US 2005OO65158A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0065158A1 Naylor et al. (43) Pub. Date: Mar. 24, 2005 (54) TREATMENT OF SEXUAL DYSFUNCTION (30) Foreign Application Priority Data (75) Inventors: Alasdair Mark Naylor, Kent (GB); Pieter Hadewijn Van Der Graaf, Kent Jul. 16, 2003 (GB)......................................... O316673.3 (GB); Christopher Peter Wayman, Aug. 1, 2003 (GB). ... O318095.7 Kent (GB) Sep. 11, 2003 (GB)......................................... O321308.9 Correspondence Address: PFIZER INC. Publication Classification PATENT DEPARTMENT, MS8260-1611 EASTERN POINT ROAD (51) Int. Cl." ............................................ A61K 31/519 GROTON, CT 06340 (US) (52) U.S. Cl. ................................... 514/252.16; 514/262.1 (73) Assignee: Pfizer Inc. (21) Appl. No.: 10/883,622 (57) ABSTRACT (22) Filed: Jul. 1, 2004 This invention relates to the use of cyclic guanosine 3', Related U.S. Application Data 5'-monophosphate phosphodiesterase type five (PDE5) inhibitors, in combination with 5HT1a agonists for the (60) Provisional application No. 60/512,030, filed on Oct. treatment of Sexual dysfunction, particularly female Sexual 17, 2003. Provisional application No. 60/513,125, arousal disorder (FSAD) with concomitant hypoactive filed on Oct. 21, 2003. sexual desire disorder (HSDD). US 2005/0065158A1 Mar. 24, 2005 TREATMENT OF SEXUAL DYSFUNCTION 0009 FOD-Persistent or recurrent delay in, or absence of, orgasm following a normal Sexual CROSS-REFERENCE TO RELATED excitement phase. Women exhibit wide variability in APPLICATION the type or intensity of Stimulation that triggers orgasm. The diagnosis of FOD should be based on 0001. This application claims priority from United King the clinician's judgement that the woman's orgasmic dom Application Number 0316673.3, filed on Jul. 16, 2003, capacity is less than would be reasonable for her age, United Kingdom Application Number 0318095.7, filed on Sexual experience, and the adequacy of the Sexual Aug. 1, 2003, United Kingdom Application Number Stimulation she receives. 0321308.9, filed on Sep. 11, 2003 and the benefit from U.S. Provisional Application No. 60/512,030, filed on Oct. 17, 0010 Sexual Pain Disorders such as Dyspareunia 2003 and U.S. Provisional Application No. 60/513,125, filed and Vaginismus. Dyspareunia is the recurrent or on Oct. 21, 2003. persistent genital pain associated with Sexual inter course. Vaginismus is the recurrent or persistent 0002 This invention relates to the use of cyclic gua involuntary Spasm of the musculature of the outer nosine 3', 5'-monophosphate phosphodiesterase type five third of the vagina that interferes with sexual inter (PDE5) inhibitors, in combination with 5HT1a agonists for COSC. the treatment of Sexual dysfunction, particularly female 0011 More recently the American Foundation for Uro sexual arousal disorder (FSAD) with concomitant hypoac logic Disease has developed definitions using the same four tive sexual desire disorder (HSDD). classes (see The Journal of Urology, 2000, Vol 163, page 0.003 Male sexual dysfunction includes male erectile 888-893). The definitions are along similar lines as follows dysfunction, ejaculatory disorderS Such as premature ejacu to DSM-IV: lation (PE), anorgasmia (inability to achieve orgasm) and 0012 HSDD is the persistent or recurrent deficiency desire disorderS Such as hypoactive Sexual desire disorder (or absence) of Sexual fantasies/thoughts, and/or (lack of interest in sex). desire for or receptivity to Sexual activity, which 0004 The categories of female sexual dysfunction (FSD) causes personal distress. are best defined by contrasting them to the phases of normal female Sexual response: desire, arousal and orgasm (see S R 0013 FSAD is the persistent or recurrent inability to Leiblum, (1998), Definition and Classification of Female attain or maintain Sufficient Sexual eXcitement, caus Sexual Disorders, Int. J. Impotence Res., 10, S104-S106). ing personal distress, which may be expressed as a Desire or libido is the drive for sexual expression. Its lack of Subjective excitement, or genital (lubrication/ manifestations often include Sexual thoughts either when in Swelling) or other Somatic responses. the company of an interested partner or when exposed to 0014 FOD is the persistent or recurrent difficulty, other erotic Stimuli. Arousal includes the vascular response delay in or absence of attaining orgasm following to Sexual Stimulation, an important component of which is Sufficient Sexual Stimulation and arousal, which genital engorgement and increased vaginal lubrication, elon causes personal distress. gation of the vagina and increased genital Sensation/sensi tivity and a Subjective eXcitement response. Orgasm is the 0015 Sexual pain disorders: Dyspareunia is the release of Sexual tension that has culminated during arousal. recurrent or persistent genital pain associated with Hence, FSD occurs when a woman has an absent, inad Sexual intercourse. Vaginismus is the recurrent or equate or unsatisfactory response in any one or more of these persistent involuntary Spasm of the musculature of phases, usually desire, arousal or orgasm. the outer third of the vagina that interferes with vaginal penetration, which causes personal distreSS. 0005 The American Psychiatric Association classifies 0016 HSDD is present if a woman has no or little desire female sexual dysfunction (FSD) into four classes: FSAD, to be sexual, and has no or few Sexual thoughts or fantasies. hypoactive sexual desire disorder (HSDD), female orgasmic This type of FSD can be caused by low testosterone levels, disorder (FOD), and sexual pain disorders (e.g. dyspareunia due either to natural menopause or to Surgical menopause. and vaginismus) see the American Psychiatric ASSocia Other causes in both pre-menopausal woman (i.e. woman tion's Diagnostic and Statistical Manual of Mental Disor who are pre-menopausal and who have not have hysterec ders, 4th Edition (DSM-IV)). tomies) as well as post menopausal women include illness, 0006 DSM-IV defines the four classes as follows: medications, fatigue, depression and/or anxiety. Factors having a potential (conscious or Sub-conscious) psychologi 0007 HSDD-Persistently or recurrently deficient cal impact Such as relationship difficulties or religious (or absent) Sexual fantasies and desire for Sexual factors may be related to the presence of/development of activity which causes marked distreSS or interper HSDD in females. Sonal difficulties. The judgement of deficiency or absence is made by the clinician, taking into account 0017 FSAD is a highly prevalent sexual disorder affect factors that affect functioning, Such as age and the ing pre-, peri-, and post menopausal women. It is associated context of the perSons life. with concomitant disorderS Such as depression, cardiovas cular diseases, diabetes and UG disorders. FSAD is charac 0008 FSAD-Persistent or recurrent inability to terised by inadequate genital response to Sexual Stimulation. attain, or to maintain until completion of the Sexual The genitalia do not undergo the engorgement that charac activity, an adequate lubrication-Swelling response terises normal Sexual arousal. The Vaginal walls are poorly of Sexual excitement. lubricated, So that intercourse is painful. Orgasms may be US 2005/0065158A1 Mar. 24, 2005 impeded. FSAD can be caused by reduced oestrogen at 0029. In an embodiment of the invention, the female menopause or after childbirth and during lactation, as well Subject is oestrogen and androgen replete. Replete levels of as by illnesses, with vascular components Such as diabetes the oestrogen and androgen may already exist in the Subject and atherosclerosis. Other causes result from treatment with or they may be achieved artificially. Replete levels or diuretics, antihistamines, antidepressants e.g. Selective Sero Oestrogen may be achieved artificially by administration of tonin reuptake inhibitors or antihypertensive agents. estradiol, estrone, estriol, a synthetic oestrogen (for example 0018 Sexual pain disorders (includes dyspareunia and Oestrogen benzoate), an agent which causes the body to vaginismus) are characterised by pain resulting from pen produce oestrogen and/or an oestrogen receptor modulator/ etration and Sexual activity and may be caused by medica agonist (for example raloxifene or lasofoxifene). Replete tions which reduce lubrication, endometriosis, pelvic levels of androgen may be achieved by administration of an inflammatory disease, inflammatory bowel disease or uri androgen (Such as include androsterone, dehydro-androster nary tract problems. one, testosterone, androstanedione or a synthetic androgen), an agent which causes the body to produce androgen and/or 0019 We have now found that PDE5 inhibitors in com bination with 5HT1a agonists work well in treating subjects androgen receptor modulator/agonist (for example tibolone) who suffer from sexual dysfunction. The combination may 0030 AS used herein the term replete means having be deemed Synergistic. concentrations of Oestrogen and androgen equal to or greater 0020 Suitable sexual dysfunctions include FSAD, than minimum physiological concentrations found in a nor HSDD and FOD in women and MED in men. mal Subject. 0021 We have found that PDE5 inhibitors in combina 0031 Oestrogen is the general term for any substance tion with 5HT1a agonists work particularly well in FSAD having the physiological activity of oestradiol. It includes subjects who suffer from concurrent significant HSDD. The