 20) may be used to stabilize the composition, providing stability in combination compared to a composition lacking one or more of these components.

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

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

[0133] Compositions

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

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

[0136] Specification 10 / 109 pages 18 CN 120981235 A

[0137] Specification 11 / 109 pages 19 CN 120981235 A

[0138]

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

[0140] Aspects of this disclosure provide compositions comprising a phosphodiesterase type 5 inhibitor for transdermal and / or transmucosal delivery or topical application to a subject. Other compounds, such as salts or derivatives of phosphodiesterase inhibitors (including salts or derivatives of the above compounds), are included in the embodiments described herein; therefore, it should be understood that this is merely illustrative in any embodiment using phosphodiesterase inhibitors described herein.

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

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

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

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

[0145] In some embodiments, the agent is a phosphodiesterase type 5 inhibitor. In some embodiments, the phosphodiesterase type 5 inhibitor is sildenafil. In some embodiments, the compositions of this disclosure include sildenafil citrate and are used to treat FSAD. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 1% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 2% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 3% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 3.6% by weight of the composition. In some embodiments, sildenafil or a salt thereof may be present at a concentration of about 3.6% by weight of the composition. (See page 21 of specification 13 / 109)CN 120981235 A is present at a concentration of about 4% by weight of the composition. In some embodiments, sildenafil or a salt thereof is present at a concentration of about 5% by weight of the composition.

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

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

[0148] In some embodiments, the composition may also contain a nitric oxide donor. In some cases, such a nitric oxide donor can be used to increase local blood flow at the site of application of the composition, which can enhance the delivery of the 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.

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

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

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

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

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

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

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

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

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

[0158] As described herein, a “stabilized polymer” means a polymer comprising xanthan gum, xanthan gum derivatives, and / or xanthan gum equivalents, for example and / or and / or

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

[0160] In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 20% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 10% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of about 0.1% to about 1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.1% by weight of the composition. In some embodiments, the stabilizing polymer may be present at a concentration of at least about 0.2% by weight of the composition. In some embodimentsIn 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.

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

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

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

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

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

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

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

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

[0169] As used herein, “polysorbate surfactant” refers to a surfactant containing polysorbate. For example, the surfactant may include sorbitol monolaurate, sorbitol monopalmitate, sorbitol monostearate, sorbitol monooleate, or another sorbitol salt.

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

[0171] In some embodiments, the pharmaceutical agent may be combined with a penetrant, which is an agent that increases the delivery of the pharmaceutical agent to the skin relative to delivery without a penetrant. Examples of penetrants include, but are not limited to, cationic, anionic, or nonionic surfactants such as capsicum oleoresin (e.g., sodium dodecyl sulfate, polyoxamer, etc.); fatty acids and alcohols (e.g., ethanol, oleic acid, lauric acid, liposomes, etc.); anticholinergic agents (e.g., benzyl bromide, oxyphenyl bromide); ketones (e.g., n-heptane); amides (e.g., urea, N,N-dimethyl-m-toluamide); fatty acid esters (e.g., butyrate); organic acids (e.g., citric acid); polyols (e.g., ethylene glycol, glycerol); sulfoxides (e.g., dimethyl sulfoxide); terpenes (e.g., cyclohexene); urea; sugars; and / or carbohydrates.

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

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

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

[0175] Delivery

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

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

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

[0179] Non-limiting examples of delivery carriers to be carried into tissues include collagen, collagen peptides, or skin or baseLiposomes or emulsions of other components of the base membrane. Non-limiting examples of charge neutralization include delivery of the agent in the form of an electronically neutral ester or salt.

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

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

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

[0183] In some cases, the kit of this disclosure may include instructions of any form associated with the composition of this disclosure in such a way that those skilled in the art will recognize that the instructions will be associated with the composition of this disclosure. For example, the instructions may include instructions for the use, modification, mixing, dilution, preservation, application, assembly, storage, packaging and / or preparation of the composition and / or other compositions associated with the kit. In some cases, the instructions may also include instructions for the delivery and / or application of the composition, for example, for a specific purpose, such as for a sample and / or a subject.

[0184] Method of Use

[0185] The present invention 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 of having FSD. In some embodiments, the subject has one or more symptoms of FSD.

[0186] This 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 of having FSAD. In some embodiments, the subject has one or more symptoms of FSAD.

[0187] This disclosure provides a method comprising: 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 of having FSIAD. In some embodiments, the subject has one or more symptoms of FSIAD.

[0188] 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 includes a nitric oxide donor. In some embodiments, the ionic salt is potassium chloride. In some embodiments, the active ingredient is present at about 1-10 wt%. In some embodiments, the composition is applied to the clitoris, vulva, vagina, and / or vaginal cavity. In some embodiments, the composition is applied to the clitoris, vestibule, vulva, and / or vagina of a subject. (See specification 20 / 109 pages 28 CN 120981235 A)In some embodiments, the composition is applied to the clitoris, glans clitoris, and / or frenulum of the subject's genital region. In some embodiments, the composition is applied to the clitoris, glans clitoris, frenulum, and / or vestibule of the subject's genital region. In some embodiments, the composition is applied to the clitoris, glans clitoris, frenulum, vestibule, and / or labia minora of the subject's genital region. In some embodiments, the composition is not applied to the labia majora of the subject's genital region. In some embodiments, the composition is applied intravaginally to the distal anterior vagina of the subject. In some embodiments, the composition is applied as a single dose. In some embodiments, the composition is applied as at least one dose.

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

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

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

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

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

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

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

[0196] In some embodiments, treating FSAD includes increasing satisfactory sexual events. In some embodiments, increasing satisfactory sexual events includes, but is not limited to, increasing orgasm or orgasm frequency, feeling close to or connecting with a sexual partner, experiencing pleasure, increasing bodily sensation, arousal sensation, passion sensation, and / or having a pleasant sexual experience.

[0197] In some embodiments, treating FSAD includes increasing sensation in the genital area. In some embodiments, sensations at the genitals include one or more of the following: tingling, pleasure, warmth, throbbing, palpitation, congestion, or fullness in the genital area. Specification 21 / 109 pages 29 CN 120981235 A

[0198] In some aspects, this document describes a method for increasing a female subject's satisfaction with sexual activity, comprising applying a topical composition containing a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

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

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

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

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

[0203] In some aspects, this document describes a method for reducing pain or discomfort in a female subject during and / or after sexual activity.Inappropriate methods include applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​a female subject.

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

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

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

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

[0208] In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an arousal diary (AD) score. In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an AD item 1 (pleasure) score. In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an AD item 2 (warmth) score. In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an AD item 3 (pulsation / throbbing) score. In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an AD item 4 (tingling) score. In an implementation, improvement in one or more criteria described herein (e.g., symptoms) is measured based on an AD item 5 (congestion / fullness) score. In an implementation, improvement means an increase of at least one point in the AD score or item score. In an implementation, improvement means an increase of at least two points in the AD score or item score.

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

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

[0211] In some embodiments, improvement in one or more criteria (e.g., symptoms) described herein is measured based on the Patient Benefit Assessment (PBE) (meaningful benefit of the investigational drug).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0231] a. an improvement of at least 1 point in the arousal cognition category of the Sexual Function Questionnaire (SFQ28);

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

[0233] c. an improvement of at least 1.5 points in the arousal sensation category of the SFQ28;

[0234] d. an improvement of at least 2 points in the desire category of the SFQ28;

[0235] e. an improvement of at least 1.20 points in the orgasm category of the SFQ28;

[0236] f. an improvement of at least 1 point in the pain category of the SFQ28;

[0237] g. an improvement of at least 7 points in the Female Sexual Distress Scale – Desire, Arousal, and Orgasm (FSDS-DAO);

[0238] h. an improvement of at least 1.45 points in the arousal sensation score;

[0239] i. an improvement of at least 1.13 points in the genital arousal score;

[0240] j. Improvement of at least 1.49 points in the genital arousal concern score;

[0241] k. Improvement of at least 0.25 points in the proportion of arousal diary item 12-SSE; and

[0242] l. Improvement of at least 1.41 points in the number of arousal diary item 12-SSE.

[0243] In some embodiments, the subject includes a preliminary diagnosis of FSAD, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Textual Revision, Fourth Edition (DSM-IV-TR).

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

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

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

[0247] The present invention generally relates to a method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: Specification 24 / 109 pages 32 CN 120981235 A

[0248] a. selecting a female subject with primary complaint of FSAD, and

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

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

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

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

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

[0254] c) determining improvements in one or more scores in step a.

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

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

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

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

[0259] d. Improvement of at least 2 points in the desire category score of the SFQ28;

[0260] e. Improvement of at least 1.20 points in the orgasm category score of the SFQ28;

[0261] f. Improvement of at least 1 point in the pain category score of the SFQ28;

[0262] g. Improvement of at least 7 points in the Female Sexual Distress Scale – Desire, Arousal, and Orgasm (FSDS-DAO);

[0263] h. Improvement of at least 1.45 points in arousal sensation;

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

[0265] j. Improvement of at least 1.49 points in genital arousal anxiety;

[0266] k. Improvement of at least 0.25 points in the proportion of arousal diary item 12-SSE; and

[0267] l. Improvement of at least 1.41 points in the number of arousal diary item 12-SSE.

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

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

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

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

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

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

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

[0275] In some embodiments, at least about 10% of the composition is applied to the extravagant tissue. In some embodiments, at least about 20% of the composition is applied to the extravagant tissue. In some embodiments, at least about 30% of the composition is applied to the extravagant tissue. In some embodiments, at least about 40% of the composition is applied to the extravagant tissue. In some embodiments, at least about 50% of the composition is applied to the extravagant tissue. In some embodiments, at least about 60% of the composition is applied to the extravagant tissue. In some embodiments, at least about 70% of the composition is applied to the extravagant tissue. In some embodiments, at least about 80% of the composition is applied to the extravagant tissue. In some embodiments, at least about 90% of the composition is applied to the extravagant tissues. In some embodiments, at least about 100% of the composition is applied to the extravagant tissues. Specification 26 / 109 pages 34 CN 120981235 A

[0276] Extravagant tissues (such as the vulva) include, but are not limited to, the anterior commissure, clitoral hood, glans clitoris, frenulum, vestibule, labia majora, and labia minora. In some embodiments, about 50% of the composition is applied to the extravagant tissues. In some embodiments, about 50% of the composition is applied to the clitoris, vestibule, vulva, and / or vagina of the subject. In some embodiments, about50% of the composition is applied to the clitoris, glans clitoris, and / or frenulum of the subject's genital region. In some embodiments, about 50% of the composition is applied to the clitoris, glans clitoris, frenulum, and / or vestibule of the subject's genital region. In some embodiments, about 50% of the composition is applied to the clitoris, glans clitoris, frenulum, vestibule, and / or labia minora of the subject's genital region.

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

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

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

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

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

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

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

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

[0285] In embodiments, a type 5 phosphodiesterase inhibitor and / or its salt is applied at least twice over a period of time. In embodiments, a type 5 phosphodiesterase inhibitor and / or its salt is applied at least three times over a period of time. In embodiments, a type 5 phosphodiesterase inhibitor and / or its salt is applied at least four times over a period of time. In embodiments, a type 5 phosphodiesterase inhibitor and / or its salt is applied at least five times over a period of time. In embodiments, a type 5 phosphodiesterase inhibitor and / or its salt is applied at least five times over a period of time.Or its salts are applied at least six times over a period of time. In an embodiment, type 5 phosphodiesterase inhibitors and / or their salts are applied at least seven times over a period of time. In an embodiment, type 5 phosphodiesterase inhibitors and / or their salts are applied at least eight times over a period of time. In an embodiment, type 5 phosphodiesterase inhibitors and / or their salts are applied at least ten times over a period of time.

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

[0287] In one embodiment, one or more symptoms improve within approximately 1 week to approximately 12 weeks after initial application. In one embodiment, one or more symptoms improve within approximately 1 week to approximately 10 weeks after initial application. In one embodiment, one or more symptoms improve within approximately 1 week to approximately 8 weeks after initial application. In one embodiment, one or more symptoms improve within approximately 1 week to approximately 6 weeks after initial application. In one embodiment, one or more symptoms improve within approximately 1 week to approximately 4 weeks after initial application. In one embodiment, one or more symptoms improve within approximately one week after initial application. In another embodiment, one or more symptoms improve within approximately two weeks after initial application. In another embodiment, one or more symptoms improve within approximately three weeks after initial application. In another embodiment, one or more symptoms improve within approximately four weeks after initial application. In another embodiment, one or more symptoms improve within approximately five weeks after initial application. In another embodiment, one or more symptoms improve within approximately six weeks after initial application. In yet another embodiment, one or more symptoms improve after initial application...Improvement is achieved within approximately 7 weeks. In one embodiment, one or more symptoms improve within approximately 8 weeks after initial administration. In one embodiment, one or more symptoms improve within approximately 10 weeks after initial administration. In one embodiment, one or more symptoms improve within approximately 12 weeks after initial administration.

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

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

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

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

[0292] Definitions

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

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

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

[0296] Terms such as “treat,” “treatment,” and “treating” include treatment of a subject who already has a disease or disorder, particularly a disease or disorder that is manifest in an obvious form. Treatment may be symptomatic to relieve signs and / or symptoms of the disease or disorder, or it may be causal to reverse, partially reverse, stop, or slow the progression of the disease or disorder. Therefore, the compositions and methods of this disclosure may be used, for example, as therapeutic treatments (e.g., for acute or chronic therapies).

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

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

[0299] The subject may be, but is not limited to, a human.

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

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

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

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

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

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

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

[0307] As used herein in the specification and claims, the phrase “to the specification 31 / 109 page 39 CN 120981235 A less than one” referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, butIt does not necessarily include at least one of each element specifically listed in the element list, nor does it exclude any combination of elements in the element list. This definition also allows for the optional presence of elements other than those specifically identified in the element list referred to by the phrase "at least one," regardless of whether such elements are related to those specifically identified elements. Thus, as a non-limiting example, in one implementation, "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 to at least one, optionally including multiple A's, without B's presence (and optionally including elements other than B); in another implementation, it can refer to at least one, optionally including more than one B's, without A's presence (and optionally including elements other than A's); in yet another implementation, it can refer to at least one, optionally including more than one A and at least one, optionally including more than one B's (and optionally including other elements); and so on.

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

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

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

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

[0312] List of Abbreviations

[0313] Definition of Abbreviations

[0314] AE Adverse Events

[0315] CD Cognitive Inquiry

[0316] CE Concept Inspiration

[0317] COS Clinical Outcome Solution

[0318] DHIF Population Health Information Form

[0319] FDA US Food and Drug Administration

[0320] FSAD Female Sexual Arousal Disorder

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

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

[0323] FSEP Female Sexual Contact Profile

[0324] FSFI Female Sexual Function Index

[0325] GAS Genital Arousal Screening Instrument Instruction Manual 32 / 109 pages 40 CN 120981235 A

[0326] GSM Urogenital Syndrome Menopause

[0327] HRQL Health-Related Quality of Life

[0328] HSDD Hypoactive Sexual Desire Disorder

[0329] ICF Informed Consent Form

[0330] IRB Institutional Review Board

[0331] MHF Medical History Form

[0332] N Number (uppercase indicates total population; lowercase indicates subgroup population)

[0333] PRO Patient Report Results

[0334] SAE Serious Adverse Events

[0335] SAS Statistical Analysis System

[0336] SD Standard Deviation

[0337] SFQ-28 Sexual Function Questionnaire-28

[0338] SOP Standard Operating Procedure

[0339] API Active Pharmaceutical Ingredient

[0340] BMI Body Mass Index

[0341] BP Blood Pressure

[0342] CFR Federal Regulations

[0343] cGMP Cyclic Guanosyl Monophosphate

[0344] CRO Contract Research Organization

[0345] CSR Clinical Research Report

[0346] eCRF Electronic Case Report Form

[0347] ECG Electrocardiogram

[0348] ED Erectile Dysfunction

[0349] FSD Female sexual dysfunction

[0350] Good Clinical Practice (GCP)

[0351] Good Laboratory Practice (GLP)

[0352] Hepatitis B surface antigen (HBsAg)

[0353] Hepatitis C virus (HCV)

[0354] High-density polyethylene (HDPE)

[0355] Human equivalent dose (HED)

[0356] Health Insurance Portability and Liability Act (HIPAA)

[0357] Human immunodeficiency virus (HIV)

[0358] Human papillomavirus (HPV)

[0359] Informed consent form (ICF)

[0360] International Council for Harmonisation of Technical Requirements for Humans (ICH)

[0361] Investigational new drug (IND)

[0362] Investigational product (IP)

[0363] Institutional Review Board (IRB)

[0364] Interactive response technology specification (IRT) 33 / 109 pages 41 CN120981235 A

[0365] MedDRA Regulatory Activities Medical Dictionary

[0366] NF National Drug List

[0367] NO Nitric Oxide

[0368] NOAEL No Observed Adverse Effect Level

[0369] OTC Non-Prescription

[0370] PANAS Positive and Negative Effects Timeline

[0371] PDE5 Phosphodiesterase Type 5

[0372] PI Principal Investigator

[0373] PK Pharmacokinetics

[0374] QA Quality Assurance

[0375] QC Quality Control

[0376] SAE Serious Adverse Events

[0377] SHBG Sex Hormone Binding Globulin

[0378] SOC System Organ Classification

[0379] TEAE Adverse Events During Treatment

[0380] TMF Trial Master File

[0381] USP United States Pharmacopeia

[0382] VPA Vaginal Pulse Amplitude

[0383] VPP Vaginal Photoplethysmography

[0384] WHODE Enhanced World Health Organization Drug Dictionary

[0385] Examples

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

[0387] Example 1: Content Verification for a Patient-Reported Outcome (PRO) Measure of Female Sexual Arousal Disorder

[0388] Study Design

[0389] In view of the need to collect evidence of the validity of arousal diaries, SFQ-28, and FSDS-DAO content, qualitative interviews were conducted on individuals clinically diagnosed with FSAD.

[0390] Preliminary eligibility was evaluated prior to the first visit. Informed consent was collected if it was determined that a participant might be eligible. After consent, inclusion / exclusion criteria were confirmed, and clinical interviews were conducted. Clinical interviews were used to collect more information and confirm the diagnosis of primary FSAD (N=35; n=20 premenopausal women; n=15 postmenopausal women). During the second visit, participants underwent an in-depth, qualitative, one-on-one interview consisting of CE and CD discussions, lasting approximately 90 minutes.

[0391] The CE and CD interview during the second visit consisted of three parts:

[0392] 1. The first part of the interview involved CE discussions to explore the participants' experiences with FSAD, expected to last approximately 45 minutes;

[0393] 2. The second part involved participants who had completed three questionnaires; and

[0394] 3. After completing each questionnaire, participants completed several questions on the questionnaire. The questions were expected to last approximately 45 minutes. As part of this study, no pharmacological interventions or treatments were administered.

[0395] Study population

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

[0397] Inclusion Criteria

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

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

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

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

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

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

[0404] a. Bilateral oophorectomy, including or excluding hysterectomy, at least 1 year prior to screening (self-reported).

[0405] b. Spontaneous amenorrhea for 12 months

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

[0407] 6. The patient's body mass index (BMI) is 18 to 33 kg / m2, inclusive.

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

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

[0410] Exclusion Criteria

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

[0412] 1. The investigator believes that the patient has any impairment that may hinder the successful completion of the study or has any history of impairment.

[0413] 2. The patient self-reports or is currently diagnosed with an uncontrolled medical condition (such as cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, skin, blood, neurological, genitourinary, or psychiatric medical condition).

[0414] 3. The patient reports a history of sexual trauma or abuse identified in a clinical interview that has led to any sexual dysfunction problems (desire, arousal, orgasm, pain, etc.).

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

[0416] 5. As determined by the clinical interview, the patient's primary complaint is anorexia, pain, vaginismus, decreased libido, or any other primary sexual complaint other than genital arousal problems.

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

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

[0419] 7. The patient has undergone major pelvic surgery that may cause nerve damage, including but not limited to vulvectomy, colostomy, cystostomy, or surgery for severe bladder (including incontinence), rectal, or abdominal conditions. (Instructions for Use 35 / 109, page 43, CN 120981235 A)

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

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

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

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

[0424] b. A total score of <10 on the Patient Health Questionnaire-8 (a screening and assessment tool for depression) indicates minimal depression or mild depression.

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

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

[0427] 11. Patients have a history of substance abuse within 1 year prior to their first visit. Patients reporting a history of substance abuse must have been in remission or sobriety for at least one year prior to the clinical interview.

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

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

[0430] 14. The patient has a positive urine drug screening result (e.g., amphetamines, barbiturates, benzodiazepines, cocaine, methadone, and opioids), unless it is a known impairment (e.g., ADHD) that will not interfere with the patient's ability to successfully complete the study.

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

[0432] 16. The patient reports an HPV or HSV genital or anal outbreak (blister, wart, or vesicle) at any point in the past month. Once the outbreak is treated and resolved, the patient can be rescreened. Patients reporting genital skin lesions, irritation, skin conditions or lesions, or any other abnormal vulvovaginal findings will also be excluded.

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

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

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

[0436] 20. The patient self-reports that she is breastfeeding or pregnant and plans to start breastfeeding during the study, or became pregnant or breastfeeding within 6 months prior to the first visit.

[0437] Clinical Diagnosis of FSAD

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

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

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

[0441] Recruitment and Screening

[0442] Recruitment Strategy

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

[0444] All recruitment procedures comply with protocols approved by the Institutional Review Board (IRB). Potential participants are scheduled for their first screening appointment.

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

[0446] Specific objectives are as follows:

[0447] • Phase 1: Conceptual Awareness (CE) interview, to:

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

[0449] • Phase 2: Cognitive Inquiry (CD) interview, to:

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

[0451] determine the patient's understanding of the items, descriptions, and answer options of the selected PRO measures

[0452] evaluate the appropriateness of the designated review period for the selected PRO measures, focusing on the 24-hour review period and the 4-week review period.

[0453] Screening Procedure (First Visit)

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

[0455] Sampling Stratification

[0456] Interview Procedure (Second Visit)

[0457] If face-to-face interaction is not possible, the interview at the second visit may be conducted in person or by telephone. CE portion of the interviewThe first part lasts approximately 45 minutes. Then, participants are asked to complete an arousal diary, SFQ-28, and FSDS-DAO, which takes about 10 minutes. Following this, the CD part of the interview begins and lasts approximately 45 minutes. Instructions 37 / 109 pages 45 CN 120981235 A

[0458] Conceptual Heuristics

[0459] The face-to-face qualitative interview begins by presenting each participant with a set of short CE questions. This will take the form of an open discussion in which each participant discusses her personal experience with sexual arousal issues and any related impacts. This is used to obtain a comprehensive and personally-led description of the impact of FSAD to ensure adequate coverage of the key arousal issues experienced and their impacts. After this, participants discuss the severity of the evoking symptoms and rank the symptoms that bother them the most and the symptoms they consider most important for treatment. Participants also discuss the emotional impact of FSAD to determine what language women spontaneously use to describe this, such as annoyance, distress, frustration.

[0460] Cognitive Inquiry

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

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

[0463] Analysis

[0464] Participant Characteristics

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

[0466] Qualitative Data Analysis

[0467] CE Data Analysis

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

[0469] Saturation Analysis

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

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

[0472] • Topic-derived concepts were converted into two ordinal arrays: “not discussed” equals 0, and “discussed” equals 1.

[0473] • Concepts appearing in the first group of interviews were compared with those appearing in the second group of interviews.

[0474] • Concepts appearing in the first two groups of interviews were then compared with those appearing in the third group of interviews.

[0475] A point where no new concepts emerge is considered a point of saturation.

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

[0477] CD Data Analysis

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

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

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

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

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

[0483] Published placebo-controlled trials of oral sildenafil citrate in premenopausal and postmenopausal women with broad-spectrum FSDs (such as hypoactive sexual activity disorder (HSDD), FSAD, female orgasmic disorder (FOD), and dyspareunia) unrelated to concomitant diseases or drug use have shown negligible efficacy compared to placebo.

[0484] This invention provides a 3.6% topical sildenafil cream for the treatment of FSAD. By delivering sildenafil topically, particularly targeting the genital anatomy at the vascular reactivity center, systemic exposure is reduced, subsequently reducing systemic side effects, thus resulting in a more favorable safety profile. The co-primary objective of this study is to evaluate the 3.6% sildenafil cream in...Safety and validity in healthy premenopausal women with FSAD. Instructions for use 39 / 109 pages 47 CN 120981235 A

[0485] Patient assessment

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

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

[0488] The study included a 28-day drug-free induction period, followed by a 28-day single-blind placebo induction period. Participants were screened for failure during these two months if they did not comply with the requirement to document sexual experiences and AEs in an electronic diary (eDiary), or if they had a pre-determined placebo response (total score ≤18) on the Female Sexual Distress Scale-Desire Arousal and Orgasm (FSDS-DAO) during the single-blind placebo induction period. Eligible participants were randomly assigned 1:1 to receive 3.6% sildenafil cream versus placebo cream at their fourth visit.

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

[0490] Patient and Partner – Study Participation and Safety Assessment

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

[0492] The eDiary prompted the patient to complete the eDiary within 24 hours of each sexual event and at any time during the study if an AE occurred. If a sexual event occurred, the patient used the eDiary to record the application of IP, record any adverse events, and complete an arousal diary. The eDiary also prompted the partner every 24 hours to assess for any partner sexual events in order to collect any adverse events.

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

[0494] Number of Patients, Demographic Characteristics, and Baseline Characteristics

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

[0496] Table 1A: Demographic and Baseline Characteristics of Participants and Sexual Partners in the Safety Population

[0497] Specification 41 / 109 pages 49 CN 120981235 A

[0498] Primary Objective:

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

[0500] The SFQ28 is a 28-item PRO questionnaire that covers most aspects of the sexual response cycle (desire, arousal, orgasm) as well as pain or discomfort. Specifically, the SFQ28 has eight categories (desire, arousal sensation, arousal lubrication, arousal cognition, orgasm, pain, pleasure, and partner), asking women about their sexual activity and sex life with their partner in the past 4 weeks. The SFQ28 defines sex life as physical sexual activity and emotional relationship with a partner.

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

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

[0503] Secondary Objectives:

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

[0505] Exploratory Objective:

[0506] To be completed within 24 hours of each sexual event using eDiary (with daily prompts).

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

[0508] Arousal diary questions included: “How much pleasure did you feel in your vaginal / genital area during sexual activity?” (item 1), “How much ‘warmth’ (e.g., a feeling of increased temperature) did you feel in your vaginal / genital area during sexual activity?” (item 2), “How much ‘throbbing’ or ‘pulsating’ did you feel in your vaginal / genital area during sexual activity?” (item 3), “How much ‘tingling’ did you feel in your vaginal / genital area during sexual activity?” (item 4), and “How much ‘congestion’ or ‘fullness’ did you feel in your vaginal / genital area during sexual activity?” (item 5). The response range was 5 points, from 1 point (no pleasure / no "warmth" / no "pulsation" or "throbbing" / no "tingling" / no "congestion" or "fullness") to 5 points (very strong pleasure / extremely "warmth" / very strong "pulsation" or "throbbing" / very strong "tingling" / very strong "congestion" or "fullness").

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0526] Instruction manual 44 / 109 pages 52 CN 120981235 A

[0527]

[0528] Note: PRO tools or evaluations are not performed at the second visit.

[0529] (a) Arousal diaries should be completed within 24 hours after each sexual activity (as per daily prompts).

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

[0531] Additional notes for Table 1B

[0532] Primary endpoint

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

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

[0535] Secondary endpoint

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

[0537] Exploratory endpoint

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0554] ·PBE: Patient Benefit Assessment

[0555] Table 2: Safety Assessment Event Schedule

[0556] Instructions for Use 46 / 109 pages 54 CN 120981235 A

[0557]

[0558] a. Patient and their partner (all partners are required to attend the 1st and 2nd visits; same-sex partners of reproductive potential will also attend the 7th visit). Partners are allowed to perform vital sign checks at home using the blood pressure cuff assigned to the study. If self-assessment is selected, the partner will be viewed remotely via telemedicine access.

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

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

[0561] d. Unless the patient has had a Pap smear within 3 years after the first visit.

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

[0563] f. At the 1st visit, a standard 12-lead ECG will be collected for medical screening.

[0564] g. After the 2nd visit, adverse events will be initially documented using an eDiary and evaluated by the PI or designated personnel. Any adverse events reported by the partner will be documented in the source document and eCRF by the study site staff.

[0565] h. All patients will receive a placebo cream at the 3rd visit.

[0566] Study Product (IP), Dosage, and Administration:

[0567] Throughout the protocol, the single-blind IP and the two double-blind IPs are collectively referred to as the study product (IP). The single-blind IP is a placebo cream. The double-blind IP is either 3.6% sildenafil cream or a placebo cream. IP is packaged in 30g tubes. Patients were randomized 1:1 to the double-blind dosing period using interactive response technology (IRT) and were equipped with the appropriate tubes. No allocation errors were made. Dosage cards were provided to ensure accurate measurement of the administered dose. Patients were instructed that approximately 50% of the IP would be applied externally to the vulva (i.e., clitoris, vestibule, labia minora) and approximately 50% would be applied internally to the vagina. Patients were instructed to use the dosage card to measure the appropriate amount of cream applied internally and externally. Patients were told to apply the cream gently internally and externally as instructed. Instructions for use 47 / 109 pages 55 CN 120981235 A

[0568] Study Design and Methods:

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

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

[0571] Medical Screening Period: (First Visit)

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

[0573] Step 1—FSAD Screening Tools for Inclusion and Establishment of Baseline Functional Function

[0574] FSAD was assessed using two patient-reported outcomes (PRO) tools after patients provided written informed consent.Symptoms (including decreased genital sensitivity and distress related to sexual problems) and baseline levels of sexual function:

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

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

[0577] 2. Sexual Function Questionnaire – SFQ28

[0578] Step 2 – Additional Inclusion Criteria – Patients may be admitted to the study if they meet all of the following criteria:

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

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

[0581] 3. The patient is able to understand and comply with the protocol and agrees to sign an informed consent form.

[0582] 4. Prior to the first visit, the patient has been in a stable, monogamous, secure, and communicative relationship for at least 6 months. This relationship is established with a sexually functional partner, both psychologically and physically. The partner will remain consistent and contactable throughout the study period.

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

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

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

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

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

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

[0589] 7. The patient's body mass index (BMI) is between 18 and 35 kg / m2, inclusive of 18 kg / m2 and 35 kg / m2. Instructions for Use 48 / 109 pages 56 CN 120981235 A

[0590] 8. The patient has undergone a Pap smear within three years prior to the first visit and can provide evidence of normal test results.Documentation of results (based on current guidelines published by the US Preventive Services Task Force).

[0591] a. If the patient cannot provide documentation, a Pap smear will be performed at the first visit. Patients with abnormalities will be excluded from the study and referred for follow-up medical care as appropriate.

[0592] 9. The patient is in good health and has no clinically significant medical history, physical examination, gynecological history and examination, laboratory profile (e.g., hematology, urinalysis), vital signs (e.g., uncontrolled hypertension) or ECG.

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

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

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

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

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

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

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

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

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

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

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

[0604] b. Spontaneous amenorrhea for 12 months;

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

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

[0607] 5. The patient has a serious cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, skin, blood, neurological, genitourinary, or other unstable medical condition that would preclude the administration of study drugs, interfere with study evaluation, limit study participation, or obscure the interpretation of study results.

[0608] 6. Patients with a history of unresolved sexual trauma or sexual abuse that has resulted in any clinically identified sexual dysfunction (desire, arousal, orgasm, etc.).

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

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

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

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

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

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

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

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

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

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

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

[0620] 17. Patients with traumatic pelvic nerve injury will be excluded.

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

[0622] a. Patients diagnosed with anxiety or depression must be controlled, and if taking medication (i.e., SSRIs, SNRIs, buspirone, bupropion, and benzodiazepines), the dose must have been stable for at least the past 6 months.

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

[0624] c. Patients must have a total score <6 indicating mild anxiety disorder according to Generalized Anxiety Disorder (GAD-7, Appendix H) (Anxiety Disorder Screening and Evaluation Tool).

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

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

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

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

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

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

[0631] 22. Patients who self-report a history of alcohol abuse within the two years prior to their first visit or who show signs of current alcohol abuse. Instructions for Use, Page 50 / 109, 58, CN 120981235 A

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

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

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

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

[0636] 26. Patients with positive urine drug screening (such as amphetamines, barbiturates, cocaine, methadone, and opioids) or alcohol breath tests.

[0637] 27. Patients with positive antibodies for sexually transmitted infections (trichomoniasis, gonorrhea, chlamydia) and human immunodeficiency virus (HIV).

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

[0639] 29. Patients who have been diagnosed with chlamydia, trichomoniasis, or gonorrhea within the past three months.

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

[0641] 31. During the physical and gynecological examinations performed at the patient's first visit, any clinically significant abnormalities were found on the vulvovaginal examination (e.g., genital skin abrasions, irritation, dermatitis, or lesions).

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

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

[0644] b. If the patient develops a vaginal infection after participating in the study, the investigational drug will be withheld, and the patient will be treated for the infection. If the infection is not resolved within two weeks, the patient will withdraw from the study. Once enrolled in the study, patients will be allowed two treatments for vaginal infections. If a patient develops a third vaginal infection, they will be withdrawn from the study.

[0645] 33. Patients have a pelvic or urinary tract infection.

[0646] 34. Patients self-report a known hypersensitivity or adverse reaction to any component of IP.

[0647] Step 4 - Laboratory Evaluation

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

[0649] Step 5 - Clinical Diagnosis of FSAD

[0650] Patients who met all the inclusion and exclusion criteria above underwent a formal clinical interview to diagnose primary FSAD, which is acquired (i.e., not lifelong) and systemic (i.e., present regardless of circumstances), and has had symptoms for at least 6 months prior to the first visit. Eligible patients must have a lack of genitalia during sexual activity.The primary complaint of genital arousal and the belief that their genital response is significant to their overall sexual experience. Eligible patients must also experience distress due to difficulty in sexual arousal. Instructions 51 / 109 pages 59 CN 120981235 A

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

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

[0653] Drug-free period - 4 weeks (second visit)

[0654] After successful completion of all medical screenings (including laboratory evaluations) and confirmation of all inclusion and exclusion criteria, eligible patients and their partners are enrolled in a 4-week drug-free trial period. The second visit is the first day of the 4-week drug-free period. During these 4 weeks, patients were not allowed to use any oral or topical products (such as Dream Cream, OTC lubricants, PDE-5 inhibitors, etc.) or receive non-pharmacological interventions (i.e., sexual therapy) to address their arousal problems. Patients and their partners received individual eDiary devices and related instructions. During the drug-free period, patients and their partners used individual eDiary devices to record adverse events. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete a daily eDiary within 24 hours after each sexual activity. Additionally, if a sexual event occurred, the eDiary prompted the patient to acknowledge the partner's sexual activity and complete an arousal diary. Eligible patients were scheduled for a third visit within four weeks. Single-blind placebo induction period – 4 weeks (3rd visit)

[0655] After completing the 4-week drug-free period, eligible patients entered a 4-week single-blind placebo induction period. The 3rd visit was the first day of the 4-week single-blind placebo induction period. At the start of the single-blind placebo induction period, inclusion and exclusion criteria for the study were established, and patient compliance with completing the eDiary was assessed.

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

[0657] 1. Sexual Function Questionnaire (SFQ28)

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

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

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

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

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

[0663] In addition, if a sexual event occurred, the patient was prompted on the eDiary to record the application of IP, confirm the partner's sexual activity, and complete an arousal diary. After the 4-week single-blind placebo induction period (4th visit), eDiary responses, including an arousal diary, SFQ28, and FSDS-DAO scores, were used to establish a baseline. Eligible patients were scheduled for their 4th visit within four weeks.

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

[0665] After completing the 4-week single-blind placebo induction period, eligible patients entered the double-blind dosing period. The 4th visit 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 patient adherence to the eDiary and use of the study product was assessed.

[0666] Eligible patients completed the following tools and assessments in the clinic using the eDiary at their 4th visit.

[0667] 1. Sexual Function Questionnaire (SFQ28)

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

[0669] a. The total score must remain >18 points to confirm distress associated with sexual dysfunction.

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

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

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

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

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

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

[0676] 1. Sexual Function Questionnaire (SFQ28)

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

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

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

[0680] Patients completed the Patient Benefit Assessment (PBE) at the clinic during their 7th visit. During the double-blind treatment period, patients and their partners recorded adverse events using a separate eDiary device. During the 4-week drug-free period, patients and their partners were instructed (via daily prompts) to complete the daily eDiary within 24 hours after each sexual activity. In addition, if a sexual event occurs, the eDiary prompts the patient to record the application of IP, confirm the sexual activity of the partner, and complete the arousal diary.

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

[0682] Safety assessment follow-up (telephone):

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

[0684] Retrospective Assessment

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

[0686] Patient Withdrawal

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

[0688] Withdrawal Standard Instructions 53 / 109 pages 61 CN 120981235 A

[0689] Patients may opt out of the study at any time for any reason. In addition, patients may opt out of the study for any of the following reasons:

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

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

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

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

[0694] • Other medical reasons

[0695] Criteria for Discontinuation

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

[0697] Inclusion Criteria – Eligibility of Patient's Partner

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

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

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

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

[0702] 4. The partner has maintained a stable, monogamous, secure, and communicative relationship with the patient for at least 6 months prior to the first visit. The partner is sexually functional both psychologically and physically. The partner will remain consistent and contactable throughout the study.

[0703] Exclusion Criteria – Eligibility of Patient's Partner

[0704] A partner who meets any of the following criteria at the first visit will not be included in the study:

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

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

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

[0708] 4. Partners with significant cardiovascular, hepatic, metabolic, renal, respiratory, gastrointestinal, endocrine, immune, skin, hematologic, neurological, genitourinary, or psychiatric disorders or other unstable medical conditions, or any concomitant medications that may contraindicate the use of study drugs, interfere with study evaluation, limit study participation, or obscure the interpretation of study results.

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

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

[0711] 7. Partners with a history of priapism or conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia). Instructions for Use, Page 54 / 109, 62 CN 120981235 A

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

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

[0714] 10. The partner self-reports a diagnosis of human immunodeficiency virus (HIV).

[0715] 11. The partner self-reports an outbreak of any of the following sexually transmitted diseases at any point in the past 3 months: genital herpes or HPV (vesicles, warts, or blisters).

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

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

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

[0719] Investigation Product (IP)

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

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

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

[0723] Instructions for Use 55 / 109 pages 63 CN 120981235 A

[0724]

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

[0726] Table 4: Formulation of placebo cream

[0727]

[0728] Single-blind placebo induction period

[0729] One 30-gram tube of placebo cream was used for the single-blind induction period and was distributed to the patient at the third visit, allowing nine (9) applications of 2 grams of cream. The patient was instructed to apply 2 grams of cream 10 to 20 minutes before each sexual activity. Specific instructions for use were provided to the patient separately. Instructions for use 56 / 109 pages 64 CN 120981235 A

[0730] Double-blind dosing period

[0731] Each month, IP was distributed into one 30-gram tube and nine 2-gram dose cards. Participants were instructed to use no more than 2 grams of the product every 24 hours, for no more than nine applications per month. After distributing the 2-gram portion onto the dose card, the participant applied 2 grams of IP with their index finger approximately 10–20 minutes before the sexual activity. One gram was applied to the anterior commissure, clitoral hood, glans clitoris, frenulum, vestibule, and labia minora. Another gram was applied to the distal anterior vagina to a depth of approximately 0–3 cm, or about halfway between the distal and proximal interphalangeal joints, targeting the lower 1 / 3 of the distal vagina. Participants were instructed to wash off the cream after sexual intercourse, and, if applicable, to have their partners wash off the cream. Applications exceeding nine times per month were recorded as a violation of the protocol.

[0732] IP Dosage Application Procedure

[0733] ​​During the single-blind placebo induction period and the double-blind dosing period, a dosing card must be used to measure the correct amount of cream according to the following instructions. The patient was instructed to measure the correct amount of cream as follows: “To measure the correct amount of cream, place the dosage card on a flat surface. Squeeze the cream onto the dosage card by evenly filling the rectangle outlined on the card. Ensure the cream covers the entire area of ​​the rectangle outlined on the dosage card.”

[0734] The rectangle on the dosage card (sized to deliver 2 grams of cream) was divided into two equal parts, one for applying the cream externally to the pre-designated vulvar area and the other for applying it internally into the vagina.

[0735] Approximately 50% of the cream will be applied externally to the vulva (i.e., clitoris, vestibule, labia minora) and approximately 50% will be applied internally into the vagina.Internal application: The patient is instructed to note the application time on the eDiary and apply an appropriate amount of cream to the vagina and vulva using the dosage card, as follows:

[0736] External application of cream:

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

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

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

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

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

[0742] Internal application of cream:

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

[0744] Patients received extensive site training prior to the single-blind placebo induction period to ensure they understood the instructions for use of the product. Patients were instructed to wash their hands and avoid rubbing or washing off any area where the cream was applied. Patients and their partners were also instructed to wash off any remaining treatment cream after all sexual activity.

[0745] IP dosing frequency

[0746] IPs were allocated to apply a total of nine (9) 2-gram doses of cream at monthly intervals (nine 2-gram doses can be reliably delivered from a 30-gram tube). Patients were instructed to apply the cream 10 to 20 minutes before each sexual activity, but not more than nine (9) doses in a 4-week period. Patients were further instructed not to apply the cream within 24 hours of the previous application.

[0747] Dosing Schedule

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

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

[0750] Double-blind dosing period (4th–7th visits) Instructions for use 57 / 109 pages 65 CN 120981235 A

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

[0752] Previous and Concomitant Medications

[0753] Permitted Concomitant Medications

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

[0755] All concomitant medications taken by participating patients and their respective partners were recorded from 28 days prior to the first visit to the end of the seventh visit.

[0756] Changes in concomitant medications were recorded in the eDiary of patients and their partners.

[0757] Concomitant Medications - Patients and their Partners

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

[0759] Throughout the study, patients are prohibited from using vaginal hormonal products (such as vaginal estrogen, vaginal pravastatin), vaginal or vulvar lubricants, spermicides, creams or gels, contraceptive foams, or vaginal douches. Partners currently taking or who have taken guanylate cyclase stimulants (such as Riociguat), clonidine, potent CYP3A4 inhibitors, phosphodiesterase (PDE) type 5 inhibitors, or nitric oxide donors (such as organic nitrates or organic nitrites) within 1 month (28 days) prior to their first visit will be excluded. Patients using contraceptive vaginal sponges will be excluded. If a patient or their partner is currently taking or has taken any of the prohibited medications listed in the relevant study inclusion and exclusion criteria, they will be excluded from the study.

[0760] Patient and Partner Safety Assessment

[0761] Adverse Events (AEs)

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

[0763] Adverse Event Reporting

[0764] Patients and their partners were instructed to immediately notify of any serious medical problems that occurred during the study. Patients and their partners were instructed to call 911 in the event of a life-threatening emergency. Patients recorded adverse events in the eDiary as provided.All adverse events (AEs) were recorded. Patients completed the eDiary within 24 hours of each sexual event and at any time during the study when AEs might occur. Partners recorded all AEs in a separate eDiary according to the provided instructions. Partners completed the eDiary within 24 hours of each sexual event and at any time during the study when AEs might occur. The eDiary prompted patients and partners every 24 hours to assess whether a sexual event had occurred. If a sexual event had occurred, the eDiary would provide patients and partners with the following prompts: Instructions 58 / 109 Page 66 CN 120981235 A “Have you had any complaints since your sexual event?” If a participant or partner answered “yes,” the eDiary would further prompt them with some of the more common side effects associated with oral sildenafil or genital cream, such as: (1) “Have you experienced any local irritation or discomfort?” (2) “Have you experienced any dizziness or lightheadedness?” and (3) “Do you have any other complaints to report?” Participants who reported complaints after sexual activity were sent electronically to the site for assessment and triage within 24 hours. In addition, participants who answered "yes" to their complaints were reminded to contact their study site. Participants were instructed to call the investigator's emergency number if they did not receive a response within 24 hours of submitting their complaints electronically. Participants were also instructed to promptly report any complaints of local irritation or discomfort to the investigator for follow-up.

[0765] If a participant confirmed a sexual encounter with their partner via eDiary, study site staff were instructed to contact the partner within 72 hours of the incident to confirm if the partner had any complaints, and if so, to further inquire about common side effects associated with oral sildenafil (e.g., dizziness) or genital cream exposure (e.g., genital irritation). If the partner did not receive a call within 72 hours of the sexual activity with the participant, they were instructed to contact the investigator.

[0766] Participants recorded TEAEs in their eDiary. If participants and their sexual partners had TEAEs for which they wished to undergo a physical examination for evaluation, or if the investigator determined based on the reported AEs, they would be invited for an ad hoc appointment.

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

[0768] Adverse Events

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

[0770] Suspected Adverse Reactions

[0771] A suspected adverse reaction is any adverse reaction (AE) for which there is a reasonable probability that the drug will cause the AE. For the purposes of an Investigational New Drug (IND) safety report, “reasonable probability” means that there is evidence of a causal relationship between the drug and the AE. A suspected adverse reaction means that the certainty of causation is less than that of an adverse reaction, which is any AE caused by the drug.

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

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

[0774] Serious AE or Serious Suspected Adverse Reactions

[0775] An AE or suspected adverse reaction is considered “serious” if it results in any of the following outcomes:

[0776] • Death,

[0777] • Life-threatening AE – see definition above,

[0778] • Hospitalization or prolongation of existing hospitalization,

[0779] • Persistent or significant loss of capacity or ability to substantially impair normal life functioning, and

[0780] • Congenital abnormality / birth defect.

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

[0782] Relationship with the investigational drug

[0783] A causal relationship assessment must be performed on all AEs (serious and non-serious). A causal relationship assessment is to determine whether there is a reasonable possibility that the investigational product (IP) caused or contributed to the AE.

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

[0785] Impossible: The current state of knowledge indicates that it is impossible to establish a relationship.

[0786] Possible: A response that begins with the administration of the investigational drug, follows a reasonable chronological order, and follows a known response pattern to the suspected investigational drug. This response may be caused by the patient's clinical condition or other treatments administered to the patient, but this is not currently certain.

[0787] Probable: A response that begins with the administration of the investigational drug, follows a reasonable chronological order, and follows a known response pattern to the suspected investigational drug.The known response pattern to the investigational drug. The response cannot be reasonably explained by known characteristics of the patient’s clinical condition or by other treatments administered to the patient.

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

[0789] Severity

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

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

[0792] Moderate: Discomfort sufficient to interfere with normal daily activities

[0793] Severe: Unable to perform normal daily activities

[0794] Life-threatening: Risk of immediate death due to the response at the time of occurrence

[0795] Screening Laboratory Evaluation

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

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

[0798] Hematology: hematocrit, hemoglobin, platelets, red blood cell count, white blood cell count, and white blood cell count differences only when total white blood cells (WBC) are abnormal

[0799] Prothrombin time

[0800] TSH

[0801] FSH

[0802] Estradiol

[0803] Total testosterone, SHBG, and albumin

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

[0805] HBsAg, HCV, HIV, and antibodies

[0806] • NAAT (Nucleic Acid Amplification Test): Bacterial vaginosis, yeast (Candida) and sexually transmitted infections (gonorrhea, chlamydia, trichomoniasis) Instructions for use 60 / 109 pages 68 CN 120981235 A

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

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

[0809] Electrocardiogram

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

[0811] Vulvar-vaginal clinical examination

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

[0813] Table 5A: Vulvoscopy - degree of irritation

[0814]

[0815] Statistical analysis

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

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

[0818] Efficacy Measurement

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

[0820] The following methods were used to assess efficacy:

[0821] Co-primary endpoint:

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

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

[0824] Secondary endpoint:

[0825] • Arousal diary (SSE): Change in the number of satisfactory sexual events (SSE) from baseline to the end of the study

[0826] Exploratory endpoint:

[0827] • Arousal diary (SSE): Change from baseline at week 4 (5th visit) and week 8 (6th visit) of the double-blind dosing period, in addition to the secondary endpoint analysis above

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

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

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

[0831] • SFQ28 (AS): Changes in the double-blind dosing period at week 4 (5th visit) and week 8 (6th visit) compared to baseline, except for the primary endpoint analysis described above.

[0832] • SFQ28 (AL): Changes in the arousal lubrication (AL) category of SFQ28 at week 4 (5th visit), week 8 (6th visit), and week 12 (7th visit) compared to baseline.

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

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

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

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

[0837] • FSDS-DAO (Q14): Changes in FSDS-DOA item 14 compared to baseline at weeks 4 (5th visit) and 8 (6th visit) during the double-blind dosing period, in addition to the primary endpoint analysis described above. Instructions for Use, Page 62 / 109, 70 CN 120981235 A

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

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

[0840] ·PBE: The proportion of patients who reported a meaningful benefit from the study drug, evaluated at the end of the study using a "yes / no" question

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

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

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

[0844] H0: μ(sildenafil) = μ(placebo)

[0845] • Alternative hypothesis (H1): There is a difference in the mean change of SFQ28 (AS) from baseline to week 12 between the 3.6% sildenafil cream treatment group and the matched placebo cream group.

[0846] H1: μ(sildenafil) ≠ μ(placebo)

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

[0848] Results

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

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

[0851] During the double-blind dosing period, the mean (standard deviation, SD) duration of IP use for sildenafil and placebo users was 10.3 (2.5) weeks and 9.7 (3.1) weeks, respectively. The cumulative doses of sildenafil and placebo creams received during this period were 23.5 (14.0) g and 22.9 (14.5) g, respectively. The median reported compliance, defined as the use of IP 10–20 minutes before sexual intercourse, was between 78.8% and 98% for 3.6% of sildenafil cream users and between 85% and 95% for placebo cream users. 3 were reported in the third month of use.The highest median compliance rate was 98% for users of the 3.6% sildenafil cream, compared to 95% for users of the placebo cream during the first month of use. During the double-blind dosing period, 1357 sexual experiences were recorded with the 3.6% sildenafil cream and 1160 with the placebo cream, respectively. The majority of sexual experiences were with partners (76% of sildenafil cream exposures and 80% of placebo cream exposures). No partner sex with a non-consenting partner was reported in the eDiary, therefore no participants discontinued the study due to protocol violation.

[0852] Table 5B shows the number of participants and sexual partners who reported at least one TEAE, as well as the total number of TEAEs categorized by severity and relevance. During the double-blind dosing period, the reporting frequency of various TEAEs with the 3.6% sildenafil cream was not significantly different from that with the placebo cream (all p-values ​​> 0.50, Table 5B). During the double-blind dosing period, the mean (SD) time to onset of the first TEAE reported by participants assigned to sildenafil and placebo cream was 21 (11) days and 20 (8) days, respectively. All TEAEs reported by participants or their sexual partners during the double-blind dosing period were rated as mild or moderate. During the dosing period, 3 TEAEs (burning at the IP application site, erythema at the IP application site, and dyspareunia caused by IP use) were reported by 2 participants assigned to sildenafil during the dosing period, all of which were considered treatment-related and resulted in IP interruption. During the double-blind treatment period, 2 TEAEs were reported by placebo cream users, which were not related to IP use (dyspareunia and vulvar fissure) but still resulted in IP interruption.

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

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

[0855] Specification 64 / 109 pages 72 CN 120981235 A

[0856]

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

[0858] . (Instructions for Use)65 / 109 Page 73 CN 120981235 A

[0859]

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

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

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

[0863]

[0864] Because oral sildenafil may be associated with orthostatic hypotension, particularly in patients taking nitrates for angina, orthostatic vital signs were obtained at baseline in participants (Table 6) and their sexual partners and then monthly during double-blind dosing. As shown in Table 6, at any point in the study, there were no differences in vital signs between participants assigned to 3.6% sildenafil cream or placebo in different positions (all p values ​​> 0.10). Consistent with normal physiological responses, mean pulse rate began to increase from the supine position, at 1 minute and 3 minutes of standing. The median change in pulse rate from baseline was 1–4 beats / minute in both the 3.6% sildenafil cream and placebo groups, with no outliers found. For systolic blood pressure, the median change from baseline ranged from -3.5 mmHg to +3.0 mmHg in both treatment groups, which did not show a clinically significant change. Finally, during the double-blind dosing period, the median change in diastolic blood pressure from baseline was -2.0 to +1.0.

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

[0866] Finally, although baseline laboratory and electrocardiogram results were not repeated at the end of the study, no TEAEs required re-evaluation of these baseline screenings.

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

[0868] Instructions for Use 67 / 109 pages 75 CN 120981235 A

[0869] Conclusion

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

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

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

[0873] The advantages of this study include participants reporting TEAEs in detail via an eDiary with daily prompts, and reporting TEAEs directly in sexual partners as described above. Based on the fact that some potential volunteers were unwilling to have their sexual partners participate in the clinical study, a protocol modification was made to allow women without partners or whose partners did not want to participate in the informed consent or safety monitoring process to enroll. In accordance with Good Clinical Practice (GCP) guidelines, participants who did not consent to their sexual partners were instructed not to have sexual intercourse with a partner within 72 hours of IP administration. Given that sexual partner TEAEs are uncommon and were all mild to moderately severe, the potential benefits of topical sildenafil outweigh the risks to the user and their sexual partner.

[0874] Postural vital signs of sexual partners were monitored in clinics or via telemedicine, but could not be measured immediately after using IP. Data from the preliminary safety study in men discussed above support that changes in heart rate during standing are likely a benign, normal, physiological response to standing, and the extensive vital signs and TEAE data collected in this study indicate that topical application of oral sildenafil citrate does not have systemic effects. Instructions for Use 68 / 109 pages 76 CN 120981235 A

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

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

[0877] To assess the Patient Reported Outcomes (PROM) measures used to evaluate the efficacy of treatment in patients with FSAD, premenopausal and postmenopausal women aged 21–70 years with FSAD were interviewed to support the content of the PROM.

[0878] The results confirmed that the PROM was effective in evaluating concepts in FSAD and supporting tools used as endpoints in clinical trials for patients with FSAD. Exit interviews were conducted to better understand meaningful changes in measures that served as primary or secondary endpoints. In addition, patients were identified as being considered if they perceived improvement in the Patient General Impression of Change (PGI-C), an improvement in severity by one or two categories in the Patient General Impression of Severity (PGI-S), or reported a meaningful benefit of the investigational drug in the Patient Benefit Assessment (PBE).

[0879] Exit interviews were conducted on a subset of patients at the end of the study (at the 7th visit).

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

[0881] • The composition of meaningful changes in the following patient-reported outcome measures (PROMs):

[0882] o SFQ-AS categories,

[0883] o FSDS-DAO item 14, and

[0884] o Arousal diary AS categories

[0885] • What was considered when answering “yes” or “no” to patient welfare assessment questions

[0886] Study Design

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

[0888] Study Population

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

[0890] Exit Interview Procedure

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

[0892] Part 1: Overall Experience with FSAD

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

[0894] Part 2: Experience with FSAD-Related Arousal or Feeling Problems

[0895] As the interview continues, the questions will focus on problems related to sexual arousal and feeling, and experiences of changes during the trial (e.g., whether these changes have improved, remained unchanged, or worsened, and whether any of these changes are meaningful). Instructions for Use, Page 69 / 109, 77 CN 120981235 A

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

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

[0898] o Four (4) items in the SFQ28 AS category

[0899] o FSDS-DAO item 14

[0900] o Five (5) items in the Arousal Diary AS category

[0901] o One (1) PGI-S item

[0902] o One (1) PGI-C item

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

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

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

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

[0907] Example 4: Assessment of Experiences with Disease-Related Symptoms and the Relative Importance of FSAD Symptoms

[0908] Objectives

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

[0910] Methods

[0911] Study Population

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

[0913] Recruitment

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

[0915] Study Interview Visit Instructions 70 / 109 pages 78 CN 120981235 A

[0916] Semi-structured interview studies combining concept-inspired (CE) and cognitive inquiry (CD) were identified as the most appropriate method to achieve the study objectives (only the CE portion of the interview is reported here). Semi-structured interviews allow for the exploration of participants’ subjective thoughts, experiences, and details that structured interviews cannot. Furthermore, semi-structured interviews allow for the use of relevant probing questions when necessary to assess participants’ responses to specific symptoms, facilitating discussions that would be impossible in unstructured interviews.

[0917] Concept-inspired interviews investigated the symptoms and effects experienced by women with FSAD. Open-ended questions were used to encourage participants to spontaneously report their experiences. When necessary, the interviewer used more direct questioning to extract more details from the participants. Examples of the types of questions asked include:

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

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

[0920] • “How do you feel when this problem occurs?”

[0921] • “How does this problem make you feel about intimacy with your partner?”

[0922] • “Think of the different types of things you mentioned. Can you rank them from least bothersome to most bothersome?”

[0923] This data collection method was used to generate participant-driven insights and allowed for bottom-up topical analysis of the data.

[0924] Analysis

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

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

[0927] Results

[0928] Study population

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

[0930] Interview Results

[0931] Sexual Activity Manual 71 / 109 pages 79 CN 120981235 A

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

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

[0934] Symptom Frequency

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

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

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

[0938] Although inability or difficulty achieving orgasm was the most reported symptom overall, more participants spontaneously reported a lack of lubrication in the premenopausal group (n=13 spontaneously reported) compared to those who agreed that inability or difficulty achieving orgasm was the most common symptom.Slippery or wet and loss of sensation / feeling, loss of sensation / feeling in the postmenopausal group (n=11 spontaneously reported).

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

[0940] Table 7: Frequency of FSAD Symptoms Reported by Participants in Premenopausal and Postmenopausal Women (Page 72 / 109, CN 120981235 A)

[0941]

[0942] *For the postmenopausal population, this concept is “no arousal”.

[0943] Most Problematic Symptoms

[0944] Participants in both the premenopausal and postmenopausal cohorts were asked to rank their FSAD symptoms from most bothersome to least bothersome to reveal the most problematic symptoms (Table 8). In the premenopausal group, the top three most frequently reported symptoms were lack of lubrication or wetness (n=17), followed by loss of sensation / feeling (n=12), and then inability to achieve orgasm (n=8). Six participants listed lack of lubrication as the most bothersome symptom, and five participants listed loss of sensation / feeling as the primary symptom. Following lack of lubrication and loss of sensation / feeling, difficulty or inability to achieve orgasm was listed as one of the top three symptoms by eight women. In n=7 and n=8 participants, the top three most frequently reported symptoms were lack of tingling (n=6) and lack of arousal / excitement. In the postmenopausal group, the top three most frequently reported symptoms were loss of sensation (n=10), followed by lack of lubrication or wetness (n=9), then inability to achieve orgasm and lack of desire (both n=6). Only n=2 women listed lack of arousal as the most difficult symptom. Each woman mentioned specific descriptions of loss of sensation, such as tingling and throbbing, and they all reported it as the third most troublesome symptom.

[0945] Table 8: Most problematic FSAD symptoms reported by premenopausal and postmenopausal women 73 / 109 pages 81 CN 120981235 A

[0946]

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

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

[0949] ***One postmenopausal woman reported that difficulty achieving orgasm and low libido were her biggest problems.

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

[0951] Most Important Symptoms Requiring Treatment

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

[0953] In the postmenopausal group, loss of sensation / feeling and lack of lubrication / wetness were considered the two most in need of treatment (n=9) (Table 9). This was followed by difficulty or inability to achieve orgasm (n=7), and then low libido (i.e., lack of interest in sexual activity) (n=5). n=2 women listed the lack of arousal (cognitive arousal) during sexual activity as the most important symptom requiring treatment, while n=1 women reported specific sensory problems of lack of pulsation and lack of warmth, respectively. Although the ranking of the most problematic symptoms (Table 8) and the most in-demand symptoms differed slightly (i.e., difficulty / inability to achieve orgasm was listed as the most problematic and the third most in-demand symptom), the results for both issues indicate a consistency between the troubling FSAD symptoms in postmenopausal women and the symptoms they most wanted treated. Overall, a total of n=11 women reported a desire for treatment for at least one genital arousal problem, including loss of sensation / feeling (n=9), lack of tingling (n=1), and lack of throbbing (n=1). This is more than the number of participants (n=9) who reported lack of lubrication or wetness as the most in-demand FSAD symptom (n=9).

[0954] Table 9: FSAD Symptoms Most Desirable for Treatment by Premenopausal and Postmenopausal Participants

[0955]

[0956] *No participant reported throbbing as the most in-demand FSAD symptom.

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

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

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

[0960] Due to the way premenopausal participants described “excitement” and “excitement,” these two concepts were combined into one concept in this group. In the postmenopausal group, “not feeling excited” was not reported as a symptom; the concept was “not feeling aroused.”

[0961] Frequency of FSAD effects

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

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

[0964] In the premenopausal group, the next two most frequently reported effects were related to relationship problems, namely the impact of FSAD on their partners (n=18) and the difficulties it caused in the relationship (n=16) (Table 10). Participants described the emotional impact of FSAD on their partners, including feelings of sadness, disappointment, and distress. Furthermore, participants noted that FSAD could lead to their partners questioning themselves, their sexual performance, and the overall relationship. Following these effects, the two most frequently discussed issues were mood problems of frustration and depression, both reported by n=15 women. M...

Claims

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

2. The method of claim 1, wherein treating FSAD includes increasing satisfactory sexual events, improving arousal sensation, increasing arousal lubrication, increasing orgasm, reducing anxiety about sexual arousal, reducing pain or discomfort during sexual activity, reducing pain or discomfort after sexual activity, and / or increasing satisfaction with sexual activity.

3. The method of claim 2, wherein treating FSAD includes increasing satisfactory sexual events.

4. The method of claim 2, wherein treating FSAD includes improving arousal sensation.

5. The method of claim 2, wherein treating FSAD includes increasing arousal lubrication.

6. The method of claim 2, wherein treating FSAD includes increasing sexual orgasm.

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

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

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

10. The method of claim 2, wherein treating FSAD includes increasing satisfaction with sexual activity.

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

12. The method of claim 11, wherein the sensation at the genital site includes one or more of the following: tingling, pleasure, warmth, throbbing, palpitation, congestion, or fullness in the genital area.

13. A method for increasing the satisfaction of a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

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

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

16. A method for increasing orgasm in a female subject during sexual activity, comprising applying a topical composition comprising a phosphodiesterase type 5 inhibitor and / or its salt to the genital area of ​​the female subject.

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

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

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

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

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

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

23. The method of claim 22, wherein the response to physical stimulation is enhanced.

24. The method of claim 22, wherein the response to psychological stimuli is enhanced.

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

26. The method according to any one of claims 1-25, wherein the type 5 phosphodiesterase inhibitor and / or its salt are administered at least twice within a time period.

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

28. The method according to claim 26 or 27, wherein one or more symptoms improve within about 1 week to about 8 weeks after the initial application.

29. The method of claim 28, wherein one or more symptoms improve within about one to four weeks after the initial application.

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

31. The method according to claim 28 or 29, wherein one or more of the symptoms include libido.

32. The method of claim 28 or 29, wherein one or more symptoms include achieving orgasm and / or experiencing orgasm.

33. The method according to any one of claims 1-32, wherein the type 5 phosphodiesterase inhibitor is sildenafil, avanafil, lodenavir, mironafil, tadalafil, vardenafil, udenafil, sulphenafil, or thiomethylsildenafil.

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

35. The method according to any one of claims 1-34, wherein the local composition further comprises: a. Stable polymers; b. Propylene glycol; c. Polysorbate surfactant; dL-arginine or L-arginine salt; and e. Ionic salts.

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

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

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

39. The method according to any one of claims 34-38, wherein the L-arginine or L-arginine salt is present at a concentration of at least about 5% by weight of the composition.

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

41. The method of claim 40, wherein the ionic salt is present at a concentration of at least about 5% by weight of the composition.

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

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

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

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

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

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

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

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

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

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

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

53. The method according to any one of the preceding claims, wherein the composition comprises primarily the following: a. Purified water; b. Potassium chloride; c. L-arginine hydrochloride; d. Glyceryl stearate; e. hexadecyl alcohol; f. Squalane; g. Xanthan gum; h. Isopropyl myristate; i. Oleic acid; j. Propylene glycol; k. Polysorbate 20; and 1. Sildenafil citrate.

54. The method according to any one of the preceding claims, wherein the composition comprises each of the following compounds at a concentration not exceeding ±20% of the stated concentration: a. Purified water with a concentration of about 35% to about 55% by weight; b. Potassium chloride with a concentration of about 2.5% to about 15% by weight; c. L-arginine hydrochloride at a concentration of about 2.5% to about 15% by weight; d. Glyceryl stearate at a concentration of about 4% to about 10% by weight; e. Hexadecyl alcohol at a concentration of about 4% to about 10% by weight; f. Squalane at a concentration of about 1% to about 8% by weight; g. Xanthan gum at a concentration of about 0.1% to about 5% by weight; h. Isopropyl myristate at a concentration of about 0.1% to about 5% by weight; i. Oleic acid with a concentration of about 0.1% to about 5% by weight; j. Propylene glycol at a concentration of about 1% to about 10% by weight; k. Polysorbate 20 at a concentration of about 0.2% to about 5% by weight; and l. Sildenafil citrate at a concentration of about 1% to about 10% by weight.

55. The method according to any one of claims 1-54, wherein the subject suffers from female sexual arousal disorder (FSAD).

56. The method according to any one of claims 1-55, wherein the subject is at risk of having female sexual arousal disorder (FSAD).

57. The method according to any one of claims 1-56, wherein the composition comprises: a. Purified water with a concentration of approximately 40% by weight; b. Potassium chloride with a concentration of approximately 5% by weight; c. L-arginine hydrochloride at a concentration of approximately 7.5% by weight; d. Glyceryl stearate at a concentration of approximately 7% by weight; e. A concentration of approximately 7% by weight of hexadecaneol; f. Squalane at a concentration of approximately 4% by weight; g. Xanthan gum with a concentration of approximately 0.8% by weight; h. Isopropyl myristate at a concentration of approximately 1% by weight; i. Oleic acid at a concentration of approximately 1% by weight; j. Propylene glycol at a concentration of approximately 8.5% by weight; k. Polysorbate 20 at a concentration of approximately 2% by weight; l. A concentration of approximately 10% by weight of trisodium citrate dihydrate; m. Sodium benzoate with a concentration of approximately 0.2% by weight; n. Gluconolactone at a concentration of about 0.25% by weight; and o. Sildenafil citrate at a concentration of approximately 5% by weight.

58. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. Select female subjects exhibiting one or more symptoms of FSAD, and b. Applying a composition to the genital area of ​​a subject, the composition comprising a type 5 phosphodiesterase inhibitor and / or its salt, a stable polymer, propylene glycol, a polysorbate surfactant, L-arginine or an L-arginine salt and its ion salt.

59. The method of claim 58, wherein the one or more symptoms are selected from decreased genital sensitivity, lack of genital response during sexual activity, reduced genital arousal, pain and / or discomfort during sexual activity, pain and / or discomfort after sexual activity and / or distress caused by difficulty in sexual arousal.

60. The method according to any one of claims 1-59, wherein about 50% of the composition is applied externally to the vulva and about 50% of the composition is applied internally to the vagina.

61. The method of claim 60, wherein applying about 50% of the composition externally comprises: a. Apply the composition to the anterior commissure, clitoral prepuce, glans clitoris, and frenulum; b. Apply the composition to the vaginal vestibule; and c. Apply the composition to the labia minora.

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

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

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

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

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

67. The method according to any one of claims 1-66, wherein the subject has not been given at least one of guanylate cyclase stimulants, clonidine, CYP3A4 inhibitors, nitric oxide donors, organic nitrates, organic nitrites or α-receptor blockers within 28 days prior to administration of the first dose of the composition.

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

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

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

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

72. The method according to any one of claims 1-71, wherein the application results in a satisfactory sexual event.

73. The method according to any one of claims 1-72, wherein the application results in an increase in genital arousal.

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

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

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

77. The method according to any one of claims 1-76, wherein the application results in an increase in orgasm during sexual activity.

78. The method according to any one of claims 1-77, wherein the application reduces the difficulty or inability to achieve orgasm during sexual activity.

79. The method according to any one of claims 1-78, wherein the application results in an increase in sensation or feeling in the genital area during sexual activity.

80. The method according to any one of claims 1-79, wherein the application results in an increased tingling sensation in the genital area during sexual activity.

81. The method according to any one of claims 1-80, wherein the application results in increased blood flow to the genital area during sexual activity.

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

83. The method according to any one of claims 1-82, wherein the application results in a reduction of pain and / or discomfort during sexual activity.

84. The method according to any one of claims 1-83, wherein the administration results in a reduction of pain and / or discomfort after sexual activity.

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

86. The method according to any one of claims 58-85, wherein one or more symptoms include a diminished response to physical stimuli.

87. The method according to any one of claims 58-85, wherein the primary complaint of the female subject is a diminished response to bodily sexual stimulation.

88. The method according to any one of claims 1-87, wherein the subject exhibits one or more of the following after administration: a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28); b. SFQ28 score improvement of at least 1 point in the lubrication category; c. Improvement of at least 1.5 points in the SFQ28 arousal category score; d. Improve your SFQ28 score in the Desire category by at least 2 points; The e.SFQ28 score for orgasm improved by at least 1.20 points; f. The SFQ28 pain category score improved by at least 1 point; g. Improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score; h. Arousal score improved by at least 1.45 points; i. Genital arousal score improved by at least 1.13 points; j. The score for genital arousal anxiety improved by at least 1.49 points; k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

89. The method according to any one of claims 1-88, wherein the subject includes a preliminary diagnosis of FSAD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Revised Edition (DSM-IV-TR).

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

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

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

93. A method for treating female sexual arousal disorder (FSAD) or its symptoms, comprising: a. Female subjects with primary FSAD as their chief complaint were selected, and b. Apply a topical composition containing a type 5 phosphodiesterase inhibitor and / or its salt to the genital area of ​​the subject.

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

95. A method for determining the efficacy of FSAD treatment, comprising: a. Obtain baseline scores for one or more of the following: Sexual Function Questionnaire (SFQ28) scores in the arousal cognition category, SFQ28 scores in the arousal lubrication category, SFQ28 scores in the arousal sensation category, SFQ28 scores in the desire category, SFQ28 scores in the orgasm category, SFQ28 scores in the pain category, Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) scores, arousal sensation scores, genital arousal scores, genital arousal anxiety, percentage of arousal diary item 12-SSE, and number of arousal diary item 12-SSE. b. Administer the FSAD treatment to female subjects; and c. Identify the improvement in one or more scores from step a.

96. The method of claim 95, wherein one or more of the following indicate that the FSAD treatment is effective: a. Improvement of at least 1 point in the arousal cognitive category score of the Sexual Function Questionnaire (SFQ28); b. SFQ28 score improvement of at least 1 point in the lubrication category; c. Improvement of at least 1.5 points in the SFQ28 arousal category score; d. Improve your SFQ28 score in the Desire category by at least 2 points; The e.SFQ28 score for orgasm improved by at least 1.20 points; f. The SFQ28 pain category score improved by at least 1 point; g. Improvement of at least -7 points in the Female Sexual Distress Scale - Desire, Arousal, and Orgasm (FSDS-DAO) score; h. Arousal of feelings improved by at least 1.45 points; i. Improvement in genital arousal by at least 1.13 points; j. Genital arousal anxiety improved by at least 1.49 points; k. The proportion of students who improved their journal entries by at least 0.25 points in the SSE (Self-Recalling and Reflection) section; and l. The number of evoking diary entries 12-SSE improved by at least 1.41 points.

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

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