Estratetraenol for the treatment of female sexual arousal disorder

Abstract

This invention relates to a treatment for female sexual arousal disorder (FSAD), related compositions, dosing units, and packaging units. Specifically, this invention relates to the use of a composition comprising about 14 mg to about 25 mg of estradiol for the treatment of FSAD. This composition has achieved beneficial effects in patients diagnosed with FSAD based on a self-report questionnaire.

Description

Technical Field

[0001] This invention relates broadly to the medical field, and more specifically to hormone therapy for subjects suffering from female sexual arousal disorder. Specifically, this invention relates to compositions comprising estradiol components for treating female sexual arousal disorder. Background Technology

[0002] In popular media, the various medical conditions associated with decreased or absent libido, sexual arousal, and pain during sexual activity in women are often referred to by the term female sexual dysfunction (FSD). However, from a medical classification perspective, the term FSD is actually considered to encompass a group of at least four distinguishable disorders: hypoactive sexual desire disorder (HSDD), characterized by decreased or absent interest in sexual activity; female sexual arousal disorder (FSAD), characterized by the inability to achieve or maintain sexual arousal; female orgasmic disorder (FOD), characterized by difficulty achieving orgasm despite adequate arousal; and dyspareunia, characterized by pain during sexual activity. In all these disorders, women must also experience personal suffering to meet the diagnostic criteria. In the DSM-5 classification system, FSAD and HSDD are combined into a single disorder, Female Sexual Interest / Arousal Disorder (FSIAD).

[0003] The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), published in 2013, first included the condition FSIAD, which was subsequently criticized by experts in the field who raised concerns when comparing the diagnostic criteria for FSAD with those in the earlier DSM-IV-TR for FSAD and HSDD (Thomas and Gurevich, Feminism & Psychology, 2021, DOI: 10.1177 / 0959353521989536 and Clayton et al., Journal of Sexual Medicine, 2012, DOI: 10.1111 / j.1743-6109.2012.02850.x). Due to the complete and thorough stratification of HSDD and FSAD, experts in the field continue to use the diagnostic criteria of the DSM-IV-TR to specifically study FSAD or HSDD, which still treat them as two distinct indications. Combining two disorders, making the individual criteria for a disorder more stringent, or requiring more diagnostic criteria is actually counterproductive, because such disorders often differ in their presentation, treatability with currently available therapies, and logical approaches to testing improvement therapies (Clayton et al., Journal of Sexual Medicine, 2012, DOI: 10.1111 / j.1743-6109.2012.02850.x). Furthermore, the FDA 2016 guidance was issued to assist sponsors in developing medicines for the treatment of low sexual interest, libido, and / or sexual arousal in women. This guidance focuses on conditions causing significant distress or interpersonal difficulties in women with low sexual interest, libido, and / or sexual arousal, including Female Sexual Interest / Arousal Disorder (FSIAD), Hypoactive Libido Disorder (HSDD), and Female Sexual Arousal Disorder (FSAD).

[0004] According to DSM IV-TR, FSAD should be diagnosed when the following three criteria are met:

[0005] A. A persistent or recurrent inability to achieve or maintain adequate lubrication-swelling response for sexual arousal until sexual activity is completed.

[0006] B. This disorder causes significant distress or difficulties in interpersonal relationships.

[0007] C. Sexual dysfunction cannot be better explained by another Axis I disorder (other than another sexual dysfunction), and is not solely due to the direct physiological effects of substances (e.g., drug abuse, medication) or general medical conditions.

[0008] There are currently no approved treatments for female sexual arousal disorder (FSAD). Sildenafil (a popular product for treating erectile dysfunction) has recently been formulated as a topical cream and is being investigated for its use in treating FSAD in a premenopausal population of women with the condition (Daré Bioscience, Phase 2b response study). Most commonly, women affected by FSAD resort to psychotherapy, such as cognitive behavioral therapy and / or couples sex therapy. Furthermore, early studies on women's sexual problems did not include all the information needed to diagnose FSAD because these studies did not inquire about levels of pain or stimulation. Additionally, some reports incorrectly use terms such as "sexual desire" and "sexual arousal" interchangeably, when these terms have very different meanings from a clinical, diagnostic, and therapeutic perspective. In fact, sexual desire refers to a general baseline interest in sexual activity (i.e., desire, libido), while sexual arousal, particularly genital arousal, refers to the physiological response of the genitals to sexual stimulation.

[0009] Given the profound adverse effects of FSAD on women's quality of life, either leading to decreased mental health and loss of the basic human right to sexual health as defined by the WHO, or to the relationship consequences of sexual difficulties, there is a need to develop effective treatments. Summary of the Invention

[0010] By conducting rigorous diagnostic interviews, the inventors were able to study subjects with FSAD in a highly specific manner, whereas previous studies included women with symptoms such as persistent or recurrent lack (or absence) of sexual fantasies and sexual desire. These are present in HSDD. However, additional criteria for diagnosing FSDs such as HSDD and FSAD must also be met, including significant distress or interpersonal difficulties caused by the disorder. In this study conducted by the inventors, participants were diagnosed through expert interviews according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised Version (DSM-IV-TR) for FSAD. Furthermore, participants at screening had to have a total score ≥18 on the Female Sexual Distress Scale - Libido / Arousal / Orgasm (FSDS-DAO) and a score ≥3 on FSDS-DAO-Item 14. A particular focus was on reporting sexually related distress as a clear and reliable indicator of clinical impact. High distress scores indicated that the subject indeed had FSAD and required treatment. Through extensive experimentation and analysis, the inventors unexpectedly discovered that estradiol components, such as estradiol, are effective in treating FSAD.

[0011] Therefore, the present invention is provided in the following aspects:

[0012] Aspect 1. A composition comprising about 14 mg to about 25 mg of estradiol component for the treatment of female sexual arousal disorder (FSAD), wherein preferably the composition is administered once daily.

[0013] Aspect 2. Use of the composition in the preparation of a medicament for treating FSAD, wherein the composition comprises about 14 mg to about 25 mg of estradiol component, and wherein preferably the composition is administered once daily.

[0014] Aspect 3. Use of a composition comprising an estradiol component for the treatment of FSAD, wherein the composition comprises about 14 mg to about 25 mg of the estradiol component, and wherein preferably the composition is administered once daily.

[0015] Aspect 4. A method of treating FSAD in subjects, wherein the method comprises the step of administering a composition containing about 14 mg to about 25 mg of estradiol once daily.

[0016] Aspect 5. The composition used according to aspect 1, the use according to aspect 2 or 3, or the method according to aspect 4, wherein the composition comprises about 15 to about 25 mg of estradiol component.

[0017] Aspect 6. The composition, use, or method of use according to any one of the preceding aspects, wherein the estradiol component is estradiol monohydrate.

[0018] Aspect 7. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition is formulated as an oral, sublingual, buccal, or sublipal dosing unit, preferably wherein the composition is formulated as an oral dosing unit (i.e., a dosing unit for oral ingestion).

[0019] Aspect 8. The composition, use or method of use according to any one of the preceding aspects, wherein the subject is a female subject who is menopausal, perimenopausal or postmenopausal.

[0020] Aspect 9. The composition, use, or method of use according to any one of the preceding aspects, wherein the subject is a subject who has undergone hysterectomy.

[0021] Aspect 10. The composition, use or method used according to the foregoing aspect, wherein the subject undergoing hysterectomy is a subject undergoing bilateral salpingo-oophorectomy (BSO).

[0022] Aspect 11. The composition, use, or method according to any one of the preceding aspects, characterized by an improvement in one or more of the following parameters after 12 weeks:

[0023] - The percentage of sexually distressed or satisfying sexual events (SSE) assessed by the total score of the Female Sexual Distress Scale-Sexual Desire / Arousal / Orgasm (FSDS-DAO) (preferably recorded in a sexual arousal diary);

[0024] - Sexual function is assessed using the total score of the Sexual Function Questionnaire-28 (SFQ-28);

[0025] - Assess sexual function and satisfaction through the Patient Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction Measurement (SexFS), or sexual function through the PROMIS SexFS-customized assessment;

[0026] - Patient overall change impression (PGIC) at week 12;

[0027] -Severity of sexual arousal disorder as assessed by the Patient Global Severity Impression (PGIS).

[0028] Aspect 12. The composition, use or method used according to any one of the preceding aspects, characterized by improved sexual arousal as assessed by FSDS-DAO item 14, preferably characterized by improved sexual arousal as assessed by FSDS-DAO item 14 after 12 weeks compared to baseline.

[0029] Aspect 13. The composition, use or method used according to the foregoing aspect, wherein, compared with the baseline, sexual arousal is improved by at least about 10% after 12 weeks, preferably at least about 25%, more preferably at least about 50% as assessed by FSDS-DAO item 14.

[0030] Aspect 14. The composition, use or method described in aspect 12, wherein, compared with baseline, the sexual arousal score is improved by at least 1 point, preferably at least 2 points, more preferably at least 3 points, and most preferably 4 points after 12 weeks as assessed by FSDS-DAO item 14.

[0031] Aspect 15. The composition, use or method used according to any one of the preceding aspects, characterized in that the percentage of satisfactory sexual events (SSE) is increased by at least about 10%, preferably at least about 20%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, more preferably at least about 90%, and most preferably at least about 100%.

[0032] Aspect 16. The composition, use or method used according to any one of the preceding aspects, characterized by improvement in the arousal-sensory field as assessed by SFQ-28 questions 6 to 9, preferably characterized by improvement in the arousal-sensory field after 12 weeks as assessed by SFQ-28 questions 6 to 9 compared to baseline.

[0033] Aspect 17. The composition, use or method used according to the foregoing aspect, wherein, compared with baseline, the arousal-sensory field is improved by at least about 10%, preferably at least about 25%, more preferably at least about 50% after 12 weeks as assessed by SFQ-28 questions 6 to 9.

[0034] Aspect 18. The composition, use, or method of use according to aspect 16, wherein the arousal-sensory domain, as evaluated by SFQ-28 questions 6 to 9, is improved by positive changes in the response to one or more of said questions 6 to 9, preferably wherein the arousal-sensory domain, as evaluated by SFQ-28, is improved by positive changes in the response to questions 6, 7, 8, 9, or any combination thereof.

[0035] Aspect 19. The composition, use or method of any of the preceding aspects, characterized by improvement in arousal and lubrication as assessed by the PROMIS Sexual Function and Satisfaction Measurement (SexFS) or PROMIS SexFS-Customized Assessment, preferably characterized by improvement in arousal and lubrication as assessed by PROMIS SexFS after 12 weeks compared to baseline.

[0036] Aspect 20. The composition, use or method used according to the foregoing aspect, wherein, compared with baseline, arousal and lubrication are improved by at least about 10%, preferably at least about 25%, more preferably at least about 50% after 12 weeks, as assessed by PROMIS SexFS or custom PROMIS SexFS.

[0037] Aspect 21. The composition, use, or method used according to any one of the preceding aspects, characterized by an improvement in arousal and lubrication as evaluated by PROMIS SexFS or PROMIS SexFS Custom Item IDs SFACT201, SFACT202, SFACT203, SFACT204, SFACT205, SFACT206, SFACT207, SFACT208, SFACT209, SFACT210, SFACT212, SFACT213, SFACT214, SFACT215, or any combination thereof.

[0038] Aspect 22. The composition, use, or method of use according to any one of the preceding aspects, characterized by an improvement in sexual arousal as assessed by the PGIC scale at week 12, preferably characterized by an improvement in sexual arousal as assessed by an improvement in sexual arousal on a 7-point Likert scale at week 12.

[0039] Aspect 23. The composition, use or method according to any one of the preceding aspects, characterized in that at week 12, the improvement in sexual arousal as expressed on a 7-point Likert scale is at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably 7 points.

[0040] Aspect 24. The composition, use or method according to any one of the preceding aspects, characterized in that the severity of sexual arousal dysfunction assessed by the PGIS scale is reduced, preferably the severity of sexual arousal dysfunction assessed on a 7-point Likert scale is reduced.

[0041] Aspect 25. The composition, use or method according to the foregoing aspect, characterized in that the severity of sexual arousal dysfunction as shown on the 7-point Likert scale is reduced by at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, more preferably 7 points.

[0042] Aspect 26. The composition, use, or method according to any one of the preceding aspects, wherein the subject has been diagnosed with FSAD, preferably wherein the subject has been diagnosed with FSAD according to the criteria for diagnosing FSAD in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised Edition (DSM IV-TR):

[0043] A. A persistent or recurrent inability to achieve or maintain adequate lubrication-swelling response for sexual arousal until sexual activity is completed;

[0044] B. The disorder causes significant distress or interpersonal difficulties;

[0045] C. Sexual dysfunction cannot be better explained by another type of Axis I disorder, and is not solely due to the direct physiological effects of substances or general medical conditions.

[0046] Aspect 27. The composition, use or method used according to the foregoing aspect, wherein standard C is understood to not exclude the diagnosis of sexual dysfunction when modifiable contributing factors and / or causes are identified.

[0047] Aspect 28. The composition, use or method used according to the foregoing aspect, wherein the modifiable contributing factor / cause is a physiological cause selected from menopause, menopausal urogenital syndrome (GSM) or a combination thereof.

[0048] Aspect 29. The composition, use or method used according to any one of the preceding aspects, wherein the subject is characterized by a total score of ≥18 on FSDS-DAO and a score of ≥3 on FSDS-DAO-Item 14 at the time of screening.

[0049] Aspect 30. The composition, use or method of use according to any one of the preceding aspects, wherein FSAD is female cognitive arousal disorder (FCAD) or female genital arousal disorder (FGAD).

[0050] Aspect 31. The composition, use, or method of any of the preceding aspects, wherein the subject is affected by at least one different female sexual disorder other than FSAD, preferably wherein the subject is affected by at least one different female sexual disorder other than FSAD, wherein the disorder is selected from: hyposexuality disorder (HSDD), female orgasmic disorder, and / or dyspareunia.

[0051] Aspect 32. The composition, use or method of any of the preceding aspects, wherein the subject is characterized by a recent decline in sexual function, preferably within the past year, more preferably within the past 6 months, and most preferably within the past 2 months.

[0052] Aspect 33. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition comprises about 15 mg to about 25 mg of estradiol component, and wherein the composition is administered once daily, preferably wherein the composition comprises about 15 mg to about 25 mg of estradiol monohydrate, and wherein the composition is administered once daily.

[0053] Aspect 34. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition comprises about 15 mg to about 20 mg of estradiol component, and the composition is administered once daily, preferably wherein the composition comprises about 15 mg to about 20 mg of estradiol monohydrate, and wherein the composition is administered once daily.

[0054] Aspect 35. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition comprises about 15 mg of estradiol component, and wherein the composition is administered once daily, preferably wherein the composition comprises about 15 mg of estradiol monohydrate, and wherein the composition is administered once daily.

[0055] Aspect 36. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition comprises about 20 mg of estradiol component, and wherein the composition is administered once daily, preferably wherein the composition comprises about 20 mg of estradiol monohydrate, and wherein the composition is administered once daily.

[0056] Aspect 37. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition further comprises a progestin-like component.

[0057] Aspect 38. The composition, use, or method of use according to aspect 37, wherein the progestin-like component is selected from: progesterone, drospirenone, norethindrone, norethindrone acetate (NETA), dydrogesterone, levonorgestrel (LNG), etogestene, norethindrone, nomegestrol, nomegestrol acetate (NOMAC), tramemone, nestorone, dydrogesterone, gestadienone, desogestrel, norgestrol acetate, cyproterone acetate, denrogesterone, and chlordrogesterone.

[0058] Aspect 39. The composition, use, or method of use according to aspect 37 or 38, wherein the progestin-like component is selected from drospirenone, progesterone, or dydrogesterone.

[0059] Aspect 40. The composition, use, or method of use according to any one of Aspects 37 to 39, wherein the progesterone-like component is drospirenone, preferably about 0.25 mg to about 10 mg of drospirenone, more preferably about 1 mg to about 4 mg of drospirenone, even more preferably about 3 mg of drospirenone, or wherein the progesterone-like component is administered in an amount equivalent to about 0.25 mg to about 10 mg of drospirenone, preferably in an amount equivalent to about 1 mg to about 4 mg of drospirenone, even more preferably in an amount equivalent to about 3 mg of drospirenone.

[0060] Aspect 41. The composition, use, or method of use according to any one of Aspects 37 to 39, wherein the progesterone-like component is progesterone, preferably about 25 mg to about 300 mg of progesterone, more preferably about 100 mg to about 200 mg of progesterone, or wherein the progesterone-like component is administered in an amount equivalent to about 25 mg to about 300 mg of progesterone, preferably in an amount equivalent to about 100 mg to about 200 mg.

[0061] Aspect 42. The composition, use or method of any one of Aspects 37 to 39, wherein the progesterone-like component is dydrogesterone, preferably about 1 mg to about 20 mg of dydrogesterone, more preferably about 5 mg to about 10 mg of dydrogesterone, or wherein the progesterone-like component is administered in an amount equivalent to about 1 mg to about 20 mg of dydrogesterone, preferably in an amount equivalent to about 5 mg to about 10 mg of dydrogesterone.

[0062] Aspect 43. The composition, use, or method of use according to any one of Aspects 1 to 36, wherein the composition further comprises bardoxifene.

[0063] Aspect 44. The composition, use, or method of use according to any one of Aspects 1 to 36, wherein the estradiol component is the single (i.e., the only) pharmaceutically active component in the composition.

[0064] Aspect 45. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition is formulated to correspond to a daily dose unit.

[0065] Aspect 46. The composition, use or method of use according to any one of the preceding aspects, wherein the composition is formulated to correspond to an oral dose unit, preferably an oral dose unit specifically formulated for oral ingestion.

[0066] Aspect 47. The composition, use, or method of use according to any one of the preceding aspects, wherein the composition is used in a multiple-dose regimen once daily.

[0067] Aspect 48. In any of the aspects defined herein, the dosage unit or composition may be present as a kit-of-parts containing a packaging unit (e.g., a blister pack) containing a daily oral dosage unit comprising the estradiol component. Those skilled in the art will also appreciate that, within the scope of this invention, each packaging unit (e.g., a blister pack) may be numbered or otherwise labeled.

[0068] Within the scope of this invention, each such packaging unit may be a sealed blister pack with cardboard, paperboard, aluminum foil plastic backing, and encapsulated in a suitable lid.

[0069] Bottles are also envisioned in any aspect of such packaging units as defined herein. The material of the bottle is not particularly limited. In a preferred embodiment, the bottle is a glass bottle, characterized by its ability to reduce or prevent the color degradation of the bottle's contents by, for example, UV light, while maintaining transparency that allows visual inspection of the bottle's contents. Suitable colors include, but are not limited to, amber, cobalt blue, or vintage green.

[0070] In a particular embodiment of the kit according to aspect 48, the packaging unit comprises 28 containers or more containers of 28, for example, 2 to 12 containers of 28.

[0071] The above and further aspects and preferred embodiments of the invention are described in the following sections and the appended claims. The subject matter of the appended claims is hereby specifically incorporated in this specification. Attached Figure Description

[0072] Figure 1Study timeline for a phase 2, randomized, double-blind, placebo-controlled proof-of-concept study (Example 1) evaluating the efficacy and safety of estradiol (E4) in postmenopausal subjects with female sexual arousal disorders. Dosage: once daily.

[0073] Figure 2 Frequency of vasomotor symptoms (VMS) (measured by the number of weekly hot flashes) in the 15 mg estradiol monohydrate, 20 mg estradiol monohydrate, and placebo treatment groups. Changes in weekly frequency of moderate to severe VMS from baseline to weeks 4 and 12 were statistically analyzed using an MMRM model; intention-to-treat (ITT) population; p-values ​​(differences in the mean LS) of changes relative to baseline between E4 treatment and placebo.

[0074] Figure 3 The proportion of subjects whose weekly frequency of moderate to severe VMS decreased by at least 50% or 75% relative to baseline over time; Efficacy Study Part—Intention-to-Treat (ITT) population; *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001.

[0075] Figure 4 VMS severity in the 15 mg estradiol monohydrate, 20 mg estradiol monohydrate, and placebo treatment groups. Weekly changes in severity of moderate to severe VMS from baseline to weeks 4 and 12 were statistically analyzed using an MMRM model according to FDA methods; intention-to-treat (ITT) population; p-values ​​(differences in mean LS values) of changes relative to baseline between E4 treatment and placebo. Detailed Implementation

[0076] As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include both singular and plural indicators.

[0077] As used herein, the terms “comprising,” “comprises,” and “compose of” are synonymous with “including,” “includes,” “containing,” and “contains,” and are inclusive or open-ended, not excluding additional, undescribed members, elements, or method steps. The terms also encompass “compose of” and “substantially composed of”, which have their generally accepted meanings in patent terminology.

[0078] The range of values ​​recorded by endpoints includes all numbers and fractions contained within their respective ranges, as well as the recorded endpoints. This applies to ranges of values ​​regardless of whether they are introduced by expressions such as “from…to…”, “between…and…”, or another expression.

[0079] As used herein, the term "about" or "approximately" when referring to a measurable value such as a parameter, quantity, or temporal duration, means encompassing variations in the specified value and variations relative to that specified value, such as + / - 10% or less, preferably + / - 5% or less, more preferably + / - 1% or less, and even more preferably + / - 0.1% or less, and these variations relative to the specified value, within which such variations are suitable for implementation in the disclosed invention. It should be understood that the values ​​referred to by the modifier "about" or "approximately" are themselves specifically and preferably disclosed.

[0080] Although the terms "one or more" or "at least one," such as one or more members or at least one member of a group of members, are self-evident through further examples, the term specifically covers references to any one of the members, or any two or more of the members, such as any ≥3, ≥4, ≥5, ≥6, or ≥7 of the members, and at most all of the members. In another example, "one or more" or "at least one" may refer to 1, 2, 3, 4, 5, 6, 7, or more.

[0081] This document includes a discussion of the background of the invention to explain the context of the invention. This should not be construed as an admission that any material mentioned is publicly available, known, or part of common general knowledge in any country up to the priority date of any claim.

[0082] Throughout this disclosure, various publications, patents, and published patent specifications are referenced by way of designation. All references cited in this specification are incorporated herein by reference in their entirety. In particular, the teachings or portions of such references specifically mentioned herein are incorporated herein by reference.

[0083] Unless otherwise defined, all terms used to disclose this invention, including technical and scientific terms, have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. Further guidance, including terminology definitions, is provided to better understand the teachings of this invention. When a particular term is defined in connection with a specific aspect or embodiment of the invention, such connotation or meaning is intended to apply throughout this specification, i.e., also in the context of other aspects or embodiments of the invention, unless otherwise defined. For example, embodiments relating to products also apply to corresponding features of methods and uses.

[0084] In the following paragraphs, different aspects or embodiments of the invention are defined in more detail. Each aspect or embodiment thus defined may be combined with any other aspect or embodiment unless the contrary is expressly indicated. In particular, any feature indicated as preferred or advantageous may be combined with one or more other features indicated as preferred or advantageous.

[0085] Throughout this specification, references to "an embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, particular features, structures, or characteristics may be combined in any suitable manner, as will be apparent to those skilled in the art based on this disclosure. Moreover, although some embodiments described herein include some features included in other embodiments but not others, combinations of features from different embodiments are intended to be within the scope of the invention and form different embodiments, as will be understood by those skilled in the art. For example, alternative combinations of the claimed embodiments are covered in the appended claims, as will be understood by those skilled in the art.

[0086] Unless otherwise stated, all methods, steps, techniques, and operations not specifically described in detail may be performed in a manner known per se and have been performed in a manner known per se, as is clear to those skilled in the art. For example, refer again to the standards manual and the general background techniques and other references cited herein.

[0087] In view of the unexpected discoveries made by the inventors and described in detail in the Examples section, a first aspect of the present invention relates to the use of an estradiol component for the treatment and / or prevention of female sexual arousal disorder (FSAD). Therefore, the present invention also covers the use of compositions in the manufacture of medicaments for treating FSAD, wherein the compositions comprise about 14 mg to about 25 mg of an estradiol component, and further covers the use of compositions comprising an estradiol component for the treatment of FSAD, wherein the compositions comprise about 14 mg to about 25 mg of an estradiol component. Therefore, the present invention covers methods for treating FSAD in a subject, wherein the method includes the step of administering a composition comprising about 14 mg to about 25 mg of an estradiol component.

[0088] As used throughout this document, the term "estradiol component" encompasses substances selected from: estradiol, estradiol esters, estradiol esters (where at least one hydrogen atom of a hydroxyl group is substituted with an acyl group of a hydrocarbon carboxylic acid, sulfonic acid, or aminosulfonic acid of 1-25 carbon atoms), estradiol hydrates (e.g., estradiol monohydrate); and combinations thereof. It should be understood that when estradiol is mentioned in any part of this specification, any estradiol-containing component (i.e., compound) and / or estradiol derivative (e.g., estradiol ester) is also contemplated. More preferably, in the context of this disclosure, particularly preferred estradiol components suitable for the dosage units, medical uses, and treatment methods described herein are estradiol (including estradiol hydrate). Most preferably, the estradiol component is estradiol monohydrate.

[0089] As used herein, the term "estradiol" refers to 1,3,5 (10)-esttrien-3,15α,16α,17β-tetraol or 15α-hydroxyestriol, as well as hydrates of estradiol, such as estradiol monohydrate. "Estradiol," or simply "E4," is an estrogenous steroid produced by the fetal human liver (PubChem CID: 27125). Estradiol can be described as a 3-hydroxy steroid corresponding to 17β-estradiol, wherein the 15α and 16α positions are replaced by two additional hydroxyl groups. Estradiol is known to be an estrogen receptor agonist (Coelingh Bennink et al., Climacteric, 2008). Estradiol can be chemically synthesized, synthesized using (mutant) recombinases, or synthesized by any combination thereof. Therefore, it is clear that the terms "estradiol" and "estradiol component" also encompass estradiol with further chemical modifications. In the art, estradiol can be derived from its molecular formula: C 18 H 24 O4 can be represented by the structural formula (I).

[0090] Formula (I)

[0091]

[0092] In a preferred embodiment, the estradiol component is estradiol or an ester thereof. In a further embodiment, the estradiol component is estradiol monohydrate. Those skilled in the art will understand that estradiol monohydrate corresponds to estradiol containing one molecule of water, and that the core structural formula of estradiol is no different from that of formula (I). By way of illustration and not limitation, the structural formula of estradiol monohydrate is represented by formula (II):

[0093] Equation (II)

[0094]

[0095] In the current context, female subjects are preferred subjects. As used herein, the terms “subject” or “patient” refer to female human subjects, preferably perimenopausal and / or postmenopausal female subjects. Female subjects envisioned herein may be subjects who need or are believed to need treatment to alleviate symptoms of estrogen deficiency (e.g., menopausal symptoms, which may include sexual arousal disorders such as FSAD), or subjects who are predicted to need such treatment at a foreseeable future time due to, for example, entering the perimenopausal stage of life.

[0096] The medical condition involved in this invention is female sexual arousal disorder (FSAD). FSAD is characterized by the inability to achieve or maintain sexual arousal until sexual activity is completed. As shown in the background section, according to DSM IV-TR, FSAD is diagnosed when the following three criteria are met:

[0097] A. A persistent or recurrent inability to achieve or maintain adequate lubrication-swelling response for sexual arousal until completion of sexual activity.

[0098] B. This disorder causes significant distress or difficulty in interpersonal communication.

[0099] C. Sexual dysfunction cannot be better explained by another axis disorder (mental health and substance use disorder (SUD)) in addition to another sexual dysfunction, and is not solely caused by the direct physiological effects of substances (e.g., drug abuse, medication) or general medical conditions.

[0100] Therefore, in the current context, particularly preferred subjects are those diagnosed with FSAD, and more preferably those diagnosed with FSAD according to the three criteria of DSM IV-TR (A, B, and C) described above. Those skilled in the art will understand that criterion C, as shown above, does not exclude a diagnosis of sexual dysfunction when modifiable contributing factors and / or causes are identified or present in the subject. Optionally, the modifiable contributing factors and / or causes are physiological factors and / or physiological causes. Optionally, the modifiable contributing factors and / or causes are selected from menopause, menopausal urogenital syndrome (GSM), or combinations thereof. "Menopausal urogenital syndrome" and its abbreviation "GSM" are well-known conditions to those skilled in the art and have been described in detail in the art (e.g., in Portman et al., Menopause, 2014, 10.1097 / GME.0000000000000329). Briefly, GSM refers to a group of undesirable effects that may result from thinning of the epithelial lining of the vagina and urethra due to estrogen deficiency. These effects include, but are not limited to, vulvovaginal atrophy (VVA) and urinary disorders, symptoms of vaginal dryness, itching, dyspareunia, dysuria, urinary frequency, and (optionally) an increased risk of recurrent urinary tract infections.

[0101] Those skilled in the art will understand that sexual arousal is distinctly different from related concepts such as libido. In fact, sexual arousal is an indication of a physiological response to sexual stimulation, while libido describes a baseline level of interest in sexual activity. The physiological aspects of female sexual arousal are complex but can be summarized as follows: During arousal, the Bartholin's glands located on either side of the vaginal opening produce mucus intended to lubricate the area for greater comfort during intercourse. Additionally, increased blood flow to the genitals leads to genital swelling. Furthermore, there is an increase in heart rate, respiratory rate, and blood pressure. Additionally, vasocongestion results in a flushing sensation that subsides after orgasm (Calabrò et al., Brain Behav, 2019, DOI: 10.1002 / brb3.1389).

[0102] Several subtypes of FSAD have been described in the art, and each subtype is contemplated in the context of this specification. FSAD subtypes can be classified according to different parameters (e.g., but not limited to onset and / or context). Thus, optionally, FSAD is lifelong FSAD. Preferably, FSAD can be acquired FSAD. Optionally, FSAD can be generalized FSAD. Alternatively, FSAD can be situational FSAD (e.g., partner-specific). The duration of FSAD presence in a subject and the degree to which it is partner- or situation-specific (as opposed to inherent universality) may be the result of different causative factors. Causative factors are not limiting to the invention.

[0103] As used in this article, the term "FSAD" encompasses subtypes such as, but not limited to, female cognitive arousal disorder (FCAD) and female genital arousal disorder (FGAD).

[0104] Female genital arousal disorder (FGAD) is characterized by painful difficulty or inability to achieve or maintain adequate genital responses, including vulvovaginal lubrication, genital engorgement, and sexually active genital sensitivity lasting ≥6 months. The causes of this disorder are associated with (i) vascular injury or dysfunction and (ii) nerve injury or dysfunction. Arousal may be associated with non-genital responses such as nipple hardening and erection, skin flushing, increased heart rate, blood pressure, and respiratory rate. FGAD should not be diagnosed if the problem with genital arousal is due to insufficient stimulation. Before making a diagnosis of FGAD, vulvovaginal conditions such as vulvar or vaginal atrophy, infectious or inflammatory disorders, vestibular pain, and clitoral pain should be ruled out (Parish et al., JSex Med, 2016, 10.1016 / j.jsxm.2016.09.020). FGAD can manifest as mild, moderate, or severe distress of symptoms, which may vary over time (American Psychological Association, DSM-5, 2013; Watters and Bagby, Psychol Assess, 2018, DOI: 10.1037 / pas0000605). FGAD is typically acquired and pervasive (present in all cases and in all couples).

[0105] FCAD is characterized by distress over the inability to achieve or maintain sufficient mental arousal associated with sexual activity, manifested as a persistent problem with feeling engaged, mentally aroused, or sexually excited for ≥6 months. FCAD may be lifelong or acquired after a period of normal functioning and may be situational (occurring only in specific situations or with specific partners) or pervasive. FCAD can present as mild, moderate, or severe distress with symptoms, which may vary over time (American Psychological Association, DSM-5, 2013; Watters and Bagby, Psychol Assess, 2018, DOI:10.1037 / pas0000605).

[0106] Women can experience FCAD and FGAD independently or in various combinations.

[0107] The aforementioned lubrication-swelling response is medically distinct from a condition known as "dyspareunia," which is an indication for painful sexual activity that can be caused by a variety of factors, including vulvar pain, postpartum dyspareunia, endometriosis, insufficient vaginal lubrication or arousal, and / or anogenital causes (such as anal fissures or hemorrhoids). Therefore, dyspareunia may result from insufficient lubrication or arousal, but it should not be used as a synonym for or interchangeably with FSAD.

[0108] Therefore, in a highly preferred embodiment, the subject (or multiple subjects) is diagnosed with FSAD. This diagnosis can be made through one or more self-report questionnaires, by a medical practitioner, or a combination thereof.

[0109] It should be understood that, in the context of this document, a subject may be diagnosed with or presumed to have FSAD, but may also be diagnosed with or presumed to have FSAD and at least one or more different female sexual disorders. Preferably, the at least one or more different female sexual disorders are selected from: hyposexuality disorder (HSDD), female orgasmic disorder (FOD), and / or dyspareunia.

[0110] In the DSM-IV-TR, HSDD is defined by the single symptom criterion of "persistent or recurrent lack (or absence) of sexual fantasies and desires for sexual activity" leading to "significant distress or difficulty in interpersonal relationships" (Brotto, Arch Sex Behav, 2010, DOI: 10.1007 / s10508-009-9543-1).

[0111] FOD is defined in DSM-IV by the following diagnostic criteria:

[0112] A. Orgasm is persistently or repeatedly delayed or absent after the normal phase of sexual arousal. Women exhibit wide variability in the type or intensity of stimulation that triggers orgasm. The diagnosis of female orgasmic disorder should be based on the clinician's judgment that the woman's orgasmic capacity is below a reasonable level for her age, sexual experience, and whether the sexual stimulation she receives is adequate.

[0113] B. This disorder causes significant distress or difficulties in interpersonal communication.

[0114] C. Orgasmic dysfunction cannot be better explained by another Axis I disorder (other than another sexual dysfunction) and is not solely due to the direct physiological effects of substances (e.g., drug abuse, medication) or general medical conditions (Graham, Arch Sex Behav, 2010, DOI: 10.1007 / s10508-009-9542-2).

[0115] Dyspareunia is defined in the DSM-IV-TR by the following diagnostic criteria:

[0116] A. Recurrent or persistent genital pain in men or women related to sexual intercourse.

[0117] B. This disorder causes significant distress or difficulties in interpersonal relationships.

[0118] C. This disorder is not caused by vaginismus or insufficient lubrication, nor can it be better explained by another Axis I disorder (other than another sexual dysfunction), and it is not solely due to the direct physiological effects of substances (e.g., drug abuse, medication) or general medical conditions (Binik, Arch Sex Behav, 2010, 10.1007 / s10508-009-9563-x).

[0119] The term "treatment" or "treat" should be interpreted as therapeutic treatment of an already developed symptom, disease, or condition, resulting in (clinical) manifestations, as well as preventative or preventive measures where the goal of treatment is to prevent, alleviate, or reduce the likelihood of undesirable suffering, such as preventing the occurrence, development, and progression of menopausal symptoms, (clinical) conditions. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction of one or more symptoms, improvement of one or more biomarkers associated with FSAD, reduction in the severity of FSAD symptoms (i.e., a decrease in the degree of severity), stabilization of FSAD symptoms (i.e., no worsening), and delay or slowing of the manifestation of FSAD disease symptoms.

[0120] As used in the context of this invention, "prevention" or "prevent" refers to preventing the manifestation of symptoms or disease in a subject, i.e., establishing preventive measures or preventative actions. Preventive treatment refers to treatment in which the aim is to prevent the subject's body or its elements from exhibiting symptoms (worsening of symptoms) of undesirable physiological or psychological changes. As used herein, the term "prevention" includes both preventing the occurrence of symptoms and preventing the worsening of symptoms.

[0121] As used herein, the terms “therapeutic treatment” or “treatment” refer to treatment in which the aim is to change a subject’s body or a part of the subject’s body from an undesirable physiological state, an age-related disease or disorder, to a desired state, such as a less severe state (e.g., improvement, or even return to its normal state of health (e.g., restoration of the subject’s health, bodily integrity, and physical well-being)) to maintain (i.e., not worsen) the undesirable physiological state (e.g., stability) or slow its progression to a state that is more severe or worse than the undesirable physiological change or disorder). Measurable reduction includes any statistically significant decrease in a measurable marker or symptom. As used herein, statistical significance means a p-value less than 0.05, which is the cutoff score generally accepted in statistical analysis as understood by a person skilled in the art.

[0122] In embodiments, the subject may be a subject with a hormonal imbalance. In the context of this invention, an imbalance is determined or established by comparing the subject's hormone levels to representative values ​​of adult, healthy female subjects. The cause of the hormonal imbalance is particularly limited in this disclosure and may be a natural cause (e.g., menopausal hormonal changes), but can also be caused by a pathological condition or deficiency. In some embodiments, the hormonal imbalance is an estrogen imbalance, such as a 17β-estradiol imbalance. In such embodiments, the 17β-estradiol level differs from the representative 17β-estradiol level of an adult female subject by at least about 15%, preferably at least about 25%, more preferably at least about 50%. In cases where the female subject has reduced endogenous estrogen production, the subject may be considered to have estrogen deficiency syndrome.

[0123] "17β-estradiol" refers to (17β)-estradiol-1,3,5(10)-trien-3,17-diol, and can be interchanged with the terms "estradiol," "estradiol," or "E2," and is an endogenously produced estrogen in the human body. More specifically, estradiol is the primary estrogen produced by the human ovary during the first half of the menstrual cycle (i.e., the follicular phase). Estradiol also participates in maintaining bone density, alleviating vasomotor symptoms, and maintaining the normal structure of female reproductive organs in postmenopausal subjects.

[0124] This invention envisions implementation schemes involving subjects characterized by estrogen depletion (i.e., estrogen deficiency or estrogen insufficiency syndrome). While this invention primarily relates to the treatment and / or prevention of FSAD symptoms in a menopausal context, those skilled in the art will understand that FSAD and FSAD symptoms can also exist in female subjects with medical conditions (which are non-menopausal but still cause similar or even the same set of symptoms). Therefore, in the context of this invention, the exact cause of FSAD in the subject is not particularly limited and can therefore be caused by non-limiting reasons such as: menopause, hypogonadism, castration, primary ovarian failure, aromatase inhibitors, treatment with gonadotropin-releasing hormone agonists, gonadotropin-releasing hormone analogue breast cancer treatment, and / or treatment with selective estrogen receptor modulators (e.g., tamoxifen, raloxifene, bardoxifen, bisphosphonates).

[0125] In some embodiments, the subjects are postmenopausal, perimenopausal, or postmenopausal women. In some embodiments, the subjects are postmenopausal, perimenopausal, or postmenopausal women with 17β-estradiol levels below about 100 pg / ml, preferably below about 50 pg / ml, more preferably below about 30 pg / ml, more preferably below about 20 pg / ml, and most preferably below about 10 pg / ml. In alternative embodiments, the subjects are postmenopausal, perimenopausal, or postmenopausal women, characterized by a follicle-stimulating hormone (FSH) concentration of at least about 20 mIU / ml, preferably at least about 25 mlU / ml, more preferably at least about 30 mlU / ml, more preferably at least about 35 mlU / ml, and most preferably at least about 40 mlU / ml.

[0126] In this field, a “menopausal subject” is a female subject who has not experienced menstrual bleeding for one year, which is accompanied by a decrease or cessation of hormones produced by the ovaries (e.g., 17β-estradiol).

[0127] According to the US FDA, the criteria for postmenopausal status are as follows:

[0128] • Spontaneous amenorrhea for at least 12 months; or

[0129] • Spontaneous amenorrhea for at least 6 months, serum FSH level >40 mIU / mL; or

[0130] • At least 6 weeks after bilateral oophorectomy (with or without hysterectomy).

[0131] Alternatively, the term "menopause" can be used to describe a biological condition characterized by impaired or ceased primary ovarian function. Menopause may be accompanied by a wide range of clinical symptoms of varying severity, such as, but not limited to, vasomotor dysfunction, vaginal dryness, mood changes, sleep disturbances, insomnia, urinary incontinence, cognitive changes, physical malaise, and sexual dysfunction. Methods for diagnosing menopause have been described in the art and are therefore known to those skilled in the art (Nelson, Menopause, Lancet, 2008).

[0132] The term "perimenopause" refers to the period of life that begins approximately three to four years before menopause and ends one year after the last menstrual period, characterized by persistent irregular menstrual cycles, extreme fluctuations in hormone levels, frequent anovulation, and the presence of vasomotor symptoms (Harlow et al., Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging, Menopause, 2012). The term "postmenopause" or "postmenopausal" indicates a female subject characterized by the permanent cessation of menstruation. This permanent cessation is retrospectively determined after observing 12 months of amenorrhea without any other apparent pathological or physiological cause. The term "postmenopause" also includes menopause as a result of premature ovarian failure, surgery (e.g., oophorectomy), chemotherapy or radiation therapy for cancer, and certain conditions (e.g., infection or hypothyroidism).

[0133] Therefore, in the context of this invention, female subjects are menopausal, perimenopausal, or postmenopausal subjects.

[0134] Preferably, the subject is an adult female subject. More preferably, the subject is a middle-aged or elderly female subject. Even more preferably, the subject is a female subject who is at least about 40 years old, preferably at least about 50 years old, preferably at least about 55 years old, more preferably at least about 60 years old, and more preferably at least about 65 years old. Alternatively, the subject may be a female subject who is between about 40 and about 90 years old, preferably between about 45 and about 85 years old, preferably between about 50 and about 80 years old, more preferably between about 55 and about 75 years old, more preferably between about 60 and about 70 years old, or between about 65 and about 75 years old. In some embodiments, the female subject is at most about 90 years old, preferably at most about 85 years old, more preferably at most about 80 years old, more preferably at most about 75 years old, more preferably at most about 70 years old, more preferably at most about 65 years old, and more preferably at most about 60 years old.

[0135] The subject can be a non-hysterectomized subject or a hysterectomized subject. Optionally, the subject is a hysterectomized subject. Thus, in some embodiments, the subject is a non-hysterectomized postmenopausal subject. In alternative embodiments, the subject is a hysterectomized postmenopausal subject. "Hysterectomy" in this context means that the subject no longer has a uterus due to surgical removal of the uterus (hysterectomy). A hysterectomy can be a partial hysterectomy or a total hysterectomy. Typically, a total hysterectomy involves complete (or nearly complete) removal of the uterus and cervix, while a partial hysterectomy means complete (or nearly complete) removal of the uterus, leaving a portion of the cervix (i.e., a cervical stump).

[0136] Subjects may be those who have undergone surgery to remove one or both ovaries (oophorectomy). Removal of the female gonads (ovaries) is interchangeably referred to in this field as female castration. Women who have undergone a total hysterectomy (bilateral salpingo-oophorectomy, i.e., castration) lose most of their hormone production, including estrogen and progesterone.

[0137] In some implementations, the subject is characterized by a decline in sexual function. Optionally, the decline in sexual function is recent, such as within the past 6 months, preferably the most recent 4 months, more preferably the most recent 3 months, and most preferably the most recent 2 months.

[0138] "Diagnosis," "diagnosis," and diagnostic indications are processes that identify, determine, or summarize a disease, condition, or (adverse side effect) in a subject based on symptoms and signs and / or the results of various diagnostic procedures (e.g., the presence, absence, and / or number of one or more biomarkers or clinical (pre) symptoms known to be characteristic of the diagnosed disease or condition).

[0139] "Effective dose of a drug" refers to the amount necessary to achieve a physiological effect and can indicate the effective dose for treatment and / or prevention. Physiological effects can be achieved through a single dose or through multiple doses.

[0140] "Therapeutic effective dose" or "therapeutic effective amount" indicates the amount of estradiol component that elicits a clinically positive response when administered to a subject suffering from (optionally menopausal-related) FSAD.

[0141] Preferably, the compositions described herein comprise a daily dose of estradiol, such as a daily dose of about 14 mg to about 25 mg of estradiol, preferably about 15 mg to about 25 mg of estradiol, or used in a manner in which the daily dose of estradiol received by the subject is about 14 mg to about 25 mg of estradiol, preferably about 15 mg to about 25 mg of estradiol. More specifically, the compositions described herein comprise a daily dose of estradiol selected from estradiol, estradiol esters, estradiol monohydrate, or any combination thereof, such as a daily dose of about 14 mg to about 25 mg of estradiol, estradiol esters, or estradiol monohydrate, or used in a manner in which the daily dose of estradiol, estradiol esters, or estradiol monohydrate received by the subject is about 14 mg to about 25 mg of estradiol, estradiol esters, or estradiol monohydrate. More specifically, the compositions described herein comprise a daily dose of estradiol component selected from estradiol, estradiol monohydrate, or any combination thereof, such as a daily dose of about 14 mg to about 25 mg of estradiol, estradiol ester, or estradiol monohydrate, or used in a manner in which the daily dose of estradiol, estradiol ester, or estradiol monohydrate received by the subject is about 14 mg to about 25 mg of estradiol, estradiol ester, or estradiol monohydrate.

[0142] More preferably, the composition described herein comprises a daily dose of estradiol, such as a daily dose of about 14 mg to about 15 mg of estradiol, more preferably a daily dose of about 14 mg to 14.5 mg of estradiol, and more preferably a daily dose of about 14.2 mg of estradiol.

[0143] More preferably, the compositions described herein comprise a daily dose of estradiol, such as a daily dose of about 18 mg to about 20 mg of estradiol, more preferably a daily dose of about 18.5 mg to 19.5 mg of estradiol, and more preferably a daily dose of about 18.9 mg of estradiol.

[0144] The term "daily" indicates that the listed amounts are the cumulative amount administered to the subject daily. Those skilled in the art will understand that if the estradiol component is administered only once daily (i.e., once daily), the amount of estrogen administered in that single administration will be the daily dose. Alternatively, those skilled in the art will understand that if the estradiol component is administered more than once daily (e.g., two or three times), the daily dose will correspond to the sum of the estradiol components administered during each administration event within a total time window of approximately 24 hours. In embodiments where the composition comprises different estradiol components (e.g., estradiol monohydrate and estradiol ester), the amount of estradiol corresponding to each estradiol component is verified to be within the capabilities of a person skilled in the art. Preferred embodiments in the context of this invention include administration of a single estradiol component, such as, but not limited to, estradiol monohydrate. Alternatively, the composition may be administered to the subject in a multiple-dose regimen once daily.

[0145] Those skilled in the art will recognize that terms such as “quantity,” “amount,” and “level” are synonyms and have well-defined meanings in the field. As used herein, terms may specifically refer to the absolute quantification of molecules, such as steroids, in a subject (from a sample taken from the subject), or the relative quantification of molecules or analytes in a sample, i.e., relative to another value, such as relative to a reference value taught herein, or a range of values ​​indicating a baseline for a parameter. These values ​​or ranges of values ​​may be obtained from a single subject or from a group of subjects (i.e., at least two subjects).

[0146] In any of the embodiments described herein, an improvement in FSAD is obtained after a period of time following administration of the composition to the subject, for example, after 12 weeks of administration. In a preferred embodiment, the improvement in FSAD is characterized by an improvement in one or more of the following parameters after 12 weeks:

[0147] - The percentage of satisfying sexual events (SSE) recorded in the sexual distress or sexual arousal diary, as assessed by the total score of the Female Sexual Distress Scale-Sexual Desire / Arousal / Orgasm (FSDS-DAO).

[0148] - Sexual function is assessed using the total score of the Sexual Function Questionnaire-28 (SFQ-28);

[0149] -Customized assessment of sexual function via the Patient Reported Outcomes Measurement Information System (PROMIS);

[0150] - Patient overall change impression (PGIC) at week 12;

[0151] -Severity of sexual arousal disorder as assessed by the Patient Global Severity Impression (PGIS).

[0152] The terms “sexual arousal diary” and “sex event diary (SED)” are used interchangeably in this article.

[0153] The terms FSDS-DAO, SFQ-28, PROMIS, PGIC, and PGIS are known to those skilled in the art. The Female Sexual Distress Scale-Revised (FSDS-R) is a 13-item distress scale that has historically been used as a measure of distress in most clinical trials treating female sexual disorders. Recently, this questionnaire has been further revised to include items specific to arousal and orgasm as clinical endpoints. This further revision is the FSDS-DAO (Sexual Desire, Arousal, Orgasm) questionnaire, which includes questions specifically designed to measure distress levels associated with female orgasmic disorders (Derogatis et al., J Patient RepOutcomes, 2021, DOI: 10.1186 / s41687-021-00359-1). Sexual Event Diaries (SEDs) are used to record satisfying sexual events (SSEs). Similarly, the Sexual Function Questionnaire (SFQ) and the later Simplified Iterative Sexual Function Questionnaire 28 (SQF-28) were developed to assess female sexual function. Notably, the SFQ can assess subtypes of arousal, such as arousal-lubrication and arousal-sensory, which is valuable for diagnosing FSAD. The SFQ-28 provides a specific assessment of sexual function (Symonds et al., J SexMed., 2023, DOI: 10.1093 / jsxmed / qdac04). The Patient Reported Outcomes Measurement Information System (PROMIS) is a set of person-centered measurements that assess and monitor the physical, mental, and social health of subjects (Bevans et al., NursOutlook, 2015, DOI: 10.1016 / j.outlook.2014.05.009). It can be used in the general population and in individuals with chronic conditions. The Patient Overall Change Impression (PGIC) is a single, self-administered question that asks subjects to assess how their condition has changed since a point in time. Similarly, the Patient Overall Severity Impression (PGIS) is a single, self-administered question that asks subjects to assess the severity of their condition at a given point in time.

[0154] In a specific implementation, treatment with the estradiol component results in an improvement in sexual arousal compared to baseline, as assessed by FSDS-DAO item 14 (“Concern about sexual arousal difficulties”). Preferably, this improvement is assessed 2 weeks after application of the composition, preferably 4 weeks, preferably 6 weeks, preferably 8 weeks, preferably 10 weeks, and most preferably 12 weeks later. Optionally, the improvement in sexual arousal (as assessed by FSDS-DAO item 14) in the subject or group of subjects compared to baseline is improved by at least about 10%, preferably at least about 15%, preferably at least about 20%, preferably at least about 25%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, and preferably at least about 90%. Optionally, the score of sexual arousal as assessed by FSDS-DAO item 14 improves by at least 1, preferably at least 2, more preferably at least 3, and most preferably 4, after 12 weeks compared to baseline.

[0155] In a specific implementation, when compared with baseline, treatment with the estradiol component results in an improvement in sexual arousal, such as by an increase in the percentage of satisfactory sexual events (SSE) of at least about 10%, preferably at least about 15%, preferably at least about 20%, preferably at least about 25%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, more preferably at least about 90%, and most preferably at least about 100% as assessed.

[0156] In a specific implementation, when compared to baseline, treatment with the estradiol component results in an improvement in the arousal-sensory domain, preferably as assessed by SFQ-28 questions 6 to 9 (frequency of warmth during sexual activity; intensity of warmth during sexual activity; frequency of pulsation during sexual activity; intensity of pulsation during sexual activity). Preferably, when compared to baseline, the improvement is assessed 2 weeks after application of the composition, preferably 4 weeks, preferably 6 weeks, preferably 8 weeks, preferably 10 weeks, and most preferably 12 weeks later. Optionally, when compared to baseline, the improvement in the arousal-sensory domain in the subject or the subject's group, as preferably assessed by SFQ-28 questions 6 to 9, is at least about 10%, preferably at least about 15%, preferably at least about 20%, preferably at least about 25%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, preferably at least about 90%. Optionally, improvements in the arousal-sensory domain assessed by SFQ-28 questions 6 to 9 are achieved through positive changes in the response to one or more of said questions 6 to 9. Preferably, improvements in the arousal-sensory domain assessed by SFQ-28 are achieved through positive changes in the response to questions 6, 7, 8, 9, or any combination thereof.

[0157] In a specific implementation, treatment with the estradiol component results in improved sexual arousal and lubrication compared to baseline, as assessed by the PROMIS Sexual Function and Satisfaction Measure (SexFS). Preferably, the improvement is assessed 2 weeks after application of the composition, preferably 4 weeks, preferably 6 weeks, preferably 8 weeks, preferably 10 weeks, and most preferably 12 weeks after baseline. Optionally, the improvement in PROMIS SexFS in the subject or group of subjects is improved by at least about 10%, preferably at least about 15%, preferably at least about 20%, preferably at least about 25%, preferably at least about 30%, preferably at least about 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, preferably at least about 80%, preferably at least about 90% compared to baseline. Optionally, the improved arousal and lubrication (as assessed by PROMIS...) The SexFS assessment is derived from the subject's improvement response to the following item IDs: SFACT201 (How often do you and your partner spend time romantically cuddling or hugging each other?), SFACT202 (How often do you and your partner romantically kiss each other?), SFACT203 (How often do you touch your partner's breasts, nipples, or genitals?), SFACT204 (How often does your partner touch your breasts, nipples, or genitals?), SFACT205 (How often do you touch your partner's genitals?), SFACT206 (How often does your partner touch your genitals?), SFACT207 (How often do you perform oral sex on your partner?), SFACT208 SFACT209 (How often do you insert your fingers, dildo, or other sex toys into your partner's vagina?), SFACT210 (How often do you insert your fingers, dildo, or other sex toys into your vagina?), SFACT212 (How often do you have vaginal intercourse (your partner inserts his penis into your vagina)?), SFACT213 (How often do you masturbate (touch yourself) when you are with your partner?), SFACT214 (How often do you masturbate (touch yourself) when you are alone?), SFACT215 (How often do you have anal intercourse?), or any combination thereof, which are considered preferred within a 30-day timeframe.

[0158] It should be understood that when "when compared to baseline" is mentioned throughout the specification, the "baseline" refers to a point in time prior to the initiation of treatment, which is the subject of this invention. At the baseline, according to a preferred embodiment, FSAD is diagnosed by an expert, preferably according to DSM-IV-TR, and at screening, the total score of FSDS-DAO is ≥18, and the score of FSDS-DAO item 14 is ≥3. Thus, in some embodiments, the baseline is a point in time prior to the initiation of treatment where the subject has not undergone treatment with the composition of the present invention. Alternatively, in some embodiments, the baseline is a point in time prior to the initiation of treatment where the subject has not been treated with any means or products containing hormones such as estrogen or progestins. In yet another alternative embodiment, the baseline is a point in time prior to the initiation of treatment where the subject has not been treated with any means or products containing estrogen. In yet another alternative embodiment, the baseline is a point in time prior to the initiation of treatment where the subject has not been treated with any means or products containing estradiol components.

[0159] In a specific implementation, treatment with the estradiol component results in improved sexual arousal, as assessed by the PGIC scale. Preferably, treatment with the estradiol component results in improved sexual arousal, as assessed by improvement in sexual arousal on a 7-point Likert PGIC scale at week 12. More preferably, the improvement in sexual arousal at week 12 is assessed by an improvement of at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, and more preferably 7 points, as shown on the 7-point Likert PGIC scale.

[0160] In a specific implementation, treatment with the estradiol component results in a reduction in the severity of sexual arousal dysfunction, as assessed by the PGIS scale. Preferably, treatment with the estradiol component results in a reduction in the severity of sexual arousal dysfunction, as assessed on a 7-point Likert PGIS scale. More preferably, the reduction in the severity of sexual arousal dysfunction indicated on the 7-point Likert PGIS scale is at least 1 point, preferably at least 2 points, preferably at least 3 points, preferably at least 4 points, preferably at least 5 points, preferably at least 6 points, and more preferably 7 points.

[0161] As detailed above, the improvements induced by the compositions, uses, or methods described herein are particularly prevalent in subjects diagnosed with FSAD. Therefore, in the context of this invention, particularly preferred subjects are those characterized by a total score of at least 18, preferably greater than 18, on the FSDS-DAO questionnaire at screening (i.e., prior to application of the composition subject of this invention). Further particularly preferred subjects in the context of this invention are those characterized by a total score of at least 3, preferably greater than 3, on FSDS-DAO item 14 at screening (i.e., prior to application of the composition subject of this invention). Highly preferred subjects in the context of this invention are those characterized by a total score of at least 18 on the FSDS-DAO questionnaire at screening and a total score of at least 3 on FSDS-DAO item 14 at screening.

[0162] The compositions of the present invention are particularly suitable for formulation into oral dosing units, as demonstrated by the examples appended herein. Preferably, the oral dosing units used according to the invention are swallowed, i.e., ingested and passed through the subject's digestive system. Or in other words, the dosing units described herein are administered orally, i.e., the dosing units are used by oral ingestion. More preferably, the oral dosing units used according to the invention are swallowed as a whole without remaining in the oral cavity for any time longer than required for swallowing. However, in alternative embodiments, dosing units formulated for alternative administration methods are also contemplated, such as, but not limited to, sublingual, buccal, or sublipal dosing units. These are intended to bypass the first-pass effect, which occurs when a drug is metabolized at a specific site in the body, resulting in a reduced concentration of the active drug upon reaching its site of action or systemic circulation. The first-pass effect is generally associated with the liver, as it is the primary site of drug metabolism. However, the first-pass effect can also occur in the lungs, vascular system, gastrointestinal tract, and other metabolically active tissues in the body. Therefore, according to the invention, sublingual, buccal, or sublipal dosing units differ from oral dosing units.

[0163] The term "dosage unit," used interchangeably with "dosage form" herein and in the art, refers to a physical formulation suitable for administration to a subject without prior adjustment of the pharmaceutical product (i.e., the ultimately beneficial product) prior to administration. Thus, a dosage unit signifies a composition that can be administered immediately. This term does not limit any other details of treatment, such as frequency of administration and / or any characteristics of the dosage unit (taste, appearance, size, etc.). "Oral dosage unit" encompasses any dosage unit intended and / or suitable for administration to a subject via the mouth. The (immediate or near-immediate) ingestion of the dosage unit is envisioned, but is not limited to the oral dosage units of the present invention, as further detailed below. The composition or dosage unit may be administered once daily or a specified number of times over a 24-hour period. In some embodiments, the oral dosage unit is specifically formulated for administration by ingestion. Therefore, as used herein, "oral dosage unit" refers to a dosage unit administered orally.

[0164] In the context of this invention, each dosage unit preferably comprises about 14 mg to about 25 mg, preferably about 15 mg to about 25 mg, of estradiol as a pharmaceutically acceptable ingredient, or comprises about 14 mg to about 25 mg, preferably about 15 mg to about 25 mg, of estradiol, preferably estradiol monohydrate. The presence of the estradiol component as a pharmaceutically acceptable ingredient does not preclude the presence of one or more other pharmaceutical ingredients and / or pharmaceutically acceptable ingredients in the dosage unit. The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with other components of a pharmaceutical composition and harmless to its recipient. Suitable excipients, without limitation, are further described throughout this disclosure.

[0165] As detailed above, the composition, which is the subject of this invention, comprises about 14 mg to about 25 mg, preferably about 15 mg to about 25 mg, of estradiol. Optionally, the composition is administered daily at an amount equivalent to about 14 mg to about 25 mg of estradiol monohydrate. Preferably, the composition comprises about 14 mg to about 20 mg of estradiol and is administered daily. More preferably, the composition comprises about 14 mg to about 20 mg of estradiol monohydrate and is administered daily.

[0166] In a further embodiment, the composition comprises about 14 mg to about 25 mg, preferably about 15 mg to about 20 mg, of an estradiol component, preferably said estradiol component being estradiol, estradiol monohydrate, or an ester of estradiol. Preferably, the composition comprises about 14 mg to about 25 mg of estradiol monohydrate, more preferably about 14 mg to about 20 mg of estradiol monohydrate. In an alternative embodiment, the composition comprises about 14 mg to about 25 mg of estradiol or an ester thereof, preferably about 14 mg to about 20 mg of estradiol or an ester thereof.

[0167] Optionally, the composition comprises about 17 mg of estradiol component, or an amount of estradiol component equivalent to a daily dose of about 17 mg of estradiol component. In a further embodiment, the composition comprises about 17 mg of estradiol monohydrate, or an amount of estradiol component equivalent to a daily dose of about 17 mg of estradiol monohydrate. In an alternative further embodiment, the composition comprises about 17 mg of estradiol or an ester thereof, or an amount of estradiol component equivalent to a daily dose of about 17 mg of estradiol or an estradiol ester.

[0168] In alternative embodiments, the composition comprises about 12 mg to about 28 mg, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg of estradiol, or equivalent to about 12 mg to about 28 mg of estradiol, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg. The daily dose of estradiol component is mg. In a preferred alternative embodiment, the composition comprises about 12 mg to about 28 mg, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg of estradiol monohydrate, or equivalent to about 12 mg to about 28 mg, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg. The daily dose of estradiol monohydrate is mg of the estradiol component.In an alternative embodiment, the composition comprises about 12 mg to about 28 mg, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg of estradiol or an ester thereof, or equivalent to about 12 mg to about 28 mg, about 13 mg to about 27 mg, about 14 mg to about 26 mg, about 15 mg to about 25 mg, about 16 mg to about 24 mg, about 17 mg to about 23 mg, about 18 mg to about 22 mg, or about 19 mg to about 21 mg, or about 13 mg to about 17 mg, or about 14 mg to about 16 mg, or about 18 mg to about 22 mg, or about 19 mg to about 21 mg. The daily dose of estradiol or its esters is the amount of estradiol component in mg.

[0169] Optionally, the composition comprises about 15 mg of estradiol (e.g., 13 to 17 mg or 14 to 16 mg), or an amount equivalent to about 14.2 mg of estradiol. Optionally, the composition may comprise about 14.2 mg of estradiol. In a further optional embodiment, the composition comprises about 15 mg of estradiol monohydrate.

[0170] Alternatively, the composition contains about 20 mg of estradiol (e.g., 18 to 22 mg or 19 to 21 mg), or an amount equivalent to about 20 mg of estradiol. Optionally, the composition may contain about 20 mg of estradiol. Preferably, the composition contains 18.9 mg of estradiol. In a further optional embodiment, the composition contains about 20 mg of estradiol monohydrate.

[0171] The estradiol component can be included in the composition as multiple particles. There is no particular limitation on the particle size of the estradiol component. Suitable particle sizes can be expressed, by way of illustration rather than limitation, by particle size distribution values, such as, but not limited to, D(10), D(50), and D(90). Those skilled in the art will readily understand how to interpret these parameters. "Particle size distribution" (often abbreviated as "PSD") is a numerical value representing the relative amount of particles according to size, wherein the relative amount of particles is preferably expressed by mass. For example, a D10 or Dv(10) value represents a point in the size distribution up to and including that point, in which 10% of the total sample volume (i.e., the collection of particles) is included. For example, a D10 of 10 µm means that 10% of the sample has a size of at most 10 µm. D10, D50, and D90 values ​​are conventionally used in the art to calculate the span of a sample, which indicates the width of the size distribution. The span is calculated according to the following formula: (D90 - D10) / D50. Those skilled in the art will understand that representative particle size distribution values ​​can only be obtained from representative samples.

[0172] Optionally, the D(10) of the estradiol particles is from about 0.5 µm to about 10 µm, preferably from about 1 µm to about 5 µm, more preferably from about 1.5 µm to about 2.5 µm. Optionally, the D(50) of the estradiol particles is less than about 20 µm, preferably less than about 12 µm, more preferably from about 5 µm to about 15 µm, preferably from about 6 µm to about 12 µm, more preferably from about 7 µm to about 11 µm, and most preferably from about 8 µm to about 12 µm. Optionally, the D(90) of the estradiol particles is from about 15 µm to about 50 µm, preferably from about 20 µm to about 30 µm, more preferably from about 22 µm to about 28 µm.

[0173] Various measurement techniques can be used to determine particle size distribution values, including sieving analysis, air panning analysis, photographic analysis, optical counting, resistivity counting, sedimentation, laser diffraction, laser masking, transition time, acoustic spectroscopy, ultrasonic attenuation microscopy, by means of a cascade impactor, or any combination thereof. Unless otherwise expressly stated, the particle size distribution values ​​disclosed herein are obtained by laser diffraction analysis. Laser diffraction analysis (interchangeably referred to in the art by laser diffraction spectroscopy) is a particle measurement technique based on the interpretation of the laser diffraction pattern through an object. Laser diffraction is capable of measuring the geometric dimensions of particles. Laser diffraction schemes have been described in detail in many contexts in the art (e.g., as reviewed in detail in the context of particle analysis in Eshel et al., Soil Science Society of America Journal, 2004).

[0174] Clearly, any composition and dosage unit may suitably contain one or more pharmaceutically acceptable excipients. The term "pharmaceutically acceptable" as used herein is consistent with the art and means compatible with other components of a pharmaceutical composition and harmless to its recipient.

[0175] The compositions and dosage units described herein may contain one or more additional active pharmaceutical ingredients in addition to the estradiol component, which are considered beneficial in the treatment or prevention of FSAD. For example, the compositions and dosage units described herein may contain sildenafil in addition to the estradiol component.

[0176] The oral dosage units described herein can be solid or semi-solid dosage units, such as tablets, capsules, pods, pellets, pills, powders, or granules, or any combination thereof. For example, the subject matter of the oral dosage unit of the present invention can be a tablet comprising granules containing an estradiol component or a capsule comprising granules containing an estradiol component. The term "solid or semi-solid dosage unit" also includes capsules containing a liquid (e.g., oil) in which the estradiol component and / or optional progestin-like component of the present invention are dissolved or dispersed.

[0177] Tablets and equivalent solid and semi-solid dosing units may suitably contain materials such as binders (e.g., hydroxypropyl methylcellulose, polyvinylpyrrolidone (Povidone, PVP), other cellulose materials, and starch), diluents (e.g., lactose (monohydrate) and other sugars, starch (e.g., corn starch), dicalcium phosphate, and cellulose materials), disintegrants (e.g., starch polymers and cellulose materials (e.g., sodium glycolate starch)), and lubricants (e.g., magnesium stearate and talc). These tablets and equivalent solid dosing units can be prepared by any suitable means already described in detail in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estradiol component in the manufacture of dosing units include wet granulation (e.g., using aqueous or organic solutions), direct compression, 3D printing, or coating carrier particles with the estradiol component using organic or inorganic solvents.

[0178] As described above, the composition and therefore the (oral) dosage unit may contain one or more suitable excipients. The term "excipient," used herein and in the art interchangeably with "carrier," can refer to any solvent, diluent, buffer (including, but not limited to, neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate, or phosphate buffer), solubilizer (including, but not limited to, Tween 80 or polysorbate 80), colloid, dispersion medium, medium, filler, chelating agent (including, but not limited to, EDTA or glutathione), amino acid, protein, disintegrant, binder, lubricant, wetting agent, stabilizer, emulsifier, sweetener, colorant, flavoring agent, aromatizer, thickener, any reagent suitable for achieving a reservoir effect, coating agent, antifungal agent, any preservative (including, but not limited to, Thimerosal) TM The excipients may include benzalkonium chloride or benzyl alcohol, antioxidants (including but not limited to ascorbic acid and sodium metabisulfite), tension control agents, absorption retardants, adjuvants, compatibilizers (including but not limited to lactose and mannitol), and any other components that may affect the subject matter of the oral dosing unit of the present invention. Those skilled in the art will understand that one or more excipients may be used in the oral dosing unit provided that one or more excipients are compatible with one or more pharmaceutical components (i.e., at least the estradiol component in the context of the present invention) and yield a pharmaceutically acceptable formulation.

[0179] In some embodiments, the excipient may be an active pharmaceutical ingredient excipient, a binder excipient, a carrier excipient, a co-processing excipient, a coating system excipient, a controlled release excipient, a diluent excipient, a disintegrant excipient, a dry powder inhalation excipient, an effervescent system excipient, an emulsifier excipient, a lipid excipient, a lubricating excipient, a modified release excipient, a penetration enhancer excipient, a penetration-enhancing excipient, a pH-adjusting excipient, a plasticizer excipient, or a preservative excipient. Excipients include: preservatives, solubilizers, solvents, sustained-release excipients, sweeteners, flavoring agents, thickeners, viscosity modifiers, fillers, compaction agents, dry granulation agents, hot-melt extrusion agents, wet granulation agents, rapid-release agents, bioavailability-enhancing agents, dispersing agents, solubility-enhancing agents, stabilizers, capsule-filling agents, or any combination thereof. Those skilled in the art will recognize that the use of such media and agents for pharmaceutically active substances is common practice, and therefore the incorporation of these excipients is well-known in the art. Clearly, all components used should be non-toxic at the concentrations contained in the final pharmaceutical composition and should not negatively interfere with the activity of one or more pharmaceutically active ingredients (at least the estradiol component herein).

[0180] Optionally, the composition is contained in a tablet and, in addition to estradiol, contains excipients that function as a first or further filler, superdisintegrant, binder, disintegrant, and lubricant. The excipients may perform several of these functions. Therefore, the binder may also be a disintegrant. The tablet may also contain two or more excipients that perform the same function, such as two different binders. In a preferred embodiment, the composition is contained in a tablet comprising estradiol, lactose, sodium glycolate starch, corn starch, povidone, and magnesium stearate. Preferably, the composition is contained in a tablet comprising estradiol monohydrate, lactose monohydrate, sodium glycolate starch type A, corn starch, povidone (e.g., povidone K30 or povidone 30LP), and magnesium stearate. Optionally, the tablet is coated with a coating agent. In a further optional embodiment, the coating agent includes hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red iron oxide, hydrogenated cottonseed oil, and talc. By way of description, and not limitation, suitable coating agents are AquaPolish Orange 0.3423 MS, AquaPolish Blue 0.6465 MS, AquaPolish Yellow 0.2415 MS, or AquaPolish Pink 0.4408 MS. Those skilled in the art understand that such coatings can be used in combination with appropriate amounts of purified water. Those skilled in the art further understand that any excipients present in any dosing unit, such as an oral dosing unit, should comply with pharmaceutical-grade industrial quality standards such as Ph. Eur. and USP-NF.

[0181] Dosing units can be suitably or even specifically manufactured for sublingual, buccal, and / or sublipal administration (i.e., implying prolonged presence in the subject's oral cavity). In such embodiments, the solid dosing unit is capable of rapidly releasing the estradiol component upon contact with an aqueous solvent such as saliva. Thus, in these embodiments, the solid dosing unit is an orally dispersible dosing unit that releases at least about 50%, preferably at least about 60%, more preferably at least about 70%, even more preferably at least about 80%, and most preferably more than about 80% of the estradiol component within about 5 minutes, preferably about 3 minutes, more preferably about 2.5 minutes, more preferably about 90 seconds, and most preferably about 90 seconds. The dosing unit can be an orally dispersible dosing unit. In such embodiments, when the dosing unit comes into contact with saliva, the dosing unit rapidly disintegrates in the oral cavity, dispersing the estradiol component into the saliva, thus allowing it to be absorbed through the inner lining of the oral mucosa. Those skilled in the art know methods for determining the release rate of the estradiol component from the dosing unit. Commonly accepted non-restrictive standardized tests in this field include those based on Ph. Eur. 2.9.1 (“Disintegration of Tablets and Capsules”) and USP. <701> Disintegration tests (“disintegration”), for example, using water as the disintegration medium.

[0182] As used in this article, the term "sublingual" refers to the pharmacological route of administration in which the estradiol component diffuses into the bloodstream through the sublingual tissue.

[0183] As used in this article, the term “transbuccal” refers to the pharmacological route of administration of estradiol components through the diffusion of the buccal vestibule into the bloodstream. The buccal vestibule is the area in the oral cavity between the buccal lining (buccal mucosa) and the teeth / gingiva.

[0184] As used in this article, the term "sublipal" refers to the pharmacological route of administration in which the estradiol component is placed between the lips and gums.

[0185] In some embodiments, the estradiol component is included in the immediate-release dosage unit or composition.

[0186] In some embodiments, the estradiol component is formulated into solid dosage units, including but not limited to hard capsules, soft capsules, tablets, coated tablets (e.g., varnished or sugar-coated tablets), granules, aqueous or oily solutions, syrups, emulsions, suspensions, ointments, pastes, lotions, gels, inhalers, or suppositories.

[0187] As described above, the term "oral administration" is intended to imply oral ingestion, i.e., swallowing. In embodiments in which an effective amount of the estradiol component is administered orally, the oral dosing unit according to the invention is preferably a solid or semi-solid dosing unit, such as tablets, capsules, sachets, pellets, pills, powders, or granules. The term "solid or semi-solid dosing unit" also includes capsules containing liquids (e.g., oils) in which the estradiol component and / or optional progestin-like components of the invention are dissolved or dispersed. Tablets and equivalent solid and semi-solid dosing units may suitably contain materials such as binders (e.g., hydroxypropyl methylcellulose, polyvinylpyrrolidone, other cellulose materials, and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate, and cellulose materials), disintegrants (e.g., starch polymers and cellulose materials), and lubricants (e.g., stearates and talc). These tablets and equivalent solid dosing units can be prepared by any suitable means already described in detail in the art (e.g., Kaur, Int Res J Pharm, 2012). Non-limiting examples of processing the estradiol component when manufacturing dosing units include wet granulation (e.g., using aqueous or organic solutions), direct pressing, 3D printing, or coating carrier particles with the estradiol component using organic or inorganic solvents.

[0188] By way of illustration and not limitation, oral dosing units incorporating the compositional subject matter of this disclosure may be manufactured by a process involving wet granulation. Those skilled in the art will understand that a wet granulation process may suitably include the following sequential steps: dispensing and sieving the active ingredient and excipients; mixing the sieved material in a processor; granulation; screening (i.e., further sieving) the particles; and mixing the sieved particles with one or more other excipients. Subsequently, if desired, and considering the final dosing unit, the granules may be compressed into, for example, tablets, optionally involving a tablet coating step.

[0189] In some embodiments, the estradiol component is the sole (i.e., single, only) pharmaceutically active ingredient of the composition. Throughout this disclosure, the term "pharmaceutical active ingredient," used interchangeably with "pharmaceutical active agent," should be interpreted according to the World Health Organization's definition of the term: "a substance used in a finished pharmaceutical product (FPP) intended to exhibit pharmacological activity or otherwise have a direct effect in the diagnosis, cure, relief, treatment, or prevention of a disease, or in the restoration, correction, or alteration of physiological function in humans." More specifically, in some embodiments, no progesterone-like component is co-administered with the estradiol component (neither in the same composition or oral dosage unit, nor in another co-administered composition or dosage unit). In embodiments involving subjects with liver injury who have undergone hysterectomy, the estradiol component is preferably administered as the sole pharmaceutically active ingredient.

[0190] In an alternative embodiment, the composition contains at least one additional pharmaceutically active ingredient in addition to the estradiol component.

[0191] Optionally, the dosage form includes a progestin-like component as an additional active pharmaceutical ingredient, or the treatment method includes a step of co-administering the progestin-like component to the subject. While embodiments in which the progestin-like component and the estradiol component are contained in the same composition are preferred, embodiments in which the progestin-like component is administered via a separate composition or dosage unit are also contemplated.

[0192] The terms “progestin,” “progestin,” or “fertility stimulant,” and their derived “progestin-like components,” as used herein and in the art, refer to any molecule that produces effects similar to those of the natural female sex hormone progesterone in a subject. Progestins are considered agonists of the progesterone receptor, and their functions have been well studied in the art (particularly discussed in Kuhl, Climacteric, 2005). Synthetic progestins are a subgroup of progestins that includes synthetic progestins. While the above terms may be used interchangeably in the art, it is generally understood that when referring to synthetic progestins, it means synthetic progestins.

[0193] Examples of progestin-like components contemplated in this invention include, but are not limited to: levonorgestrel, norethindrone, dydrogesterone, drospirenone, 3-β-hydroxydesogestrel, 3-ketodesogestrel, 17-deacetylgonone, 19-norprogesterone, acetyloxygestrelone, allylestradiol, amgestone, chlormedroxygestrel, cyproterone acetate, dimegestrol, desogestrel, dinogest, dihydroprogesterone, dimethynone, ethinylestradiol, diethynol, fluoropregnane acetate, gastrione, gestadienone, gestrinone, hydroxymethylprogesterone, hydroxyprogesterone, ethinylestradiol, mecirogestone, medroxyprogesterone, mesodyne, meropenemone, normegestrol, norethindrone, isethindrone, methylnorethindrone (including d-methylnorethindrone and dl-methylnorethindrone). Normethisterone, progesterone, quinone, (17α)-17-hydroxy-11-methylene-19-norpregn-4,15-diene-20-yn-3-one, tibolone, trimeprogesterone, algestone-acetophenide, nestorone acetate, primeprogesterone, 17-hydroxyprogesterone ester, 19-nor-17-hydroxyprogesterone, 17α-ethynil-19-nortestosterone, d-17β-acetoxy-13β-ethyl-17α-ethynylster-4-en-3-one oxime, 6β, 7β;15β,16β-dimethylene-3-oxo-17-pregn-4,9(11)-diene-21,17β-carbolactone or tanaproget and precursors of these components capable of releasing these progestins in vivo.

[0194] The progestin-like components may be selected from: progesterone, drospirenone, norethindrone, norethindrone acetate (NETA), dydrogesterone, levonorgestrel (LNG), etogestene, methylnorethindrone, normegestrol, normegestrol acetate (NOMAC), tramemone, enrogesterone acetate, dydrogesterone, gestrinone, desogestrel, norgestrol acetate, cyproterone acetate, denogestrol, and chlordrogesterone. Progestins particularly preferred in the context of this invention include, but are not limited to, drospirenone, progesterone, and dydrogesterone.

[0195] In some embodiments, the progestin is a naturally occurring progestin. In alternative embodiments, the progestin is a synthetic progestin.

[0196] "Drospironone" (abbreviated as DRSP, PubChem CID: 68873) is an example of a progestin-like component and is widely used in combination oral contraceptives (commonly abbreviated as COC) due to its anti-mineralocorticoid and anti-androgenic activities along with generally low off-target activity. COCs containing drospironone are generally referred to as fourth-generation COCs. A non-restrictive example of a commercially available COC containing drospironone is called "Yaz". ®” and "Yasmin ® The only illustrative example of a drospirenone progestin pill is "Slynd". ® It is also commercially available. Furthermore, hormone replacement therapy compositions containing estrogens such as estradiol and drospirenone are available, such as "Angeliq®". Drospirenone is alternatively available in the art from its molecular formula C 24 H 30 O3 can be represented by structural formula (III):

[0197] Equation (III)

[0198]

[0199] It should be understood that when the term "drospirenone" is used in this document, any drospirenone derivative may also be contemplated.

[0200] The methods described herein may include administering drospirenone to a subject receiving an estradiol component. In some embodiments, the composition may contain about 0.25 mg to about 10 mg of drospirenone, or an amount equivalent to a daily dose of about 0.25 mg to about 10 mg of drospirenone. Preferably, the composition may contain about 1 mg to about 4 mg of drospirenone, or an amount equivalent to a daily dose of about 1 mg to about 4 mg of drospirenone. More preferably, the composition may contain about 1 mg to about 3 mg of drospirenone, or an amount equivalent to a daily dose of about 1 mg to about 3 mg of drospirenone. Even more preferably, the composition may contain about 2.5 mg to about 3.5 mg of drospirenone, or an amount equivalent to a daily dose of about 2.5 mg to about 3.5 mg of drospirenone.

[0201] Optionally, the composition comprises about 15 mg to about 25 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 0.25 mg to about 10 mg of drospirenone. In a further optional embodiment, the composition comprises about 15 mg to about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 1 mg to about 4 mg of drospirenone. In yet another further optional embodiment, the composition comprises about 15 mg or about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 3 mg of drospirenone.

[0202] "Progesterone" (usually abbreviated as "P4"; PubChem CID 5994) is an endogenous steroid and progestinous sex hormone that participates in the female menstrual cycle, pregnancy, and embryogenesis, and constitutes the main progestin in the body. Progesterone is a well-documented substance and has been used in the art for indications including, but not limited to, contraception, female hormone replacement therapy, and feminizing hormone therapy. Progesterone can be described in the art by referring to its structural formula C 21 H 30 O2 can also be indicated by the structural formula (IV):

[0203] Formula (IV)

[0204]

[0205] It should be understood that when the term "progesterone" is used in this document, any progesterone derivative may also be contemplated.

[0206] In some embodiments, the composition may contain about 10 mg to about 500 mg, preferably about 25 mg to about 300 mg, of progesterone, or an amount equivalent to a daily dose of about 10 mg to about 500 mg, preferably about 25 mg to about 300 mg of progesterone. Preferably, the composition may contain about 100 mg to about 200 mg of progesterone, or an amount equivalent to a daily dose of about 100 mg to about 200 mg of progesterone.

[0207] Optionally, the composition comprises about 15 mg to about 25 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 25 mg to about 300 mg of progesterone. In a further optional embodiment, the composition comprises about 15 mg to about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 100 mg to about 200 mg of progesterone. In yet another optional embodiment, the composition comprises about 15 mg or about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 100 mg to about 200 mg of progesterone. In another embodiment, when progesterone is used sequentially, for example, when progesterone is administered over a period of about 14 days per month, progesterone is administered at a daily dose of about 100 mg to about 200 mg. In yet another embodiment, when progesterone is used sequentially, for example, when it is administered for approximately 14 days after at least 12 weeks and no longer than 13 weeks of treatment with the estradiol component, progesterone is administered at a daily dose of approximately 100 mg to approximately 200 mg. Preferably, progesterone is administered once daily for 14 consecutive days after completion of treatment with the estradiol component.

[0208] The synthetic progestin “dydrogesterone” (PubChem CID 9051), which is interchangeably referred to in the art as, for example, “isogestrinone” or “didrogesteron”, has been used for a variety of medical indications, including dysfunctional bleeding, infertility, dysmenorrhea, endometriosis, and menopausal hormone therapy. Dydrogesterone can be referred to in the art by referring to its structural formula C 21 H 28 O2 can also be represented by the structural formula (V):

[0209] Formula (V)

[0210]

[0211] It should be understood that when the term "dydrogesterone" is used in this document, any dydrogesterone derivative may also be contemplated.

[0212] In some embodiments, the composition may contain about 1 mg to about 20 mg of dydrogesterone, or a progestin-like component in an amount equivalent to a daily dose of about 5 mg to about 10 mg of dydrogesterone. Preferably, the composition may contain about 1 mg to about 20 mg of dydrogesterone, or a progestin-like component in an amount equivalent to a daily dose of about 5 mg to about 10 mg of dydrogesterone.

[0213] Optionally, the composition comprises about 15 mg to about 25 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 1 mg to about 20 mg of dydrogesterone. In a further optional embodiment, the composition comprises about 15 mg to about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 5 mg to about 10 mg of dydrogesterone. In yet another further optional embodiment, the composition comprises about 15 mg or about 20 mg of an estradiol component (preferably estradiol or estradiol monohydrate) and about 5 mg to about 10 mg of dydrogesterone.

[0214] In the context of this invention, other compounds (i.e., components, reagents) may be used in combination with the estradiol component for administration to women with a uterus. Selective estrogen receptor modulators (SERMs) define a class of compounds that are considered useful supplements to the estradiol component in the methods of this invention. A preferred SERM for the context of this invention is bardoxifene. In the methods and compositions further described herein, it must be understood that when referring to “progesterone-like components,” such references include SERMs, and particularly bardoxifene. Preferably, bardoxifene is administered at a daily dose of about 10 mg to 50 mg. More preferably, bardoxifene is administered at a daily dose of about 15 to about 25 mg. Most preferably, bardoxifene is administered at a daily dose of about 20 mg.

[0215] The composition can be formulated into dose units to be administered to a subject at any time interval deemed appropriate by a person skilled in the art. In the context of this invention, a preferred administration regimen is a daily administration regimen (i.e., once every approximately 24 hours). In such embodiments, the composition described herein therefore represents a daily composition, a daily dose unit. In alternative embodiments, the composition is formulated into a multiple-daily administration regimen, which is then accumulated to achieve a dose consistent with the present invention, such as approximately 15 to approximately 25 mg of the estradiol component.

[0216] Optionally, the dose units are administered to the subject via a continuous administration regimen. As used herein, the terms "continuous" and "continuously" mean that the dose units are administered at relatively regular intervals without significant (therapeutic) interruptions. Of course, minor interruptions may occur that do not affect the overall effectiveness of the method, and such an anomaly is indeed included in the invention. In a preferred embodiment, and more arithmetically, an administration regimen is considered continuous if the longest interval between two subsequent administrations does not exceed about 3.5 times the average interval. Even more preferably, the longest interval does not exceed about 2.5 times the average interval, and most preferably does not exceed about 1.5 times the average interval. By way of illustration and not limitation, the treatment strategies and methods described herein preferably employ continuous administration of the estradiol component over a period of at least 10 days, preferably at least 20 days.

[0217] Alternatively, the dose unit may be administered to the subject via a sequential administration regimen. It should be understood that the term "sequential" means administration over, for example, a period of 10 to 14 days per month or a period of 14 days every 3 months. Sequential administration regimens are particularly envisioned in which the progestin-like component is part of the composition or treatment described herein.

[0218] A further aspect of the invention relates to packaging units comprising the dosage units described herein. The packaging unit may comprise at least 14, preferably at least 21, and even more preferably at least 28 containers for containing separately packaged and individually removable dosage units, wherein each container contains at least one dosage unit consisting of about 14 to about 25 mg of estradiol. Preferably, the separately packaged and individually removable dosage units are oral dosage units. More preferably, each of the separately packaged and individually removable dosage units contains about 14 mg or about 20 mg of estradiol, preferably about 15 mg or about 20 mg of estradiol or estradiol monohydrate.

[0219] Optionally, the packaging unit further comprises at least 10, preferably 12, more preferably 14 additional containers for containing separately packaged and individually removable dosage units, wherein each additional container contains at least one dosage unit containing a progestin-like component. Optionally, when the two dosage units must be administered on the same day, each additional container for containing the dosage unit containing the progestin-like component is arranged visually adjacent to the container containing the dosage unit containing the estradiol component. Optionally, the packaging unit further comprises the same number of additional containers for containing separately packaged and individually removable oral dosage forms, wherein each additional container contains at least one daily, preferably solid, oral dosage form containing a progestin, preferably selected from drospirenone, progesterone, and dydrogesterone.

[0220] Those skilled in the art will understand that the above-described embodiments involving packaging units can be equivalently presented as a kit containing a first packaging unit, such as a blister pack containing a daily oral dose unit comprising an estradiol component, and a second different packaging unit, such as a second different blister pack containing a daily oral dose unit comprising a progestin.

[0221] Those skilled in the art will also know that, within the scope of this invention, each packaging unit, such as a blister pack, may be numbered or otherwise marked.

[0222] The packaging unit may be provided in any suitable packaging manner known in the art, and non-limiting examples are tablets, sachets, cigarette pouches, bottles, films, sprays, microcapsules, implants, sticks or blister packs.

[0223] By way of illustration rather than limitation, each packaging unit may be a sealed blister pack with a cardboard, paperboard, or foil plastic backing and sealed in a suitable cap. Packaging units, such as bottles, are also contemplated in any of the aspects defined herein. There are no particular limitations on the material of the bottle. In a preferred embodiment, the bottle is a glass bottle, characterized by its color being able to reduce or prevent degradation of the bottle's contents, for example, by ultraviolet light, while maintaining transparency that allows visual inspection of the bottle's contents. Suitable colors include, but are not limited to, amber, cobalt blue, or vintage green.

[0224] In a particular embodiment of the invention, the packaging unit comprises 28 containers or multiples thereof, such as 2 to 12 times 28 containers.

[0225] Although the invention has been described in conjunction with specific embodiments thereof, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be readily apparent from the foregoing description. Therefore, all such alternatives, modifications, and variations are intended to be included within the spirit and broad scope of the appended claims. The aspects and embodiments of the invention disclosed herein are further supported by the following non-limiting examples. The following specific experimental examples are provided to support the claimed invention, but should not be construed as limiting the scope of the invention.

[0226] Example

[0227] Example 1: A phase 2 randomized, double-blind, placebo-controlled proof-of-concept study evaluating the efficacy and safety of estradiol in postmenopausal subjects with female sexual arousal disorder.

[0228] The drug product under investigation (IMP):

[0229] Test product: Estradiol monohydrate 20 mg (E420 mg), equivalent to 18.9 mg estradiol.

[0230] Reference product: placebo

[0231] Indications:

[0232] Female sexual arousal disorder in postmenopausal subjects

[0233] Expected number of participants:

[0234] Approximately 76 enrolled / randomized subjects (38 subjects in each treatment group) (based on the estimated withdrawal rate).

[0235] A total of 52 evaluable subjects were included (26 evaluable subjects in each treatment group).

[0236] Basic principle:

[0237] Female sexual arousal disorder (FSAD) (a subtype of female sexual dysfunction) is the inability to achieve or maintain an adequate lubrication-swelling response for sexual arousal; it may manifest as reduced vaginal lubrication and decreased genital sensation associated with blood flow, and may lead to significant distress and / or interpersonal difficulties (DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). There are currently no approved treatments for FSAD. Estrogen plays a crucial role in maintaining the structural integrity of genital tissues and genital blood flow to the pelvic nerves. This study will use a natural estrogenic steroid called estradiol, which is normally produced by the human fetal liver. Phase 2 and 3 studies of estradiol (E4) for vasomotor symptom relief have shown improvement in dyspareunia and vaginal dryness in subjects with these symptoms at baseline. This phase 2 proof-of-concept (POC) study will evaluate the efficacy and safety of E4 20 mg for the treatment of menopausal FSAD.

[0238] Research objectives:

[0239] Primary objective: To evaluate the efficacy of E4 20 mg in the treatment of menopausal FSAD.

[0240] Secondary objectives: assess changes in sexual function and satisfaction, and patient-reported improvements in sexual arousal symptoms.

[0241] Safety objective: To assess adverse events and other safety outcomes of the investigational drug.

[0242] Research Design and Methods:

[0243] This study is a pilot, randomized, double-blind, placebo-controlled, two-arm parallel-group, phase 2 prognostic study that will be conducted in postmenopausal women diagnosed with FSAD who have undergone hysterectomy.

[0244] Eligible participants will be randomly assigned in a 1:1 ratio and will receive either E4 20 mg or placebo, orally, once daily for 12 weeks.

[0245] The research timeline is summarized in Figure 1 middle.

[0246] Study population:

[0247] Postmenopausal women who have undergone hysterectomy and are ≥40 to ≤65 years old at randomization / treatment allocation, diagnosed with FSAD by an expert and according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised Edition (DSM-IV-TR), and whose total score on the Female Sexual Disturbances Scale-Sexual Desire / Arousal / Orgasm (FSDS-DAO) at screening time is ≥18 and whose score on FSDS-DAO-Item 14 is ≥3, will be included.

[0248] Study duration:

[0249] Treatment with IMP (E4 20 mg or placebo) lasts for 12 weeks. Individual participation can last up to 28 weeks. This includes a washout period of up to 8 weeks, a screening period of up to 4 weeks, a treatment period of 12 weeks, followed by a follow-up period of 4 weeks.

[0250] Evaluation criteria:

[0251] effect:

[0252] • Common primary endpoint:

[0253] o Changes in feelings of concern about sexual arousal difficulties from baseline to week 12, as assessed by the FSDS-DAO project 14.

[0254] Changes in the arousal-sensory domain (questions 6 to 9) of the Sexual Function Questionnaire (SFQ-28) from baseline to week 12.

[0255] •Key secondary endpoints:

[0256] o Changes in arousal and lubrication from baseline to week 12 were assessed using the Patient Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction (SexFS) indicators.

[0257] • Secondary endpoint:

[0258] o Changes in sexual function (i.e., pain) from baseline to week 12, as assessed by the following:

[0259] -FSDS-DAO-Total Score

[0260] - The percentage of satisfying sexual events (SSEs) recorded in the sexual arousal diary.

[0261] o Changes in sexual function from baseline to week 12, assessed by the SFQ-28 total score.

[0262] o Changes in sexual function from baseline to week 12 as assessed by PROMIS-SexFS-customized evaluation.

[0263] o Patient Overall Change Impression (PGIC) at week 12.

[0264] o, for example, the change in the severity of sexual arousal disorder from baseline to week 12 as assessed by the Patient Global Severity Impression (PGIS).

[0265] Security:

[0266] o The frequency of adverse events (TEAEs) occurring during treatment (including serious adverse events [TESAE] occurring during treatment).

[0267] o Vital signs measurements and routine clinical laboratory test results (hematology and chemistry) at each measurement time point.

[0268] Statistical methods:

[0269] Sample size determination:

[0270] Assuming a standard deviation (SD) of 1.25, and considering the use of a two-sample t-test for a 5% two-sided Type I error and 80% power to detect a 1-point difference between groups in SFQ-28 arousal scores (items 6 to 9), the sample size has been determined. Since there is no information regarding the variability of FSDS-DAO item 14, this scale was not considered in the sample size estimate. However, this trial will provide important information for considering this parameter in future study designs. Based on the above assumptions regarding SFQ-28 arousal scores, this calculation requires approximately 26 evaluable subjects / groups (52 subjects total). Based on an estimated dropout rate of approximately 30%, approximately 38 subjects / groups will be randomized in this study, resulting in a total of 76 subjects.

[0271] Key variables:

[0272] FSDS-DAO-Project 14, SFQ-28 Arousal-Sensory Domain (Questions 6 to 9).

[0273] Secondary variables:

[0274] PROMIS-SexFS, FSDS-DAO total score, percentage of SSE recorded in the sexual arousal diary, SFQ-28 total score, PROMIS-SexFS customization, PGIC and PGIS.

[0275] Security parameters:

[0276] Adverse events (AEs) include serious adverse events (SAEs), while TEAEs include TESAES, clinical laboratory parameters, and vital signs.

[0277] Analysis of primary and secondary variables:

[0278] All primary and secondary power variables at each measurement time point will be provided with descriptive statistics according to IMP.

[0279] Categorical factors will be summarized using frequency and / or percentage. Continuous and ordinal (where applicable) variables will be described using the mean and SD, minimum, maximum, median, and quartiles.

[0280] The analysis of primary and secondary variables will be performed on the full analysis set (FAS, i.e., all subjects randomized in the study assessed at baseline and week 12).

[0281] Sensitivity analysis will be performed on the intention-to-treat (ITT, i.e., all randomized subjects) set.

[0282] Differences between treatment groups can be presented to compare continuous and discrete outcomes. Differences and comparisons may be accompanied by 95% confidence intervals (CI) and p-values.

[0283] The changes in feelings of concern about sexual arousal difficulties assessed by FSDS-DAO Project 14 from baseline to week 12, as well as the changes in the arousal domain (questions 6 to 9) of SFQ28 from baseline to week 12, will be descriptively summarized and analyzed using an analysis of covariance (ANCOVA) model.

[0284] The model will include the treatment group as a fixed effect. The corresponding baseline score will be included as a covariate in the model. Estimates of treatment differences, 95% CI, and p-values ​​will be provided.

[0285] Changes in arousal and lubrication (PROMIS-SexFS), FSDS-DAO-total score, SSE percentage, sexual function (SFQ-28-total score and PROMIS-SexFS customized) and PGIS from baseline to week 12 will be descriptively summarized and analyzed by ANCOVA, as co-primary endpoints.

[0286] The number and percentage of subjects reporting improvement in PGIS severity or PGIC improvement (minimum, significant, or very significant) will be presented along with treatment comparisons using a chi-square test. PGIS and PGIC scores will also be analyzed as response frequencies using a Cochran-Mantel-Haenszel (CMH) test for differences in mean scores.

[0287] The analysis will be performed in a safe and validated environment using SAS® v9.4 or later, with a two-sided significance level of 0.05. No adjustments will be made for test multiplicity in this exploratory POC study.

[0288] Safety parameter analysis:

[0289] Safety assessments will be based on the frequency of adverse events (AEs) and severe adverse events (SAEs) (with and without causation) and a review of individual values ​​of clinical laboratory data and vital signs, with a focus on the detection of outliers and potential clinically significant abnormalities identified according to the investigator's considerations. Clinical laboratory parameters and vital signs will be summarized using descriptive statistics (as applicable). The number of subjects with at least one outlier will be tabulated by IMP in a summary transformation table for each parameter (count and percentage).

[0290] Reasons for clinical research

[0291] The diagnostic criteria for FSAD in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Textual Revision (DSM-IV-TR) include several criteria for an appropriate diagnosis:

[0292] A. A persistent or recurrent inability to achieve or maintain adequate lubrication-swelling response for sexual arousal until completion of sexual activity.

[0293] B. This interference causes significant distress or interpersonal difficulties.

[0294] C. Sexual dysfunction cannot be better explained by another Axis I disorder (other than another sexual dysfunction) and is not solely due to the direct physiological effects of substances (e.g., drug abuse, medication) or general medical conditions.

[0295] The standard "C" is the primary recommendation for psychiatric diagnosis.

[0296] The American Urological Foundation defines FSAD as "a persistent or recurrent inability to achieve or maintain adequate sexual arousal, resulting in personal distress." FSAD can occur independently of or concurrently with other distinct female sexual disorders, such as HSDD, female orgasmic disorder, and / or dyspareunia. While psychosocial factors clearly contribute to this disorder, medical and physiological factors, including reduced vaginal / clitoral blood flow, hormonal changes, prior pelvic surgery (e.g., hysterectomy), vaginal injury during childbirth, or the use of certain medications, may be the primary underlying cause. Previous research on female sexual arousal problems has primarily focused on self-reported lack of vaginal lubrication.

[0297] There are currently no approved treatments for FSAD. In this study, participants had to be diagnosed with FSAD through an expert interview according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revised Edition (DSM-IV-TR). In addition, participants had to have a total score of ≥18 on the Female Sexual Disturbances Scale-Liberty / Arousal / Orgasm (FSDS-DAO) and a score of ≥3 on FSDS-DAO-Item 14 at the time of screening.

[0298] This Phase 2 proof-of-concept (POC) study will evaluate the efficacy and safety of E4 20 mg for the treatment of menopausal FSAD.

[0299] Research objectives and endpoints

[0300]

[0301]

[0302] Research Plan

[0303] Overall Research Design and Planning

[0304] This is a pilot, randomized, double-blind, placebo-controlled, two-arm parallel-group, phase 2 (POC) study that will be conducted in postmenopausal women diagnosed with FSAD who have undergone hysterectomy. Eligible participants will be randomized 1:1 to receive either E4 20 mg or placebo orally once daily for 12 weeks.

[0305] Subjects will be enrolled in the study after obtaining informed consent, completing medical and gynecological history checks, and meeting inclusion / exclusion criteria. Subjects must have a clinical diagnosis of FSAD to be eligible for inclusion in this study. FSAD will be diagnosed through a structured expert interview and according to the DSM-IV-TR, with a total score ≥18 on the FSDS-DAO and a score ≥3 on FSDS-DAO item 14 at screening.

[0306] For the washout period, if a subject uses a prohibited medication during the duration of the study, she will be asked to discontinue that medication. After a variable washout period depending on the type of medication previously used, the subject will return for screening. Subjects who are not using medications that need to be discontinued and washed out may continue the screening process. At the washout visit and screening visit, only the available inclusion / exclusion criteria at that time point will be checked.

[0307] Final eligibility will be confirmed during the screening process; if screening requirements cannot be met within 4 weeks, the screening period may be extended with prior approval from the medical inspector, but the screening period shall not exceed 8 weeks. Initial efficacy measurements will be provided during screening to provide baseline measurements.

[0308] Treatment will begin on day 1, at which time eligibility for randomization will be confirmed prior to allocation of the study drug product (IMP). Participants will be informed of the use of the electronic patient-reported results (ePRO) system, daily management of the IMP, the need to maintain adherence, and how to contact the site to address any issues or report changes in health status. Treatment will last 12 weeks, with an additional visit at week 4. Efficacy assessments will be collected at week 12.

[0309] There will be a 30-day follow-up period after treatment to report any episodes of health changes and to monitor any TEAEs.

[0310] Basic Principles of Research Design

[0311] The design of this study complies with the requirements of the FDA guidance draft "Female low sexual interest, libido and / or sexual arousal: Development of medicines for treatment, industry guidance" (U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research [CDER]), October 2016.

[0312] Selection of research population

[0313] Inclusion criteria

[0314] Subjects who meet all of the following criteria are eligible to participate in this study:

[0315] 1. After explaining the nature of the study in accordance with local regulations, a signed and dated written informed consent form and any required privacy authorization must be provided before any research procedure begins.

[0316] 2. Females aged ≥40 to ≤65 years at the time of randomization / treatment assignment visit, with vasomotor menopausal symptoms.

[0317] 3. FSAD is diagnosed by experts according to DSM-IV-TR, with a total score of ≥18 on FSDS-DAO and a score of ≥3 on FSDS-DAO-Item 14 at the time of screening.

[0318] 4. The postmenopausal status of subjects who have undergone hysterectomy is defined as any of the following:

[0319] - Serum FSH > 40 mIU / mL and E2 < 20 pg / mL (values ​​obtained after eluting drugs containing estrogen / synthetic progesterone, see exclusion criteria 17, 19 and 20).

[0320] - Or at least 6 months after a bilateral oophorectomy.

[0321] 5. A recorded hysterectomy (with or without oophorectomy) must have occurred at least 6 months prior to the start of screening. The hysterectomy may be a total hysterectomy or a partial hysterectomy (i.e., without removal of the cervix).

[0322] 6. Body Mass Index (BMI) ≥ 18.0 kg / m² 2 Up to ≤38.0 kg / m 2 .

[0323] 7. A mammogram taken during the screening period or within 9 months prior to the start of screening that does not show significant signs of disease. Participants must have a Breast Imaging Reporting and Data System (BI-RADS) score of 1 or 2 for the study. Incomplete mammogram results, i.e., a BI-RADS score of 0, are unacceptable and require further evaluation. The site must obtain a formal report copy of the participant's study file.

[0324] 8. Has a vagina.

[0325] 9. According to clinical interviews, the subjects had experienced “normal” past sexual function.

[0326] 10. Have engaged in sexual activity at least twice a month for the past 6 months and agree to maintain this commitment for the duration of the study. Sexual activity may include any activity that may result in sexual stimulation or pleasure, such as intercourse, caressing, foreplay, masturbation, and oral sex.

[0327] 11. Good physical and mental health, as determined by researchers based on medical history, physical and gynecological examinations, and clinical assessments conducted prior to visit 1.

[0328] 12. Be able to understand and comply with the requirements, instructions and limitations stipulated in the agreement.

[0329] 13. Able to and willing to complete the research daily journal and questionnaire.

[0330] Exclusion criteria

[0331] Subjects who meet any of the following criteria during the screening visit are ineligible for inclusion in this study.

[0332] 1. History of malignant tumors, excluding basal cell carcinoma or squamous cell carcinoma of the skin (if diagnosed more than one year prior to the screening visit). The only exception is basal cell carcinoma or squamous cell carcinoma of the skin, if diagnosed more than one year prior to the subject's screening.

[0333] 2. Any clinically significant findings made by the investigator during a breast examination and / or on a mammogram suspected of being a breast malignancy will require further clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are permissible).

[0334] 3. Abnormal cervical cytology on a Pap smear within the previous year will require any subsequent evaluation or treatment during the study. Subjects must have a normal Pap smear within the year prior to enrollment in the study. The site must obtain a formal report copy of the subject's study file. If no written normal result is available within one year prior to the start of screening, the subject must undergo a Pap test during screening.

[0335] 4. Systolic blood pressure (BP) above 140 mmHg and diastolic blood pressure above 90 mmHg during screening. If the value exceeds the inclusion criteria after sitting for another 5 to 10 minutes, the BP measurement at screening can be repeated. Use the last reading for eligibility assessment. Subjects with mild to moderate hypertension who meet all inclusion / exclusion criteria may be enrolled based on the investigator's judgment if they have mild to moderate hypertension controlled by a stable blood pressure-lowering regimen. Subjects using antihypertensive medications containing methyldopa or clonidine are excluded.

[0336] 5. A history of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or a first-degree family history of VTE.

[0337] 6. A history of known acquired congenital coagulopathy or coagulation factor abnormalities, including known thrombophilia.

[0338] 7. Laboratory values ​​for glycated hemoglobin are higher than 7.5%. Laboratory values ​​for hemoglobin A1c assessed over the past 6 months, as well as during elution and screening, should be considered.

[0339] 8. Currently a smoker.

[0340] 9. Presence or history of gallbladder disease, unless cholecystectomy has been performed.

[0341] 10. Diagnosis or treatment of systemic lupus erythematosus.

[0342] 11. Any malabsorption disorder, including gastric bypass surgery.

[0343] 12. History of acute liver disease within the 12 months prior to the start of screening, or presence or history of chronic or severe liver disease (alanine aminotransferase or aspartate aminotransferase >2x upper limit of normal (ULN), bilirubin >1.5 ULN), or liver tumor.

[0344] 13. Chronic or current acute renal impairment (estimated glomerular filtration rate <60 mL / min).

[0345] 14. Hyperthyroidism is not adequately treated at screening, with abnormal thyroid-stimulating hormone (TSH) and free thyroxine (T4). Subjects with low or high TSH are permitted if their free T4 is within the normal range at screening. A reflex T4 test is only performed at screening if TSH is outside the normal range at screening.

[0346] 15. Diagnosis or treatment of porphyria.

[0347] 16. The diagnosis or treatment of major mental disorders (such as schizophrenia, bipolar disorder, etc.) shall be determined by the researcher.

[0348] 17. Maximum use of medications containing estrogen / synthetic progesterone:

[0349] a. For vaginal non-systemic hormonal products (rings, creams, gels), 1 week prior to the start of screening.

[0350] b. For vaginal or transdermal estrogens or estrogen / synthetic progestin products, 4 weeks prior to the start of screening.

[0351] c. For oral estrogen and / or synthetic progestin products and / or selective estrogen receptor modulatory therapy, 8 weeks prior to the start of screening.

[0352] d. For synthetic progestin implants or estrogen monotherapy, 3 months prior to the start of screening.

[0353] e. For estrogen pill therapy or synthetic progestin injection therapy, 6 months prior to the start of screening.

[0354] 18. Use of medications containing androgens / dehydroepiandrosterone (DHEA):

[0355] a. For oral, topical, vaginal, or transdermal androgens, 8 weeks prior to the start of screening.

[0356] b. For implantable or injectable androgen therapies, 6 months prior to the start of screening.

[0357] 19. Use phytoestrogens or black cohosh for the treatment of vasomotor symptoms up to 2 weeks prior to the start of screening.

[0358] 20. Use an estrogen agonist / antagonist, such as opemifene, during the 8 weeks of screening.

[0359] 21. During their participation in the study, they were unwilling to discontinue any hormone products as described in exclusion criteria 17, 18, 19, and 20.

[0360] 22. History of allergy / intolerance to this type of IMP or drug or any component thereof, or history of allergy to drugs or other allergens that the investigator deems inadvisable for the subject to participate.

[0361] 23. History of alcohol or substance abuse (including cannabis, even if legally permissible) or dependence within the 12 months prior to the start of screening, as determined by the researcher based on reported observations.

[0362] 24. Sponsor or contract research organization (CRO) employees or employees who are directly supervised by investigators and / or directly involved in the research.

[0363] 25. Subjects with a known or suspected clinically significant systemic disease, unstable medical condition, life-threatening illness, or a current history of malignancy that the investigator considers to pose a risk to the subject.

[0364] 26. Participated in another clinical study of the investigational drug within one month (30 days) prior to the start of screening or received the investigational drug within the last month (30 days) prior to the start of screening.

[0365] 27. Deemed unsuitable by researchers for any reason.

[0366] 28. Major surgery is planned to be performed during the clinical trial.

[0367] 29. Screen for any clinically significant abnormalities found on a 12-lead electrocardiogram (ECG).

[0368] 30. Unresolved history of sexual trauma or abuse that results in any sexual dysfunction problems (sexual desire, sexual arousal, orgasm, etc.), as determined by a clinical interview.

[0369] 31. Recently experienced significant life stress (such as loss of income, death of a family member) or relationship discord that may disrupt activities (excluding distress associated with FSAD).

[0370] 32. Major symptoms include loss of sexual desire, vaginismus, low libido, or any other major sexual symptoms other than genital arousal problems, as determined by a clinical interview.

[0371] 33. Has undergone major pelvic or abdominal surgery that could have caused nerve damage, including vulvectomy, colostomy, cystostomy, and bladder neck suspension.

[0372] 34. Had undergone vulvovaginal laser treatment within 3 months of screening.

[0373] 35. Vaginal infections that currently require drug treatment (can be enrolled after treatment is completed).

[0374] 36. History of human immunodeficiency virus (HIV) and / or hepatitis B and / or hepatitis C.

[0375] 37. A recent sexually transmitted infection that requires ongoing treatment.

[0376] 38. Abnormal gynecological findings of clinical significance.

[0377] treat:

[0378] The treatments used in this study are summarized in Table 1 below.

[0379] Table 1. Study Treatment

[0380]

[0381] FCT: Film-coated tablets; FCT: Film-coated tablets

[0382] Active therapy

[0383] Active ingredient: Estradiol monohydrate

[0384] Specification: E4 20 mg

[0385] Dosage form: Film-coated tablets (FCT)

[0386] Excipients: Lactose monohydrate, sodium adipic acid starch, corn starch, purified water, povidone, magnesium stearate, AquaPolish® Yellow 024.15 MS (containing hydroxypropyl methylcellulose, hydroxypropyl cellulose, cottonseed oil, talc, titanium dioxide, iron oxide yellow and iron oxide red).

[0387] Primary packaging: Blister packaging (PVC / aluminum), each blister contains 28 tablets.

[0388] Placebo (visually matches active treatment)

[0389] Active substances: Inactive substances

[0390] Dosage form: FCT

[0391] Excipients: StarLac® (co-processed excipient containing lactose monohydrate and corn starch), magnesium stearate, AquaPolish® Yellow 024.15 MS (containing hydroxypropyl methylcellulose, hydroxypropyl cellulose, cottonseed oil, talc, titanium dioxide, iron oxide yellow and iron oxide red).

[0392] Primary packaging: Blister packaging (PVC / aluminum), each blister contains 28 tablets (primary packaging)

[0393] Dosage selection and timing for each subject

[0394] Participants will be instructed to take IMP once daily at approximately the same time of day for 12 weeks. An electronic diary will be provided to participants to track their adherence to the daily intake.

[0395] Permitted companion drugs / vaccines

[0396] Thyroid treatment

[0397] Thyroid treatment is permitted (exclusion criterion 14).

[0398] Antihypertensive drugs

[0399] Subjects with mild to moderate hypertension who meet the BP criteria (systolic BP <140 mmHg, diastolic BP <90 mmHg) at screening are eligible for enrollment if their hypertension is controlled with a stable antihypertensive regimen. Subjects using antihypertensive medications containing methyldopa or clonidine are not eligible for enrollment.

[0400] Vaccination

[0401] According to national guidelines, participants can receive a regulatory-approved coronavirus disease 2019 (COVID-19) vaccine, but should not participate in COVID-19 clinical trials.

[0402] Recommendations regarding the timing of COVID-19 vaccination in relation to research evaluations, given the potential for acute reactions to vaccination:

[0403] • Vaccination should preferably be administered after a scheduled blood test visit.

[0404] • Otherwise, at least one week before the scheduled blood sample collection visit.

[0405] Reasons for timing restrictions: Acute reactions during vaccination may cause transient changes in biochemistry (liver enzymes, lactate dehydrogenase (LDH), etc.), which is not a common reaction but can occur. A possible transient increase in temperature may lead to changes in drug absorption, pharmacokinetic (PK) fluctuations, etc.

[0406] In any acute situation, the scheduled visit should be postponed (if there are no safety concerns) until the subject's condition improves.

[0407] Vaccinations administered during the study period should be reported as concomitant medications. Any adverse events (AEs) occurring after vaccination should be reported truthfully.

[0408] Prohibited concomitant medications

[0409] Drugs or vaccines explicitly prohibited in the exclusion criteria are not permitted during the ongoing study. As indicated by the criteria for drugs and therapies discontinued during the washout period, the drugs prohibited during the treatment period and the corresponding duration of the washout period are listed in Table 2:

[0410] Table 2. Elution of previous drugs

[0411]

[0412] DHEA = Dehydroepiandrosterone.

[0413] 1If the researcher's medical judgment necessitates a gradual reduction in the medication, the washout period should only begin after the last dose of such medication.

[0414] 2 When subjects begin the washout period, it is important to ensure that subjects have sufficient time to be randomized during the enrollment period.

[0415] To confirm compliance with the rules regarding unauthorized concomitant therapy, blood samples will be collected during visits 2 and 3 at weeks 4 and 12, respectively, for E2 concentration analysis.

[0416] FSAD Diagnosis Structured Interview

[0417] During screening, based on the partially completed initial in-person screening criteria, all potentially eligible participants will be scheduled for a structured interview to determine the primary FSAD (DSM IV criteria). This interview will be conducted using a video conferencing interview process with a sex medicine specialist trained in FSAD assessment, guided by telemedicine regulations governed by the Health Insurance Portability and Accountability Act (HIPAA).

[0418] Efficacy Measurement and Evaluation

[0419] The following efficacy measurement scale will be provided to the participants for completion:

[0420] Female Sexual Distress Scale - Libido / Arousal / Orgasm (FSDS-DAO)

[0421] The FSDS-DAO is a validated 15-item self-assessment of sexual feelings and problems. All responses range from 0 (“never annoyed”) to 4 (“always annoyed”). Total scores range from 0 (never annoyed) to 60 (always annoyed). Lower scores on the scale represent an increase in libido and indicate a better outcome (improvement). Higher scores on the scale indicate a worse outcome. The FSDS-DAO will be assessed during the screening period and at week 12 (±3 days). Changes in feelings of anxiety about sexual arousal difficulties, assessed by FSDS-DAO item 14, from baseline to week 12 will be evaluated. The FSDS-DAO has been described in numerous instances in the art and is publicly available (e.g., Derogatis et al., J Patient Rep Outcomes, 2021, DOI: 10.1186 / s41687-021-00359-1).

[0422] Sexual Function Questionnaire (SFQ-28)

[0423] The Sexual Function Questionnaire (SFQ) is a self-reported outcome measure of female sexual function. It has recently been improved, resulting in a 28-item version (SFQ-28) that includes the addition of a new arousal-cognitive domain. The SFQ-28 is a multidimensional and patient-centered tool used to examine all areas of sexual response. The SFQ-28 is used to identify sexual dysfunction and consists of 28 questions across seven dysfunction domains. The SFQ-28 can also be used as a screening tool for women with sexual dysfunction, capable of detecting the presence of the dysfunction and the specific components of affected sexual function. The SFQ-28 will be evaluated at screening and week 12 (+3 days). Further improvements and validation of the SFQ to SFQ-28 have been described in this field (Symonds et al., J Sex Med, 2012; DOI:10.1111 / j.1743-6109.2011.02627.x).

[0424] Patient-Reported Outcomes Measurement Information System (PROMIS) Sexual Function and Satisfaction Measurement (SexFS)

[0425] PROMIS SexFS provides researchers with a reliable and effective suite of tools to measure self-reported sexual function and satisfaction across diverse men and women. PROMIS SexFS v2 is a comprehensive, customizable measurement system with evidence of validity across various populations. A score of 50 (SD 10) for each domain corresponds to the average sexual activity of U.S. adults over the past 30 days. Domains shared across the measurements include desire / interest in sexual activity, lubrication and vaginal discomfort / pain, orgasm, and satisfaction. Items in PROMIS SexFS rate sexual function experienced over the past 30 days on a 5-point scale. PROMIS SexFS is a suite of measurements that includes separate domains for interest in sexual activity (4 items), overall satisfaction with sexual life (7 items), orgasm (1 item), lubrication (8 items), and vaginal discomfort (10 items). PROMIS SexFS assessments will be conducted during the screening period and at week 12 (+3 days). The development of PROMIS SexFS has been published, for example, in Flynn et al., J Sex Med, 2014, DOI: 10.1111 / j.1743-6109.2012.02995.x.

[0426] Sexual Function Questionnaire and Sexual Event Diary (SED) to record satisfying sexual events (SSE).

[0427] SED is a patient-reported outcomes tool that has been developed to assess sexual satisfaction and sexual function during discrete sexual events. The SED is an 11-item questionnaire completed by the subject within 24 hours of the sexual event. Items assess the type and timing of the sexual event and whether medication was used; two binary items assess whether the sexual event was satisfactory and whether the subject achieved orgasm; and six 5-point Likert scale items assess desire, mental arousal / excitement, physical arousal / excitement, presence and intensity of distracting thoughts, ability to let go, and experienced pleasure. The percentage of SSE is calculated. The SED is described in detail, for example, in van Nes et al., J Seks Med, 2017, DOI: 10.1016 / j.jsxm.2017.09.008.

[0428] Patient Overall Change Impression (PGIC)

[0429] The PGIC is used to assess the status of the sexual arousal disorder under investigation and to evaluate whether the status has improved or decreased as judged by the patient. At week 12, each enrolled participant will be asked to rate their overall experience using a reproduced 7-point Likert scale.

[0430] "My overall situation since the start of the research is as follows:"

[0431] Select only one box:

[0432] [ ] A very significant improvement (score 1)

[0433] [ ] Significant improvement (score 2)

[0434] [ ] Minimum improvement (score 3)

[0435] [ ] No change (score 4)

[0436] [ ] Minimum deterioration (score 5)

[0437] [ ] Significant deterioration (score 6)

[0438] [ ] A very significant deterioration (score 7)

[0439] Reference: Hurst and Bolton, J Manipulative Physiol Ther, 2004, DOI:10.1016 / j.jmpt.2003.11.003.

[0440] Patient Global Severity Impression (PGIS)

[0441] Participants used the PGIS to assess their perceived severity of the clinical condition under study and, consequently, their sexual arousal disorder in the current context. At week 12, each enrolled participant was asked to rate the severity of their sexual arousal disorder on a reproduced 7-point Likert scale as follows:

[0442] Please assess the severity of your sexual arousal disorder now:

[0443] Select only one box:

[0444] [ ] does not exist (score 1)

[0445] [ ] Very slight (score 2)

[0446] [ ] Mild (score 3)

[0447] [ ] Moderate (score 4)

[0448] [ ] Moderately severe (score 5)

[0449] [ ] Severe (Score 6)

[0450] [ ] Extremely serious (score 7)

[0451] Safety measurement and assessment

[0452] A safety assessment, as indicated in the assessment schedule, may be performed in a blind manner by a PI as shown in the specific site authorization log or by a properly authorized and trained designated person.

[0453] Statistical methods

[0454] All primary and secondary power variables at each measurement time point will be provided with descriptive statistics according to IMP.

[0455] Categorical factors will be summarized using frequency and / or percentage. Continuous and ordinal (where applicable) variables will be described using mean and standard deviation (SD), minimum, maximum, median, and quartiles.

[0456] Differences between treatment groups can be presented to compare continuous and discrete outcomes. Differences and comparisons may be accompanied by 95% confidence intervals (CI) and p-values. Further details will be provided in the Statistical Analysis Plan (SAP).

[0457] The analysis will be conducted in a secure and validated environment using server-based SAS® v9.4 or later, with a two-sided significance level of 0.05.

[0458] During the study, participants may be exposed to known or unknown concomitant events that could affect the evaluables, such as discontinuation of treatment due to specific adverse effects or potential lack of effect. Treatment policy strategies will be employed to address all known or unknown concomitant events in this study. Therefore, the ITT principle will serve as the basis for interpreting the evaluables. In other words, treatments will be compared regardless of the occurrence of any such concomitant events. Although no further data will be collected after participants discontinue the study, all data collected up to the time of discontinuation will be used in the analysis.

[0459] Efficacy and safety endpoints

[0460] Primary efficacy endpoint

[0461] • Common primary endpoint:

[0462] o Changes in feelings of concern about sexual arousal difficulties from baseline to week 12, as assessed by the FSDS-DAO Project 14.

[0463] o SFQ-28 Arousal-Sensory Domain (Questions 6 to 9) Changes from baseline to week 12.

[0464] Secondary efficacy endpoint

[0465] •Key secondary endpoints:

[0466] o Changes in arousal and lubrication from baseline to week 12, as assessed by the PROMIS SexFS index.

[0467] • Secondary endpoint:

[0468] o Changes in sexual function (i.e., pain) from baseline to week 12, as assessed by the following:

[0469] -FSDS-DAO-Total Score

[0470] - Percentage of SSEs recorded in the sexual arousal diary.

[0471] o Changes in sexual function from baseline to week 12, assessed by the total score of the SFQ-28.

[0472] o Changes in sexual function from baseline to week 12 as assessed by PROMIS SexFS - a customized evaluation.

[0473] o PGIC in week 12.

[0474] o The change in the severity of sexual arousal disorder from baseline to week 12 as assessed by PGIS.

[0475] Safety endpoint

[0476] Safety endpoints include the following:

[0477] • Adverse events (AEs)

[0478] • Serious adverse events (SAE)

[0479] •TEAE

[0480] •TESAES

[0481] • Clinical laboratory parameters

[0482] • Vital signs

[0483] Analyzing the population

[0484] Three population groups will be used in the analysis of clinical data:

[0485] The target population for analysis will include the following:

[0486] • Safety set: Includes all subjects who have received at least one dose of IMP. This will be used for all safety analyses.

[0487] • FAS: Includes all randomized subjects with baseline and week 12 efficacy assessment. This will be the primary population for the efficacy analysis.

[0488] • ITT set: Includes all randomized subjects. This will be used as a sensitivity analysis for validity analysis.

[0489] Efficacy Analysis

[0490] Demographic and baseline variables

[0491] Demographic and baseline variables included age, ethnic origin, height, weight, and BMI. Other baseline information included medical and surgical history, as well as past and concurrent medications.

[0492] Previous and concomitant medications will be coded using the WHO Drug Dictionary and summarized by drug class and name for all subjects in each treatment group and combination. Medical and surgical history will be coded using the Dictionary of Medical Regulatory Activities (MedDRA, latest version) and summarized by system organ class and preferred terminology, as well as by high-level terminology and preferred terminology for all subjects in each treatment group and combination.

[0493] Primary efficacy endpoint

[0494] The changes in feelings of concern about sexual arousal difficulties assessed by FSDS-DAO Project 14 from baseline to week 12, as well as the changes in the arousal-sensory domain (questions 6 to 9) of SFQ28 from baseline to week 12, will be descriptively summarized and analyzed using an analysis of covariance (ANCOVA) model.

[0495] The model will include the treatment group as a fixed effect. The corresponding baseline score will be included as a covariate in the model. Estimates of treatment differences, 95% CI, and p-values ​​will be provided.

[0496] The primary analysis will be based on FAS. The ITT set will be used for sensitivity analysis.

[0497] Secondary efficacy endpoint

[0498] Changes in arousal and lubrication (PROMIS – SexFS), FSDS-DAO-total score, SSE percentage, sexual function (SFQ-28-total score and PROMIS – SexFS customized) and PGIS from baseline to week 12 will be descriptively summarized and analyzed by ANCOVA, as co-primary endpoints.

[0499] The number and percentage of subjects reporting improvement in PGIS severity or PGIC improvement (minimum, significant, or very significant) will be presented along with treatment comparisons using a chi-square test. PGIS and PGIC scores will also be analyzed as response frequencies using a Cochran-Mantel-Haenszel (CMH) test for differences in mean scores.

[0500] Security Analysis

[0501] Safety data include TEAEs, vital signs, and clinical laboratory assessments. Safety analysis will be performed on the safety set. All safety data will be listed in the data list by treatment and subject. No inferential analysis is planned.

[0502] Descriptive statistics will be used to summarize the level of exposure.

[0503] The accompanying medications will be coded using the WHO Drug Dictionary and summarized by drug category and name for each treatment group.

[0504] Adverse events will be coded using MedDRA. TEAEs will be defined as any event that occurs on or after day 1 of treatment.

[0505] The incidence of TEAEs will be summarized by body system and MedDRA preferred terminology, overall and by treatment group. If a subject reports the same AE more than once, the subject will be counted only once for the summary of that AE, using the most severe intensity or the highest relationship with the study drug.

[0506] TEAE will summarize as follows:

[0507] • All TEAEs.

[0508] • All TEAEs classified by intensity.

[0509] • All TEAEs categorized according to their relationship to the investigational drug.

[0510] • All SAEs occurring during treatment

[0511] • All TEAEs led to premature termination of the study.

[0512] Clinical laboratory parameters will be summarized using descriptive statistics (as applicable). The number and percentage of subjects with clinically significant laboratory values ​​will be calculated. Laboratory conversion tables (e.g., cross-tabulations of levels below the lower limit of normal [LLN], within the normal range [WNL], and above the upper limit of normal [ULN] relative to baseline at each scheduled visit) will be used to show changes in levels from normal to high, etc.

[0513] For vital signs, descriptive statistics (e.g., n, mean, SD, median, minimum and maximum, number and percentage of subjects in a specified category) will be used to summarize the absolute values ​​and changes relative to baseline at each time point.

[0514] Determining the sample size

[0515] The sample size determination in this exploratory study focused on the arousal sensory portion of SFQ-28 questions 6-9 and FSDS-DAO item 14 (concerns about arousal difficulties). Both scales have been validated for their respective entities based on previously developed tools.

[0516] Epidemiological studies have found that approximately 12-64% of people experience arousal difficulties. Having a questionnaire that can assess these difficulties, such as the SFQ-28, was a primary objective of this study and is crucial for the diagnosis of FSAD. The SFQ-28 also demonstrated excellent internal consistency, test-retest reliability, and known group validity in both FSAD and HSDD populations.

[0517] The SFQ-28 has three subsections for assessing arousal in terms of sensation, lubrication, and cognition. For this study, the sensation subsection is contained in items 6 through 9 (Arousal Sensation). During the validation study, for this subsection, the mean validity score of the SFQ-28 for 114 participants was 8.25 (standard error [SE] 0.31), and the within-subjects correlation coefficient (ICC) was 0.87. Therefore, it is expected that the sub-scores for items 6 through 9 will be suitable for measuring changes in arousal sensation over time. The total variance can then be estimated as (0.31 × √114)² = 10.955, the between-subjects variance as (0.87 × 10.955) = 9.531, and the within-subjects residual variance as (10.955 - 9.531) = 1.424. Assuming a moderate correlation of 0.5 between baseline and post-drug administration rating, the expected standard deviation of change relative to baseline can be estimated as √(2×1.421×(1 – 0.5)) = 1.193.

[0518] The 15-item FSDS-DAO retained 13 items from the Likert-type FSDS-R scale, including two new items that asked women to rate their level of distress related to sexual arousal and orgasm. These items were relevant to the expected effects of IMP in this study. The total score was calculated as the sum of responses and ranged from 0 to 60, with higher scores indicating greater distress. In the validation publication, item 14 was reported as having no lower or upper limit response. Unfortunately, the variance of this item was not available in this publication or other publications using this questionnaire. Therefore, changes over time and among participants could be measured in this study to determine if there were significant changes in arousal response over time.

[0519] Secondary endpoints will provide the change in the overall FSDS-DAO score over time. FSDS-DAO has shown evidence supporting its validity, reliability, and responsiveness, and is therefore considered suitable for the purposes of this study.

[0520] Assuming an SD of 1.25, and considering the use of a two-sample t-test for 5% two-sided Type I error and 80% power to detect a 1-point difference between groups in SFQ-28 arousal scores (items 6 to 9), the sample size has been determined.

[0521] Because there was no information available regarding the variability of FSDS-DAO item 14, this scale was not considered in the sample size estimation. However, this trial will provide important information for considering this parameter in future study designs.

[0522] Based on the assumptions made above regarding the SFQ-28 arousal score, this calculation requires approximately 26 evaluable subjects / groups (52 subjects in total). Based on an estimated dropout rate of approximately 30%, approximately 38 subjects / groups will be randomized in this study, resulting in a total of 76 subjects.

[0523] Statistical / Analytical Problems

[0524] Covariate adjustment

[0525] Statistical analysis of primary and secondary endpoints will be adjusted based on their values ​​at baseline (where applicable).

[0526] The plan is not to adjust for any other covariates during the data analysis.

[0527] Example 2: A dose-exploratory study of daily oral estradiol (E4) for the treatment of menopausal symptoms in postmenopausal women.

[0528] Study enrollment and duration:

[0529] Enrollment was approximately 18 months. Individual participants participated for a maximum of 27 weeks: a maximum of 6 weeks of pre-screening and washout, a maximum of 4 weeks of screening and induction, a maximum of 91 days (13 weeks) of E4 / placebo treatment, followed by 2 weeks (14 days) of synthetic progestin therapy, and only in non-hysterectomized participants were they followed up for 1 week after the completion of synthetic progestin therapy.

[0530] Main efficacy goals:

[0531] The minimum effective dose (MED) of oral E4 is defined by assessing changes in the frequency and severity of moderate to severe vasomotor symptoms (VMS).

[0532] Methodology:

[0533] This is a prospective, multicenter, randomized, placebo-controlled, double-blind, dose-exploration study.

[0534] Subject population:

[0535] Eligible participants were postmenopausal women aged 40 to 65 years (inclusive) who had undergone hysterectomy or non-hysterectomy and presented with at least 7 episodes of moderate to severe hot flashes per day or at least 50 episodes of moderate to severe hot flashes per week.

[0536] Diagnostic and inclusion criteria:

[0537] At the randomization visit, participants met all of the following inclusion criteria. These criteria were assessed during the screening period:

[0538] 1. Women aged 40 to 65 years (inclusive) who had at least 7 episodes of moderate to severe hot flashes per day or at least 50 episodes of moderate to severe hot flashes per week in the week prior to randomization.

[0539] 2. Body Mass Index (BMI) between 18.0 and 35.0 kg / m² 2 Between (including end values).

[0540] 3. The postmenopausal state is defined as a follicle-stimulating hormone (FSH) level >40 IU / L and:

[0541] - Amenorrhea lasting for at least 12 consecutive months, or

[0542] - Amenorrhea lasting at least 6 months and estradiol (E2) <20 pg / mL, or

[0543] - A statement confirming the removal of both oophores must be made at least 6 weeks after the bilateral oophorectomy (with or without hysterectomy) and on a copy of the pathology report or in the subject's physician's letter.

[0544] 4. For women who have not undergone hysterectomy: an intact uterus with a double endometrial thickness ≤5 mm on TVUS.

[0545] 5. Negative pregnancy test.

[0546] 6. Based on medical, surgical, and gynecological history, physical examination, gynecological examination, clinical laboratory tests, and vital signs, the patient is in good physical and mental health, according to the judgment of the principal investigator (PI).

[0547] 7. Subjects provided signed and dated written informed consent before being allowed to enter the study.

[0548] 8. The subject is able to understand and comply with the requirements, instructions and limitations stipulated in the agreement.

[0549] Exclusion criteria:

[0550] Potential study participants are excluded if any of the following exclusion criteria are met at randomization visits. These criteria are assessed during the screening period:

[0551] 1. For women who have not undergone hysterectomy: Uterine conditions or medical conditions include:

[0552] a. For example, the double-layered endometrial thickness determined by TVUS is >5mm;

[0553] b. The presence of fibroids that obscure the TVUS assessment of the endometrium;

[0554] c. History of uterine cancer or presence of uterine cancer;

[0555] d. Endometrial hyperplasia is present;

[0556] e. The presence of endometrial polyps with proliferative or malignant epithelium.

[0557] 2. Undiagnosed vaginal bleeding within the last 12 months.

[0558] 3. Any history of malignancy other than basal cell carcinoma of the skin (excluding if within the previous 2 years) or squamous cell carcinoma (excluding if within the previous year). Any clinically significant findings on breast examination and / or on mammography suspected of breast malignancy that require further clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are permissible). Note: Screening mammography is required unless the subject has written documentation of mammograms taken within the past 9 months.

[0559] 4. Non-hysterectomized subjects with abnormal cervical Pap smears (written documentation of a previous test or screening within the past 18 months) and evidence of cervical dysplasia larger than low-grade squamous intraepithelial lesion (LSIL). Women diagnosed with atypical squamous cells of no significant significance (ASCUS) were included.

[0560] 5. Systolic blood pressure (BP) exceeding 90 to 140 mmHg, diastolic blood pressure exceeding 60 to 90 mmHg, and / or heart rate exceeding 40 to 100 bpm. Subjects with mild to moderate hypertension controlled on a stable antihypertensive regimen were included if they met the inclusion / exclusion criteria.

[0561] 6. Any clinically significant abnormalities identified on a screening 12-lead ECG.

[0562] 7. History of venous or arterial thromboembolic diseases (e.g., deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or a history of known coagulation disorders or coagulation factor abnormalities.

[0563] 8. Diabetes with poor glycemic control in the past 6 months is assessed by laboratory glucose levels exceeding the normal range and glycated hemoglobin levels above 7%.

[0564] 9. Dyslipoproteinemia predisposes subjects to atherosclerotic cardiovascular disease (ASCVD). Subjects with a 10-year ASCVD score ≥ 5% (as calculated using the ASCVD risk estimator (ACC / AHA Cardiovascular Risk Assessment Guidelines, 2013)) will not be included in the trial. In all cases, LDL cholesterol levels ≥ 190 mg / dL or plasma triglyceride levels > 400 mg / dL are excluded. If a subject is receiving lipid-lowering therapy, her treatment must have been at a stable dose for at least one month prior to screening, and the same eligibility criteria must be used.

[0565] 10. Smoking >10 cigarettes / day or using >1 ml / day of nicotine-containing e-cigarette liquid.

[0566] 11. Presence or history of gallbladder disease, unless cholecystectomy has been performed.

[0567] 12. Systemic lupus erythematosus.

[0568] 13. Multiple sclerosis.

[0569] 14. Acute or chronic liver disease.

[0570] 15. Acute or chronic renal impairment, including severe renal impairment.

[0571] 16. Uncontrolled thyroid disorders.

[0572] 17. Subjects must have a history of major depressive disorder or post-traumatic stress disorder (PTSD) within the past 2 years, or a history of other major mental disorders (such as schizophrenia, bipolar disorder, etc.) at any time.

[0573] 18. Use of medications containing estrogen or synthetic progestin. A washout period is required before the introduction period when using the following substances:

[0574] a. Vaginal hormonal products (rings, creams, gels): wash-off after at least 4 weeks;

[0575] b. Transdermal estrogen or estrogen / synthetic progesterone: washout for at least 4 weeks;

[0576] c. Oral estrogen and / or synthetic progestin: at least a 4-week washout period;

[0577] Users of current synthetic progestin implants or estrogen monotherapy should not participate unless they have stopped treatment for more than 3 months. Users of current estrogen pills or synthetic progestin injections should not participate unless they have stopped treatment for more than 6 months.

[0578] 19. Use non-hormonal treatments to reduce hot flashes. When using non-hormonal prescription and over-the-counter (OTC) treatments for hot flashes (such as antidepressants like paroxetine, escitalopram, venlafaxine, norvenlafaxine, and clonidine; or phytoestrogens, black cohosh, etc.), a one-week washout period is required before the induction period. If one of these treatments is taken concurrently with medications containing estrogen or synthetic progestin, the washout period can be combined and does not need to be performed sequentially.

[0579] 20. Use of medications that may affect VMS endpoint results within 28 days prior to the induction period. This includes (but is not limited to): SSRIs (selective serotonin reuptake inhibitors), SNRIs (serotonin and norepinephrine reuptake inhibitors), dopaminergic or anti-dopaminergic drugs, or gabapentin.

[0580] 21. History or presence of allergy to such research products or drugs, or history of allergies to drugs or other allergens that the investigator deems inadvisable for the subject to participate.

[0581] 22. History or presence of allergy or intolerance to any component of the research product.

[0582] 23. A history of alcohol or substance abuse or dependence within 12 months, as determined by the investigator, i.e., excessive alcohol consumption, drug abuse, or having a condition that the investigator believes may impair the subject's ability to comply with research requirements.

[0583] 24. Sponsor or contract research organization (CRO) employees, or personnel in the investigator's department and their relatives related to this study.

[0584] 25. Subjects with porphyria and subjects with a known or suspected clinically significant systemic disease, unstable medical condition, life-threatening disease, or current history of malignancy, which the investigator considers to pose a risk to the subject.

[0585] 26. Participated in another clinical study of an investigational drug within 1 month (30 days) or received an investigational drug within the past 3 months (90 days).

[0586] 27. Deemed unsuitable by researchers for any reason.

[0587] Number of participants:

[0588] Principles of intention therapy

[0589] This principle argues that the effectiveness of a treatment policy can be best evaluated based on the treatment subjects' intentions (i.e., the planned treatment regimen) rather than the actual treatment administered. As a result, subjects assigned to the treatment group should be followed up, evaluated, and analyzed as members of that group, regardless of their adherence to the planned treatment.

[0590] Furthermore, the intention-to-treat principle means that the primary analysis should include all randomized subjects.

[0591] Preserving the initial randomization in the analysis is important in preventing bias and providing a safety basis for statistical tests. In many clinical trials, the use of the full analysis set provides a conservative strategy. In many cases, it can also provide estimates of treatment effects that are more likely to reflect those observed in subsequent practice.

[0592] In this study, the intention-to-treat group included 257 patients.

[0593] Subjects were randomly assigned to one of five treatment groups in a 1:1:1:1:1 ratio. Randomization was stratified by center.

[0594] Research visits:

[0595]

[0596] Test products and reference therapies, dosages and routes of administration

[0597] All treatments (estradiol monohydrate, hereinafter referred to as E4, [2.5 mg, 5 mg, 10 mg, 15 mg] capsules) were administered orally once daily (QD) for at least 12 consecutive weeks until the completion of the last biological assessment (maximum day 91).

[0598] Placebo, 1 capsule QD orally administered for at least 12 consecutive weeks until the last biological assessment is completed (maximum day 90).

[0599] If, during the trial, a double endometrial thickness ≥15 mm is detected on TVUS and / or abnormal uterine bleeding is reported by a woman who has not undergone hysterectomy (as determined by a gynecologist based on estrogen therapy), she undergoes an endometrial biopsy and, in addition to E4 / placebo therapy, is treated with synthetic progestin (10 mg dydrogesterone) QD in a sequential manner (i.e., a 14-day synthetic progestin therapy period, followed by a 14-day break from synthetic progestin therapy) until the end of week 11. If the endometrial biopsy reveals endometrial hyperplasia, the subject is immediately discontinued and treatment for the hyperplasia is initiated according to local guidelines. If abnormal uterine bleeding recurs after the first normal endometrial biopsy, a thorough gynecological examination and TVUS are performed. A second endometrial biopsy is performed if necessary at the gynecologist's discretion.

[0600] Following the E4 / placebo treatment period, all non-hysterectomized subjects (including those who had previously received synthetic progestins) received synthetic progestin therapy at 10 mg dydrogesterone QD for 14 days.

[0601] result

[0602] Genitourinary symptoms (GSM)

[0603] Record the changes in the following GSM symptoms (VVA subject self-assessment) from baseline to week 12:

[0604] a) Vaginal dryness (a feeling of dryness or burning in the vagina; none = 0, mild = 1, moderate = 2, severe = 3):

[0605]

[0606] *At week 12, p<0.05 compared to placebo.

[0607] E4 = Estradiol monohydrate

[0608] b) Vaginal and / or vulvar irritation / itching (a sensation of abnormal irritation or sensitivity in the vagina; none = 0, mild = 1, moderate = 2 or severe = 3):

[0609]

[0610] E4 = Estradiol monohydrate

[0611] c) Vaginal pain associated with sexual activity (sensory perception of pain during intercourse: none = 0, mild = 1, moderate = 2 or severe = 3):

[0612]

[0613] * At week 12, p < 0.05 compared to placebo; ** At week 12, p < 0.001 compared to placebo.

[0614] E4 = Estradiol monohydrate

[0615] The evolution of VVA symptoms pointed to overall improvement, with the 15 mg daily dose showing the strongest effect. For vaginal pain associated with sexual activity, significant differences were observed compared to placebo at daily doses of 5, 10, and 15 mg (p values ​​0.0246, 0.0004, and 0.0006, respectively). However, vaginal dryness, often considered the most troublesome symptom, was significantly improved only with the next 15 mg daily dose (p value 0.0291).

[0616] Measurements related to treatment side effects

[0617] 1. Number of patients who underwent biopsies

[0618]

[0619] E4 = Estradiol monohydrate

[0620] 2. Adverse Events (AEs)

[0621]

[0622] E4 = Estradiol monohydrate

[0623] As shown in the table above, patients in the 15 mg group experienced fewer TEAEs than those in the 10 mg group. Among patients in the 10 mg group with AEs, the average number of AEs per patient was 3.2. In contrast, the average number of AEs per patient in the 15 mg group was 2.6. Overall, these data suggest that the 15 mg daily dose provides significant relief for VMS without incurring additional AEs. Furthermore, the 15 mg daily dose required fewer biopsies than the 10 mg daily dose.

[0624] This was confirmed by the following statistical analysis. Using a Poisson regression model with random effects on patients and the treatment group as a covariate to model the counts of TEAEs in different treatment groups showed no statistically significant difference between the treatment groups (p = 0.099). Secondly, the chi-square test was used to assess whether the prevalence of reported TEAEs was similar across the treatment groups. No statistically significant difference was found between the treatment groups (p = 0.575).

[0625] 3. Patients who left the study

[0626]

[0627] E4 = Estradiol monohydrate

[0628] Example 3: A clinical study evaluating the impact of estradiol monohydrate treatment on sexual domain scores as part of quality of life.

[0629] A clinical study was designed to evaluate the effect of treatment with E4 (estradiol monohydrate) 15 mg or 20 mg or placebo for up to 13 consecutive weeks on the severity and frequency of vasomotor symptoms (VMS) in postmenopausal participants who had undergone hysterectomy or non-hysterectomy. To protect the endometrium, all non-hysterectomy participants were treated with 200 mg progesterone (P4) once daily for 14 consecutive days after completion of E4 / placebo treatment.

[0630] Result metrics:

[0631] As one of the outcome measures, the change in health-related quality of life assessment (HRQoL) from baseline to week 12 was assessed using the menopausal-specific quality of life (MENQOL) questionnaire [time range: baseline and week 12].

[0632] MENQOL is a self-administered questionnaire used to assess changes in quality of life over a one-month period. It consists of 29 questions indicating whether the subject has experienced a problem (yes / no), and if so, the rating scale ranges from 0 = no distress to 6 = extreme distress. For analysis, raw scores are converted into analytical scores ranging from 1 to 8, where no = 1, 0 = 2, 1 = 3... and 6 = 8. The scale comprises four domains: vasomotor, psychosocial, physical, and sexual.

[0633] Inclusion criteria:

[0634] • Before any trial procedure begins, after explaining the nature of the trial as required by local regulations, obtain signed and dated written informed consent and any necessary privacy authorizations;

[0635] • Female, aged ≥40 to ≤65 years at the time of randomization;

[0636] • For subjects who have undergone hysterectomy: The recorded hysterectomy must have occurred at least 6 weeks prior to the start of screening. The hysterectomy may be a total hysterectomy or a partial hysterectomy (i.e., without removal of the cervix);

[0637] • For subjects who have not undergone hysterectomy: Uterus with a double endometrial thickness ≤4 mm on TVUS;

[0638] • For subjects who have not undergone hysterectomy: Evaluable endometrial biopsy performed during screening should show no abnormalities, i.e., the presence of hyperplasia (simple or complex, with or without atypia), the presence of cancer, or the presence of disordered hyperplastic endometrium. Screening biopsies should include sufficient endometrial tissue for diagnosis;

[0639] • Seek treatment to alleviate menopausal-related VMS;

[0640] 1. During the last 7 consecutive days of the screening period, at least 7 moderate to severe troublesome VMS per day or at least 50 moderate to severe troublesome VMS per week;

[0641] • Body mass index ≥ 18.0 kg / m 2 Up to ≤38.0 kg / m 2 ;

[0642] • Mammograms taken during the screening period or within 9 months prior to the start of screening that do not show significant signs of disease;

[0643] • Postmenopausal status is defined as any of the following:

[0644] • For subjects who did not undergo hysterectomy:

[0645] 1. Spontaneous amenorrhea for at least 12 months, serum follicle-stimulating hormone (FSH) >40 mIU / mL (value obtained after elution of drugs containing estrogen / synthetic progesterone, see exclusion criteria 18 and 20);

[0646] 2. Or at least 6 months of spontaneous amenorrhea, serum FSH > 40 mIU / mL and E2 < 20 pg / mL (< 73.4 pmol / L, values ​​obtained after elution of drugs containing estrogen / synthetic progesterone, see exclusion criteria 18 and 20);

[0647] 3. Or at least 6 weeks after a bilateral oophorectomy;

[0648] • For subjects who have undergone hysterectomy:

[0649] 1. Serum FSH > 40 mIU / mL and E2 < 20 pg / mL (< 73.4 pmol / L, values ​​obtained after elution of drugs containing estrogen / synthetic progesterone, see exclusion criteria 18 and 20);

[0650] 2. Or at least 6 weeks after a bilateral oophorectomy.

[0651] • Researchers judged good physical and mental health based on medical history, physical and gynecological examinations, and clinical assessments conducted prior to visit 1;

[0652] • Able to understand and comply with the requirements, instructions, and limitations stipulated in the agreement;

[0653] • Able and willing to complete the daily paper diary (if applicable) and questionnaires for the trial.

[0654] Exclusion criteria:

[0655] • History of malignant tumors, except for basal cell carcinoma or squamous cell carcinoma of the skin (if diagnosed more than 1 year prior to the screening visit);

[0656] • Any clinically significant findings made by researchers during breast examination and / or on mammography in cases of suspected breast malignancy that require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are permissible).

[0657] • In subjects who underwent subtotal hysterectomy and non-hysterectomy, a Pap swab test was performed, and the result was atypical squamous cells not determined to be significant (ASC-US) or higher (low-grade intraepithelial lesion [LSIL], atypical squamous cells - high-grade intraepithelial lesion [HSIL][ASC-H], HSIL, dysplastic or malignant cells). Note: ASC-US is allowed if a reflex human papillomavirus (HPV) test is performed and negative for high-risk oncogene HPV subtypes 16 and 18;

[0658] • For patients who do not undergo hysterectomy:

[0659] 1. History or presence of uterine cancer, endometrial hyperplasia, or proliferative endometrial disorders;

[0660] 2. The presence of endometrial polyps;

[0661] 3. Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;

[0662] 4. Endometrial ablation;

[0663] 5. Any uterine / endometrial abnormalities that the researcher determines preclude the use of estrogen and / or synthetic progestin therapy. This includes the presence or history of adenomyosis or significant fibroids;

[0664] • During the screening period, systolic blood pressure (BP) is above 130 mmHg and diastolic blood pressure is above 80 mmHg;

[0665] • A history of venous or arterial thromboembolic diseases (such as superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.) or a first-degree family history of venous thromboembolism (VTE).

[0666] • A history of known acquired or congenital coagulopathy or coagulation factor abnormalities, including known thrombophilia;

[0667] • Fasting blood glucose levels above 125 mg / dL (>6.94 mmol / L) and / or glycated hemoglobin levels above 7%;

[0668] • Dyslipoproteinemia (LDL >190 mg / dL [>4.91 mmol / L]] and / or triglycerides >300 mg / dL [>3.39 mmol / L]);

[0669] • Subjects who smoked more than 15 cigarettes per day;

[0670] • The presence or history of gallbladder disease, unless cholecystectomy has been performed;

[0671] • Systemic lupus erythematosus;

[0672] • Any malabsorption disorder, including gastric bypass surgery;

[0673] • History of acute liver disease, or presence or history of chronic or severe liver disease [alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN), bilirubin > 1.5 ULN] within the 12 months prior to the start of screening; or liver tumor;

[0674] • Chronic or current acute renal impairment (estimated glomerular filtration rate <60 ml / min);

[0675] • Porphyria;

[0676] • The diagnosis or treatment of major mental disorders (such as schizophrenia, bipolar disorder, etc.) shall be determined by the researcher;

[0677] • The maximum use of medications containing estrogen / synthetic progesterone is:

[0678] 1. For vaginal non-systemic hormonal products (rings, creams, gels), one week prior to the start of screening;

[0679] 2. For vaginal or transdermal estrogen or estrogen / synthetic progestin products, 4 weeks prior to the start of screening;

[0680] 3. For oral estrogen and / or synthetic progestin products and / or selective estrogen receptor modulatory therapy, 8 weeks prior to the start of screening;

[0681] 4. For intrauterine synthetic progestin therapy, 8 weeks prior to the start of screening;

[0682] 5. For synthetic progestin implants or estrogen monotherapy, 3 months prior to the start of screening;

[0683] 6. For estrogen pill therapy or synthetic progestin injection therapy, 6 months prior to the start of screening;

[0684] • Use of medications containing androgens / dehydroepiandrosterone (DHEA):

[0685] 1. For oral, topical, vaginal, or transdermal androgens, 8 weeks prior to the start of screening;

[0686] 2. For implantable or injectable androgen therapies, 6 months prior to the start of screening;

[0687] • Use phytoestrogens or black cohosh for the treatment of VMS up to 2 weeks before screening begins;

[0688] • For women participating in the efficacy study: those who have used prescription or over-the-counter products for the treatment of VMS, such as antidepressants: paroxetine, escitalopram, methyldopa, opioids and clonidine, for up to 4 weeks prior to the start of screening, and those who have used venlafaxine and norvenlafaxine for up to 3 months prior to the start of screening, and who do not wish to discontinue these medications during their participation in the trial.

[0689] • They were unwilling to discontinue any hormone products as described in exclusion criteria 18, 19 and 20 during their participation in the trial;

[0690] • Untreated hyperthyroidism with abnormal TSH and free T4 at screening. Subjects with low or high TSH are allowed if their free T4 is within the normal range at screening;

[0691] • A history of allergy / intolerance to such investigational products or drugs or any of their components, or a history of allergy to drugs or other allergies that the investigator deems inadvisable for the subject to participate;

[0692] • Based on the observations in the report, such as a history of alcohol or substance abuse (including cannabis, even if legally permissible) or dependence within the 12 months prior to the start of screening, as determined by the researchers;

[0693] • Employees of the sponsor or contract research organization (CRO), or employees who are directly supervised by investigators and / or directly involved in the trial;

[0694] • Subjects with a known or suspected clinically significant systemic disease, unstable medical condition, life-threatening illness, or a current history of malignancy that the investigator considers to pose a risk to the subject;

[0695] • Participated in another clinical trial of the investigational drug within one month (30 days) prior to the start of screening or received the investigational drug within the last month (30 days);

[0696] • Deemed unsuitable by researchers for any reason;

[0697] • For non-hysterectomized subjects included in the United States and Canada: history or presence of peanut allergy.

[0698] result:

[0699] When compared with placebo, subjects treated with two doses of estradiol monohydrate showed significant improvement in their sexual function domain scores, which are part of the MENQOL score. This improvement was attributed to different parameters contributing to the sexual function domain scores: “avoidance of intimacy,” “changes in libido,” and “vaginal dryness.”

[0700]

[0701] *Sexual Function Score = Sum of all parameters in the Sexual Domain

[0702] E4 = Estradiol monohydrate

[0703] Example 4: Comparison of endometrial thickness in subjects receiving 15 mg or 20 mg estradiol monohydrate

[0704] Further data from the Phase III clinical trial indicated no difference in endometrial thickening between 15 mg and 20 mg estradiol. No significant difference in endometrial thickness was observed when comparing the 15 mg and 20 mg estradiol treatment groups, as confirmed by the adjusted p-value of 0.8560 for the ANCOVA analysis summarized in the table below. Full details of the referenced clinical study “C301” can be found online (https: / / clinicaltrials.gov / ct2 / show / NCT04209543).

[0705] surface: Endometrial thickness (mm) at week 13 - ANCOVA-differential (C301 efficacy component - SAF - unremoved hysterectomy) Tukey adjustment

[0706]

[0707] E4 = Estradiol monohydrate

[0708] In addition, a clinical study was designed to evaluate the effects of 15 or 20 mg estradiol (E4) monohydrate or placebo on the severity and frequency of vasomotor symptoms (VMS) and the safety of E4 20 mg. This study was a prospective, multicenter, randomized, placebo-controlled, double-blind, dose-exploratory study. Eligible participants were postmenopausal women aged 40 to 65 years (inclusive) who had undergone hysterectomy or non-hysterectomy and presented with at least 7 episodes of moderate to severe hot flashes per day or at least 50 episodes of moderate to severe hot flashes per week. All treatments (15 mg or 20 mg estradiol monohydrate capsules or placebo) were administered orally once daily for at least 12 consecutive weeks until the completion of the last biological assessment.

[0709] The data suggests that estradiol significantly reduced the frequency of moderate to severe VMS. Figure 2 Furthermore, compared to placebo, estradiol treatment resulted in a greater number of women experiencing a decrease in VMS frequency. Figure 3 Finally, estradiol monohydrate significantly reduced the severity of moderate to severe VMS. Figure 4In terms of VMS frequency and VMS intensity, 20 mg estradiol monohydrate further improved the effect obtained with 15 mg estradiol monohydrate.

Claims

1. A composition comprising about 14 mg to about 25 mg of estradiol component for the treatment of female sexual arousal disorder (FSAD).

2. The composition according to claim 1, wherein the estradiol component is estradiol monohydrate.

3. The composition used, wherein the composition comprises about 20 mg of estradiol monohydrate.

4. The composition used according to any one of claims 1 to 3, wherein the subject is a female subject in menopause, perimenopause, or postmenopause.

5. The composition used according to any one of claims 1 to 4, characterized in that... Improvement in one or more of the following parameters after 12 weeks: - The percentage of sexual distress assessed by the total score of the Female Sexual Distress Scale-Sexual Desire / Arousal / Orgasm (FSDS-DAO) or, if preferred, the percentage of satisfying sexual events (SSE) recorded in a sexual arousal diary. - Sexual function is assessed using the total score of the Sexual Function Questionnaire-28 (SFQ-28); - Sexual function is assessed through the Patient Reported Outcomes Measurement Information System (PROMIS) SexFS or PROMIS SexFS-customized assessment; - Patient overall change impression (PGIC) at week 12; - The severity of sexual arousal disorder as assessed by the Patient Global Severity Impression (PGIS).

6. The composition used according to any one of claims 1 to 5, characterized in that... An improvement in sexual arousal as assessed by FSDS-DAO Project 14 is preferably characterized by an improvement in sexual arousal as assessed by FSDS-DAO Project 14 after 12 weeks, compared to baseline.

7. The composition used according to any one of claims 1 to 6, characterized in that... An improvement in the arousal-sensory domain, as assessed by questions 6 to 9 of SFQ-28, is preferably characterized by an improvement in the arousal-sensory domain after 12 weeks, as assessed by questions 6 to 9 of SFQ-28, compared to baseline.

8. The composition used according to any one of claims 1 to 7, characterized in that... Improvements in arousal and lubrication as assessed by PROMIS SexFS, preferably characterized by improvements in arousal and lubrication after 12 weeks compared to baseline, as assessed by PROMIS SexFS.

9. The composition used according to any one of claims 1 to 8, characterized in that... Improvement in sexual arousal as assessed by the PGIC scale at week 12, preferably characterized by improvement in sexual arousal as assessed by improvement in sexual arousal on a 7-point Likert scale at week 12.

10. The composition used according to any one of claims 1 to 9, characterized in that... A reduction in the severity of sexual arousal dysfunction as assessed by the PGIS scale, preferably characterized by a reduction in the severity of sexual arousal dysfunction as assessed on a 7-point Likert scale compared to baseline.

11. The composition used according to any one of claims 1 to 10, wherein the subject has been diagnosed with FSAD, preferably wherein the subject has been diagnosed with FSAD according to the diagnostic criteria for FSAD in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revised Edition (DSM-IV-TR): -The lubrication-swelling response is not able to achieve or maintain sufficient sexual arousal until the completion of sexual activity; -This disorder causes significant distress or difficulties in interpersonal relationships; This sexual dysfunction cannot be better explained by another Axis I disorder, and is not solely due to the direct physiological effects of substances or general medical conditions.

12. The composition of claim 11, wherein the subject is further characterized by having a total score of ≥18 on FSDS-DAO and a score of ≥3 on FSDS-DAO-item 14 at screening.

13. The composition used according to any one of claims 1 to 12, wherein the FSAD is female cognitive arousal disorder (FCAD) or female genital arousal disorder (FGAD).

14. The composition used according to any one of claims 1 to 13, wherein the subject is affected by at least one different female sexual disorder in addition to FSAD, preferably wherein the subject is affected by at least one different female sexual disorder in addition to FSAD, wherein the disorder is selected from: hyposexuality disorder (HSDD), female orgasmic disorder and / or dyspareunia.

15. The composition used according to any one of claims 1 to 14, wherein the composition further comprises a progestin-like component, preferably wherein the progestin-like component is drospirenone, more preferably wherein the progestin-like component is 1 mg to 4 mg of drospirenone.

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