CA2933921A1 - Methods of treating women for hypoactive sexual desire disorder (hsdd) with bupropion and trazodone combination treatment - Google Patents

Abstract

The present invention relates to methods of treating women for hypoactive sexual desire disorder (HSDD) with oral daily treatments of low dose and high dose combinations of trazodone and bupropion.

Description

Methods of Treating Women for Hypoactive Sexual Desire Disorder (HSDD) with Bupropion and Trazodone Combination Treatment Cross-Reference to Related Patent Applications This application is related and claims priority to U.S. provisional Application No. 62/351,904, filed on June 17, 2016 and entitled "Methods of Treating Women for Hypoactive Sexual Desire Disorder (HSDD) with Bupropion and Trazadone Combination Treatment", which is incorporated herein by reference in its entirety.
This application is also related to U.S. Patent Application No. 14/045,677, filed on October 3, 2013 and entitled "Treatment Regimens", and U.S. Patent Application No.
14/120,112, filed on August 6, 2013 and entitled "Treatment Regimens", each of which is incorporated herein by reference in its entirety as if fully set forth herein.
Background Hypoactive sexual desire disorder (HSDD) is one of, if not, the most common sexual dysfunction problems presented today to clinicians for diagnosis and treatment. HSDD
affects men and women of all ages. According to myVMC, it is estimated that approximately 20%
of men and 33% of women are affected by low or absent sexual desire. See "Hypoactive Sexual Desire Disorder (HSDD)", reported at http://www.myvinc.com/diseases/hypoactive-sexual-desire-disorder-hsdd/.
HSDD is defined as "a deficiency or absence of sexual fantasies and desire for sexual activity.
The disturbance must cause marked distress or interpersonal difficulty." See Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV-TR), 4th Ed., Text Rev.
Washington, DC: American Psychiatric Association, 2000; and International Classification of Diseases (ICD-10, F52.0).
HSDD can have serious deleterious effects on the overall health of women, their quality of life, and the well-being of their personal relationships. The lack of sexual desire in women may not only cause severe psychological, emotional and/or relationship distress which, in some cases, can be severe and debilitating, it can negatively impact their personal relationships, quality of life, and well-being. HSDD can be a major impediment to life satisfaction and happiness.
[0004] Thus, Clinicians need to understand the implications and address the concerns of their patients.
Unlike other physical disorders, HSDD diagnosis is generally a subjective diagnosis by the health care provider. HSDD diagnosis therefore typically relies upon clinical judgment based on the individual's characteristics, the interpersonal determinants including relationship, the life and home context, and the cultural setting. Women with HSDD typically have a decline in sexual thoughts, a decline in interest in initiating sexual relations, and a decline in being receptive to a partner's initiation.
While HSDD is the most common sexual disorder for women of all ages, to date, it has been difficult to address and the prevalence rates have varied from study to study, as exemplified above and as follows. For example, Segraves and Woodard referenced reports that HSDD
affects between about 5.4% and about 13.6% women. See Segraves R, Woodard T:
Female hypoactive sexual desire disorder: history and current status. J Sex Med, 3(3):408-418 (2006).
West et al. reports that HSDD affects about 8.3% women. See West SL, D'Aloisio AA, Agans RP, Kalsbeek WD, Borisov NN, Thorp JM: Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Intern Med., 168(13):1441-1449 (2008). The Prevalence of Female Sexual Problems Associated with Distress and Determinants of Treatment Seeking study (the PRESIDE Study) reports that HSDD
affects about 8.9% of women between the ages of 18 to 44, about 12.3% of women between the ages of 45 to 64, and about 7.4% of women who are 65 years in age or older.
Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB: Sexual problems and distress in United States women:
prevalence and correlates. Obstet Gynecol., 112(5):970-978 (2008). Meanwhile, the International Society for Sexual Medicine reports that HSDD affects about 10%
of all women.
See "Hypoactive Sexual Desire Disorder In Women", as reported at http://www.issminfo/who-we-are/public-policy/hypoactive-sexual-desire-disorder-in-women/. See also West SL1, D'Aloisio AA, Agans RP, Kalsbeek WD, Borisov NN, Thorp JM: Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women.

2 Arch Intern Med., 168(13):1441-9 (July 14, 2008). The variation in prevalence between studies could be due to differences in, for example, the definition of HSDD utilized, data collection methods utilized, age-groups studied, and other selected criteria utilized.
On August 18, 2015, the FDA approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. To date, Addyi (flibanserin) is the first and only treatment approved by the FDA to treat HSDD.
Unfortunately, Addyi (flibanserin) so far has not apparently enjoyed the same level of success as Viagra or other phosphodiesterase (PDE) inhibitors for the treatment of erectile dysfunction in men. Rather, the sales for Addyi (flibanserin), since launch, have been met with what appears to be considerable disappointment. See, e.g., "Selling 'Female Viagra': Agreement With FDA Forces Sprout Pharmaceuticals To Market Its Low Sexual Desire Pill In New Ways", as reported at http://www.ibtimes.com/selling-female-viagra-agreement-fda-forces-sprout-pharmaceuticals-market-its-low-2147020; "Why Sales of 'Female Viagra' Addyi Have Been So Anticlimactic", as reported at http://time.com/money/4116171/female-viagra-addyi-sales/; "The Female Libido Pill Is No Viagra", as reported at http://www.bloomberg.com/news/articles/2015-11-17/valeant-s-newest-problem-the-female-libido-pill-isn-t-selling; "Female Sex Drug Addyi Not Sprouting Sales for Valeant (VRX)", as reported at http://www.biospace.com/News/female-sex-drug-addyi-not-sprouting-sales-for/399895; and "Pill for Low Libido in Women Goes on Sale on Saturday", as reported at https://www.nlm.nih.gov/medlineplus/news/fullstory 155191.html.
According to the article entitled "Five Studies: Does Flibanserin Provide Real Sexual Benefits for Women?", as reported in Pacific Standard, the Addyi (flibanserin) placebo-controlled trials in HSDD showed only about a 7% improvement over placebo. More specifically, "Nile trial found a trend among outcomes: Women achieved an average of one more "satisfying sexual event" per month on flibanserin. These could include any type of genital stimulation. More than 23 percent of women on flibanserin felt that they were "very much" or "much"
improved, compared with 16.2 percent on placebo." See http://www.psmag.com/health-and-behavior/is-flibanserin-the-real-deal-or-a-pharmaceutical-ploy. In that same Pacific Standard article, it

3 suggests that `Thesearch suggests that the now-FDA-approved female libido-booster is¨at least in part¨a pharmaceutical ploy." See http://www.psmag.com/health-and-behavior/is-flibanserin-the-real-deal-or-a-pharmaceutical-ploy.
Thus, notwithstanding the overwhelming and growing need to effectively treat women for HSDD, and the approval of Addyi0 (flibanserin) by the FDA, such a treatment still remains elusive and unmet. Consequently, it is apparent that HSDD needs greater attention from healthcare professionals across all clinical disciplines. It is equally apparent that there still is a need for an effective HSDD treatment that can be prescribed to women to treat women for HSDD with therapeutic confidence.
Summary of the Invention The present invention overcomes the drawbacks and disadvantages of the current state of treatments of women for HSDD through the discovery of a novel and effective combination treatment for treating women for HSDD.
Generally speaking, the novel combination treatments of the present invention comprise treating women for HSDD, who are in need of HSDD treatment, with a combination of two drugs, namely, bupropion and trazodone, in accordance with specific treatment regimens. Specifically, the combination treatments of the present invention comprise administering to a woman bupropion either once or twice daily and trazodone once daily, each in amounts effective to treat the woman for HSDD. More specifically, and in accordance with the present invention, the bupropion is administered to a woman in the morning or in the morning and again about 8 hours later in the latter part of the afternoon in two equal dosage amounts and the trazodone is administered to the woman at night, preferably at bedtime, in a single dosage amount. Even more specifically, the bupropion dosage strength that is used in accordance with the present invention to treat women for HSDD, whether administered once daily or twice daily, is 150 mg, and the trazodone dosage strength that is used in accordance with the present invention to treat women for HSDD is 75 mg or 150 mg. Preferably, both the bupropion and trazodone are oral extended release (ER) or sustained release (SR) dosage forms, and the women that are treated for HSDD are premenopausal women.

4 The moderate dose treatment regimen in accordance with the present invention, i.e., oral bupropion 150 mg twice daily (preferably ER or SR), wherein the first bupropion dosing is administered in the morning and the second bupropion dosing is administered about 8 hours thereafter, and oral trazodone 150 mg once daily (preferably ER or SR), wherein the trazodone is administered once daily at bedtime, is referred to herein as "Moderate Dose Lorexys". The lower dose treatment regimen in accordance with the present invention, i.e., oral bupropion 150 mg once daily (preferably ER or SR), wherein the bupropion is administered once daily in the morning, and oral trazodone 75 mg once daily (preferably ER or SR), wherein the trazodone is administered once daily at night at bedtime, is referred to herein as "Low Dose Lorexys". Thus, the present invention contemplates a daily treatment combination dosage range of between about 75 mg and about 150 mg of trazodone and between about 150 mg and 300 mg of bupropion administered daily. While the trazodone is preferably administered at night and most preferably at bedtime and the bupropion is preferably administered in the morning and/or at night, and more preferably in the morning, the present invention contemplates the administration of both trazodone and bupropion together at any time of the day either in separate dosage forms or in a unitary dosage form that contains both drugs.
Uniquely, the novel combination treatments of the present invention show unexpected superiority over the HSDD treatments for woman available heretofore in efficacy and/or inducing fewer or no side effects. In an HSDD clinical trial for premenopausal women to test safety and efficacy of the Moderate Dose Lorexys and the Low Dose Lorexys, in which standard measures of sexual desire and sexual distress were used, the percentage of women treated with Low Dose Lorexys and Moderate Dose Lorexys who met responder criteria were at about 76%
and about 88%, respectively. In contrast, only 36% and 45%, respectively, of the same women, who were treated with only bupropion SR at the same dosage strengths and in accordance with the same treatment regimens, met responder criteria.
These advantages of the present invention are not just highly statistically significant, p 0.01, they are highly unexpected. The % of women who met the criteria for remission on Low Dose Lorexys and Moderate Dose Lorexys showed similar advantage over bupropion treatment.

In addition, the Low Dose Lorexys and Moderate Dose Lorexys treatments of the present invention are also an advantage over prior treatments in how rapidly patients responded.
Remission typically takes at least 3 months with other treatments, but, with the Low Dose Lorexys and Moderate Dose Lorexys treatments of the present invention, about 58% of the treated women surprisingly met remission criteria within about 4 weeks.
As to side effects, the main side effects of concern to the FDA for drugs in this field have been related to over-sedation, i.e., somnolence, fatigue, dizziness, depression, accidents, and fainting, all of which worsen with alcohol. However, surprisingly and quite unexpected, no sedative-type side effect during the clinical trial was rated as severe for the women treated with the Low Dose Lorexys and Moderate Dose Lorexys of the present invention. Also quite surprising and unexpected, treatment of the women with the Low Dose Lorexys and Moderate Dose Lorexys of the present invention during the clinical trial did not lead to discontinuation and no depression, fainting, or accidents were observed.
A "Responder", as used herein, means a sexual desire Responder, one who improve by 2 points on the standard scale from 2-10. Responder is defined on the desire subscale of the Female Sexual Function Inventory; the subscale ranges from 2 (desire at very low or none and almost never or never) to 10 (desire at very high and almost always or always).
A "Remitter", as used herein is one whose score is at least 5.
Alternatively, a sexual distress Responder is one who improves by one point on the standard scale from 0 to 4. The measure is the "bothered by low sexual desire" item of the Female Sexual Distress Scale - Revised, and it ranges from 4, always, to 0, never, and a Remitter is one whose score is no higher than 2, occasionally.
In one aspect, the invention provides compositions and methods of treating a subject suffering from or susceptible to a sexual disorder or symptom thereof (e.g., HSDD, erectile disorder, sexual interest arousal disorder, FSD, MSD, and the like) comprising administering to a subject in need thereof a therapeutically effective amount of a composition delineated herein.
In one aspect, the invention provides a composition comprising a 5-HT2A
antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier. In another aspect the composition is that wherein the 5-HT2A antagonist is also a

5-HTIA receptor agonist. In another aspect the composition is that comprising trazodone and bupropion. In another aspect the composition is that comprising trazodone in a dosage range of 25-450 mg and bupropion in a dosage range of 200-450 mg. In another aspect the composition is that comprising trazodone in a dosage range of 25-450 mg and bupropion in a dosage range of 25-450 mg.
In one embodiment, the composition is that comprising bupropion, comprising bupropion in a dosage range of 200-450 mg; comprising bupropion in a dosage range of 225-300 mg; or comprising bupropion in a dosage range of 200-275 mg; comprising bupropion in a dosage range of 100-450 mg; comprising bupropion in a dosage range of 100-275 mg;
comprising bupropion in a dosage range of 25-275 mg; comprising bupropion in a dosage range of XX-YY mg, wherein XX is an integer between 5 and 400 and YY is an integer between 50 and 450.
In one embodiment, the composition is that comprising trazodone, comprising trazodone in a dosage range of 25-450 mg; comprising trazodone in a dosage range of 75-150 mg; or comprising trazodone in a dosage range of 50-100 mg; comprising trazodone in a dosage range of XX-YY mg, wherein XX is an integer between 25 and 400 and YY is an integer between 50 and 450.
In one aspect, the invention provides a method of treating a subject suffering from or susceptible to a hypoactive sexual desire disorder (HSDD) comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a 5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier. In one aspect, one compound is both a 5-HT2A antagonist and a 5-HTIA receptor agonist (e.g., trazodone). In another aspect, the norepinephrine-dopamine reuptake inhibitor is also a alpha adrenergic blocker (e.g., bupropion).

In one aspect, the invention provides a method of treating a subject suffering from or susceptible to a hypoactive sexual desire disorder (HSDD) comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a 5-HTIA receptor agonist, a 5-HT2A antagonist, and a pharmaceutically acceptable carrier. In one aspect, one compound is the 5-HTIA receptor agonist and the 5-HT2A antagonist (e.g., trazodone).
In aspects, the method is that wherein the sexual disorder (SD) is female sexual disorder (FSD).
In aspects, the method is that wherein the SD is female orgasm disorder (FOD);
wherein the SD
is female sexual arousal disorder (FSAD); or wherein the SD is sexual pain disorder or dysfunction. In aspects, the method is that wherein the FSD includes one or more simultaneous dysfunctions of sexual desire, arousal, orgasm, and/or pain. In aspects, the method is that wherein the SD is male sexual disorder (MSD).
Another aspect is a method of treating a disease, disorder or symptom thereof described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) in a subject comprising administering to the subject a compound or composition herein.
Another aspect is a method of treating erectile dysfunction (ED) in a subject comprising administering to the subject a compound or composition herein.
Another aspect is a method of treating male HSDD in a subject comprising administering to the subject a compound or composition herein.
Another aspect is an extended release composition comprising a 5-HT2A
antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier.
In one aspect, the invention provides a composition comprising the 5-HTIA
receptor agonist and 5-HT2A antagonist nefazodone and a pharmaceutically acceptable carrier.
In one aspect, the invention provides a composition comprising the 5-HTIA
receptor agonist and 5-HT2A antagonist mirtazapine and a pharmaceutically acceptable carrier.

Other aspects include those, wherein the composition is administered orally;
wherein the composition is administered topically; wherein the subject is diagnosed and being treated for depression; wherein the subject is not undergoing treatment for depression;
wherein the subject is concurrently prescribed an additional therapeutic agent; or wherein the subject is concurrently not prescribed an additional therapeutic agent; wherein the subject is concurrently administered an additional therapeutic agent; or wherein the subject is concurrently not administered an additional therapeutic agent.
In one aspect, the invention provides a composition comprising a 5-HTIA
receptor agonist, a 5-HT2A antagonist, and a pharmaceutically acceptable carrier.
In one embodiment, the composition is that comprising bupropion, comprising bupropion in a dosage range of 100-450 mg qd; comprising bupropion in a dosage range of 200-450 mg qd;
comprising bupropion in a dosage range of 100-300 mg qd; comprising bupropion in a dosage range of 225-300 mg qd; comprising bupropion in a dosage range of 100-275 mg qd; or comprising bupropion in a dosage range of 200-275 mg qd; comprising bupropion in a dosage range of XX-YY mg qd, wherein XX is an integer between 5 and 400 and YY is an integer between 50 and 450.
In one embodiment, the composition is that comprising trazodone, comprising trazodone in a dosage range of 25-450 mg qd; comprising trazodone in a dosage range of 75-150 mg qd; or comprising trazodone in a dosage range of 50-100 mg qd; comprising trazodone in a dosage range of XX-YY mg qd, wherein XX is an integer between 25 and 400 and YY is an integer between 50 and 450.
In one embodiment, the composition is that comprising bupropion and trazodone, comprising bupropion in a dosage range of 50-450 mg and trazodone in a dosage range of 25-450 mg;
comprising bupropion in a dosage range of 200-450 mg and trazodone in a dosage range of 25-450 mg; comprising bupropion in a dosage range of 100-300 mg qd and comprising trazodone in a dosage range of 75-150 mg qd; comprising bupropion in a dosage range of 225-300 mg qd and comprising trazodone in a dosage range of 75-150 mg qd; comprising bupropion in a dosage range of 100-275 mg qd and comprising trazodone in a dosage range of 50-100 mg qd; or comprising bupropion in a dosage range of 200-275 mg qd and comprising trazodone in a dosage range of 50-100 mg qd.
In one aspect, the invention provides a method of making a composition comprising combining a 5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising combining a 5-HTIA receptor agonist, 5-HT2A antagonist, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising combining a 5-HTIA receptor agonist, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising combining a 5-HTIA antagonist, and a pharmaceutically acceptable carrier.
In one aspect, the method of making a composition comprises combining a 5-HTIA
receptor agonist, a norepinephrine-dopamine reuptake inhibitor and a pharmaceutically acceptable carrier such that the composition comprises a range of 25-450 of a 5-HTIA receptor agonist. In another aspect, the method of making comprises combining a 5-HT2A antagonist and a pharmaceutically acceptable carrier such that the composition comprises a range of 25-450 mg of a 5-HT2A
antagonist and a norepinephrine-dopamine reuptake inhibitor.
In one embodiment, the method comprises combining bupropion, trazodone, and a pharmaceutically acceptable carrier.
In one aspect, the invention provides a kit comprising a composition delineated herein and a label providing instructions for administration of the composition to a subject for treating or ameliorating HSDD or symptoms thereof in the subject.
In another aspect, the invention provides a method of treating hypoactive sexual desire disorder (HSDD) in a subject comprising administering to the subject a 5-HTiA receptor agonist, and a 5-HT2A antagonist. The methods herein can further comprise those wherein the subject is identified as in need of such treatment, and those wherein the subject is treated upon administration of the compounds and/or compositions herein. The methods can include those wherein the subject has not previously been administered the compounds and/or compositions herein, or wherein the subject has not previously been administered the compounds and/or compositions herein at the stated dosage levels or administration regimens.
In another embodiment, the invention a method of treating a subject suffering from or susceptible to a hypoactive sexual desire disorder (HSDD) comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising any one of a 5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HTIA
receptor agonist, an endocrine active agent, or any combination thereof and a pharmaceutically acceptable carrier.
In another aspect, the invention provides a method of treating hypoactive sexual desire disorder (HSDD) in a subject comprising administering to the subject a therapeutically effective amount of any one of a 5-HT2A antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HTIA
receptor agonist, an endocrine active agent, or any combination thereof.
In aspects the endocrine agent is testosterone, which can be in an amount of a dosage range of 25 to 1000 mg.
In aspects, the subject is that wherein the subject is not being treated with a selective serotonin reuptake inhibitor (SSRI) agent.
In aspects, the subject is that wherein the subject is being treated with a selective serotonin reuptake inhibitor (S SRI) agent.
In aspects, the subject is that wherein the subject is identified as having selective serotonin reuptake inhibitor (SSRI) agent induced HSDD.
In aspects, the subject is that wherein the subject is being treated with a PDE-5 inhibitor compound (i.e., sildenafil, tadalafil, and the like).
In aspects, the subject is that wherein the subject is not concurrently being treated with a PDE-5 inhibitor compound (i.e., sildenafil, tadalafil, and the like).
In aspects, the subject is that wherein the subject is being treated with an endocrine agent (e.g., testosterone).
In aspects, the subject is that wherein the subject is not concurrently being treated with an endocrine agent (e.g., testosterone).
In another aspect, the methods herein comprise taking a sample (i.e., fluid, blood, urine, saliva, tissue, etc.) and assessing a biological marker (i.e., liver enzymes, CYP3A4, and/or a genetic marker of the transport, receptor type, receptor density, receptor affinity, metabolism, or activity of serotonin, serotonin lA or 2A subtype, dopamine, or a receptor subtype of dopamine) to measure health status of the subject either prior to, during or after administration of the compositions herein.
Brief Description of the Figures The foregoing and other objects, advantages and features of the present invention, and the manner in which the same are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying figures and example, which illustrate embodiments, wherein:
FIG. 1 summarizes the results of a Phase ha 3-way open label cross-over study in which proprietary combinations of trazodone and bupropion were used to treat premenopausal women for hypoactive sexual desire disorder (HSDD);
FIG. 2 summarizes the design and doses of the Phase ha 3-way open label cross-over study;
FIG. 3 summarizes the entry criteria: inclusions of the Phase Ha 3-way open label cross-over study;

FIG. 4 summarizes the entry criteria: exclusions of the Phase Ha 3-way open label cross-over study;
FIG. 5 depicts a graph showing sample size: 30 for > 80% power to detect a delta of 35%
between control (bupropion) and Low Dose Lorexys and Moderate Dose Lorexys of the Phase ha 3-way open label cross-over study;
FIG. 6 summarizes the dispositions of the patients in the of the Phase ha 3-way open label cross-over study;
FIG. 7 summarizes the % responders for Moderate Dose Lorexys vs Bupropion of the Phase Ha 3-way open label cross-over study;
FIG. 8 summarizes the % of patients reaching remission for Low Dose Lorexys vs Bupropion of the Phase Ha 3-way open label cross-over study;
FIG. 9 summarizes Low Dose Lorexys intermediate efficacy as to patients' global impression of change, that is, % improved, for all those patients with an end of study evaluation of the Phase Ha 3-way open label cross-over study;
FIG. 10 summarizes the adverse events of the Phase ha 3-way open label cross-over study; and FIG. 11 summarizes the conclusions of the Phase Ha 3-way open label cross-over study.
Detailed Description of the Invention The present inventors have now discovered a therapeutic strategy that addresses hypoactive sexual desire disorder (HSDD) in a woman and, in particular, a pre-menopausal woman.
The present invention relates, at least in part, to the discovery that a combination of a 5-HT2A
antagonist (which is optionally a 5-HTIA receptor agonist), a norepinephrine-dopamine reuptake inhibitor, (and optionally an endocrine active agent) provides unexpected superior and synergistic results in addressing hypoactive sexual desire disorder (HSDD) in a subject.
1. Definitions Before further description of the present invention, and in order that the invention may be more readily understood, certain terms are first defined and collected here for convenience.

The term "administration" or "administering" includes routes of introducing the compound of the invention(s) to a subject to perform their intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), oral, buccal, sublingual, inhalation, rectal and transdermal.
The pharmaceutical preparations may be given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administration is preferred. The injection can be bolus or can be continuous infusion. Depending on the route of administration, the compound of the invention can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function. The compound of the invention can be administered alone, or in conjunction with either another agent as described above or with a pharmaceutically-acceptable carrier, or both. The compound of the invention can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
Furthermore, the compound of the invention can also be administered in a pro-drug form which is converted into its active metabolite, or more active metabolite in vivo.
The language "biological activities" of a compound of the invention includes all activities elicited by compound of the inventions in a responsive cell. It includes genomic and non-genomic activities elicited by these compounds.
"Biological composition" or "biological sample" refers to a composition containing or derived from cells or biopolymers. Cell-containing compositions include, for example, mammalian blood, red cell concentrates, platelet concentrates, leukocyte concentrates, blood cell proteins, blood plasma, platelet-rich plasma, a plasma concentrate, a precipitate from any fractionation of the plasma, a supernatant from any fractionation of the plasma, blood plasma protein fractions, purified or partially purified blood proteins or other components, serum, semen, mammalian colostrum, milk, saliva, placental extracts, a cryoprecipitate, a cryosupernatant, a cell lysate, mammalian cell culture or culture medium, products of fermentation, ascites fluid, proteins induced in blood cells, and products produced in cell culture by normal or transformed cells (e.g., via recombinant DNA or monoclonal antibody technology). Biological compositions can be cell-free. In a preferred embodiment, a suitable biological composition or biological sample is a red blood cell suspension. In some embodiments, the blood cell suspension includes mammalian blood cells. Preferably, the blood cells are obtained from a human, a non-human primate, a dog, a cat, a horse, a cow, a goat, a sheep or a pig. In preferred embodiments, the blood cell suspension includes red blood cells and/or platelets and/or leukocytes and/or bone marrow cells.
The term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat a hypoactive sexual desire disorder in a subject. An effective amount of compound of the invention may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound of the invention to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound of the invention are outweighed by the therapeutically beneficial effects.
A therapeutically effective amount of compound of the invention (i.e., an effective dosage) may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
Moreover, treatment of a subject with a therapeutically effective amount of a compound of the invention can include a single treatment or, preferably, can include a series of treatments. In one example, a subject is treated with a compound of the invention in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks. It will also be appreciated that the effective dosage of a compound of the invention used for treatment may increase or decrease over the course of a particular treatment. Administration regimens herein where designated are in accordance with the following abbreviations: SID or QD=Once a day; BID=Twice a day, TID=Three times a day; QID=Four times a day;
q.h.s=every night.
The term "homeostasis" is art-recognized to mean maintenance of static, or constant, conditions in an internal environment.
The language "improved biological properties" refers to any activity inherent in a compound of the invention that enhances its effectiveness in vivo. In a preferred embodiment, this term refers to any qualitative or quantitative improved therapeutic property of a compound of the invention, such as reduced toxicity.
The term "modulate" refers to an increase or decrease, e.g., the alteration in hypoactive sexual desire disorder and/or symptoms thereof in a subject such that a desired end result is achieved, e.g., a therapeutic result.
The term "obtaining" as in "obtaining a compound useful in treating hypoactive sexual desire disorder" is intended to include purchasing, synthesizing or otherwise acquiring the compound.
The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
The language "a prophylactically effective amount" of a compound refers to an amount of a compound of the invention any formula herein or otherwise described herein which is effective, upon single or multiple dose administration to the patient, in preventing or treating a sexual disorder.

The language "reduced toxicity" is intended to include a reduction in any undesired side effect elicited by a compound of the invention when administered in vivo.
The term "subject" includes organisms which are capable of suffering from a sexual disorder or who could otherwise benefit from the administration of a compound or composition of the invention, such as human (male or female) and non-human animals (male or female). Preferred humans include human patients suffering from or prone to suffering from hypoactive sexual desire disorder or associated state, as described herein. The term "non-human animals" of the invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians, reptiles, etc.
The term "susceptible to a hypoactive sexual desire disorder" is meant to include subjects at risk of developing hypoactive sexual desire disorder, e.g., subjects previously diagnosed as having or having a family or medical history of hypoactive sexual desire disorder, and the like.
The phrases "systemic administration, "administered systemically", "peripheral administration"
and "administered peripherally" as used herein mean the administration of a compound of the invention(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
The language "therapeutically effective amount" of a compound of the invention of the invention refers to an amount of an agent which is effective, upon single or multiple dose administration to the patient, in modulating hypoactive sexual desire disorder and/or symptoms of hypoactive sexual desire disorder, or in improving the patient (either objectively or subjectively according to the patient or health care provider) beyond that expected in the absence of such treatment.
2. Compounds of the Invention In one aspect, the invention provides compounds capable of modulating hypoactive sexual desire disorder in a subject. Such compounds include a 5-HT2A antagonist, a 5-HTIA
receptor agonist, a norepinephrine-dopamine reuptake inhibitor, and an endocrine active agent.
Compositions of the invention further include a pharmaceutically acceptable carrier.
The compounds delineated herein include a 5-HT2A antagonist, that is a compound that demonstrates antagonistic activity against the 5-HT2A receptor; a norepinephrine-dopamine reuptake inhibitor; that is a compound that exhibits inhibition activity in norepinephrine-dopamine reuptake; a 5-HTIA receptor agonist, that is a compound that demonstrates agonist activity against the 5-HTIA receptor; and an endocrine active agent, that is an agent that is active in modulating the endocrine system.
In one embodiment, the invention provides a compound (e.g., a compound herein) capable of modulating hypoactive sexual desire disorder; and pharmaceutically acceptable esters, salts, hydrates, solvates, isomers and prodrugs thereof Naturally occurring or synthetic isomers can be separated in several ways known in the art.
Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., "Chiral Liquid Chromatography," W. J.
Lough, Ed. Chapman and Hall, New York (1989)). Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers. For the separation of enantiomers of carboxylic acids, the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
3. Uses Of The Compounds of the Invention In one embodiment, the invention provides methods of treating hypoactive sexual desire disorder (HSDD) in a subject comprising administering to the subject a composition delineated herein. In certain embodiments, the subject is a mammal, e.g., a primate, e.g., a human.
In aspect, the disease, disorder or symptom thereof in which the compounds, compositions, and methods of treatment relate to is one described in the Diagnostic and Statistical Manual of Mental Disorders 4^th edition--Text Revision, (DSM-I-TRV), American Psychiatric Association.
In certain embodiments, the methods of the invention include administering to a subject a therapeutically effective amount of a compound of the invention in combination with another pharmaceutically active compound. Examples of pharmaceutically active compounds include compounds known to treat hypoactive sexual desire disorder (HSDD) in a subject. Other pharmaceutically active compounds that may be used can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T. R. Harrison et al. McGraw-Hill N.Y., NY; and the Physicians Desk Reference 50th Edition 1997, Oradell N.J., Medical Economics Co., the complete contents of which are expressly incorporated herein by reference. The compound of the invention and the pharmaceutically active compound may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
Determination of a therapeutically effective hypoactive sexual desire disorder (HSDD) effective amount, a prophylactically effective hypoactive sexual desire disorder amount of the compound of the invention, can be readily made by the physician or veterinarian (the "attending clinician"), as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. The dosages may be varied depending upon the requirements of the patient in the judgment of the attending clinician; the severity of the condition being treated and the particular compound being employed. In determining the therapeutically effective hypoactive sexual desire disorder amount or dose, and the prophylactically effective hypoactive sexual desire disorder amount or dose, a number of factors are considered by the attending clinician, including, but not limited to: the specific hypoactive sexual desire disorder involved;
pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal;
its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the compound of the invention with other co-administered therapeutics); and other relevant circumstances.
The dosage administration can be in a single dosage form or multiple dosage forms. The dosages can be administered concurrently, simultaneously, or sequentially. The dosages can be a single dosage immediately prior to sexual activity, or can be one or more doses daily without regard to timing prior to sexual activity. Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. A
therapeutically effective amount and a prophylactically effective amount of a compound of the invention of the invention is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day.
The identification of those patients who are in need of prophylactic treatment for hypoactive sexual desire disorder is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing hypoactive sexual desire disorder which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient (e.g., use of antidepressant drugs, hormonal contraceptives, antihormonal and/or cytotoxic chemotherapies, sedatives, antipsychotic drugs, antiepileptic drugs, mood stabilizer drugs, opioid drugs, alcohol, or narcotic drugs). A
clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination and medical/family history.
As used herein, "obtaining a biological sample from a subject," includes obtaining a sample for use in the methods described herein. A biological sample is described above.
In another aspect, a compound of the invention is packaged in a therapeutically effective amount with a pharmaceutically acceptable carrier or diluent. The composition may be formulated for treating a subject suffering from or susceptible to a hypoactive sexual desire disorder, and packaged with instructions to treat a subject suffering from or susceptible to a hypoactive sexual desire disorder.
The subject may be at risk of a hypoactive sexual desire disorder, may be exhibiting symptoms of a hypoactive sexual desire disorder, may be susceptible to a hypoactive sexual desire disorder and/or may have been diagnosed with a sexual desire disorder.
If the modulation of the status indicates that the subject may have a favorable clinical response to the treatment, the subject may be treated with the compound. For example, the subject can be administered therapeutically effective dose or doses of the compound.
Kits of the invention include kits for treating a hypoactive sexual desire disorder in a subject.
The kit may include a compound of the invention, for example, a compound described herein, pharmaceutically acceptable esters, salts, and prodrugs thereof, and instructions for use. The instructions for use may include information on dosage, method of delivery, storage of the kit, etc. In aspects, the kits (and methods of using them) comprise instructions indicating that the compositions and/or treatment methods are contraindicated for (or not to be administered to) subjects that: (1) require and/or are taking CYP3A4, CYP 2B6-, or CYP 2D6-metabolized drugs;
(ii) take any sex hormone other than an approved hormonal contraceptive; (iii) drink more than one alcoholic drink per day (e.g., 12-oz beer, 4-oz wine, etc).
Alternatively, the effects of compound of the invention can be characterized in vivo using animals models.
4. Pharmaceutical Compositions The invention also provides a pharmaceutical composition, comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In a further embodiment, the effective amount is effective to treat a hypoactive sexual desire disorder, as described previously.
In an embodiment, the compound of the invention is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the compound of the invention to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
In certain embodiments, these pharmaceutical compositions are suitable for topical or oral, buccal or sublingual administration to a subject. In other embodiments, as described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound or composition herein.
The phrase "pharmaceutically acceptable" refers to those compound of the inventions of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase "pharmaceutically-acceptable carrier" includes pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body. Each carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch;
(3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
Compositions containing a compound of the invention(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, more preferably from about 10 percent to about 30 percent.
Methods of preparing these compositions include the step of bringing into association a compound of the invention(s) with the carrier and, optionally, one or more accessory ingredients.
In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
Compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, caplets, gel caps, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention(s) as an active ingredient. A compound may also be administered as a bolus, electuary or paste.
In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
Liquid dosage forms for oral administration of the compound of the invention(s) include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
In addition to inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
Suspensions, in addition to the active compound of the invention(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof Pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compound of the invention(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
Compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
Dosage forms for the topical or transdermal administration of a compound of the invention(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound of the invention(s) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to compound of the invention(s) of the present invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of the invention(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
The compound of the invention(s) can be alternatively administered by aerosol.
This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers, The carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention(s) to the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the invention.
Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compound of the invention(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions.
In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of compound of the invention(s) in biodegradable polymers such as polylactide-polyglycolide.
Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemuisions which are compatible with body tissue.
When the compound of the invention(s) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
Regardless of the route of administration selected, the compound of the invention(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. An exemplary dose range is from 0.1 to 10 mg per day.
A preferred dose of the compound of the invention for the present invention is the maximum that a patient can tolerate and not develop serious side effects. Preferably, the compound of the invention of the present invention is administered at a concentration of about 0.001 mg to about 100 mg per kilogram of body weight, about 0.001--about 10 mg/kg or about 0.001 mg--about 100 mg/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
5. Example The invention is further illustrated by the following example which is intended to illustrate but not limit the scope of the invention.
Low Dose Lorexys and High Dose Lorexys HSDD Clinical Study in Premenopausal Women We sought to estimate the prevalence of low sexual desire and hypoactive sexual desire disorder (HSDD) in US women, focusing on their menopausal status.
Methods:
An open cross-sectional study was performed. From a probability sample of households, 2207 US women aged 30 to 70 years and in stable relationships (>or=3 months) were interviewed by telephone. The analysis focused on 755 premenopausal women and 552 naturally and 637 surgically menopausal women. Low sexual desire was defined using the Profile of Female Sexual Function desire domain, and HSDD was defined using the Profile of Female Sexual Function and the Personal Distress Scale.
Results:
Prevalence of low sexual desire ranged from 26.7% among premenopausal women to 52.4%
among naturally menopausal women. The prevalence of HSDD was highest among surgically menopausal women (12.5%). Compared with premenopausal women and adjusting for age, race/ethnicity, educational level, and smoking status, the prevalence ratios for HSDD were 2.3 (95% confidence interval, 1.2-4.5) for surgically menopausal women and 1.2 (0.5-2.8) for naturally menopausal women; the prevalence ratios for low sexual desire were 1.3 (0.9-1.9) and 1.5 (1.0-2.2) for surgically and naturally menopausal women, respectively.
Conclusions:

Prevalence of low sexual desire is elevated among surgically and naturally menopausal women vs premenopausal women. Distress about low desire (HSDD) appears to be more than twice as prevalent among surgically menopausal women vs premenopausal women, although the estimate is fairly imprecise.
Hyposexual desire disorder {HSDD) remains without approved pharmacotherapies, though one CNS agent, bupropion, is recommended. This study tested the efficacy and safety of Lorexys, a proprietary combination of bupropion and trazodone, in premenopausal women.
A clinical study was conducted with Lorexys to treat premenopausal women for HSDD. The study's primary objective was to evaluate Lorexys' safety, tolerability and pro-sexual efficacy as compared to bupropion, one of its constituent drugs. Other objectives included exploration of the onset and duration of action of Lorexys.
The study had an adaptive, three-way crossover, open-label design. It enrolled 30 premenopausal women who met the DSM-IV-TR criteria for HSDD, and it also assessed patients for the newly defined DSM-5 Sexual Interest and Arousal Disorder. Each subject received a daily dose of bupropion as an active control for four weeks followed by a week-long washout period, then daily administration of a low dose of Lorexys for four weeks followed by another washout period, and, finally, a moderate dose of Lorexys for four weeks followed by another washout period.
The dosing and treatment regimens for the study were as follows:
Active Control: Bupropion SR 300 mg was administered once daily in the morning for four weeks.
Low Dose Lorexys: Low dose Lorexys is combination therapy that consists of two drugs: buproprion and trazadone. burpropion SR 150 mg was administered once daily in the morning and trazadone ER 75 mg was administered once daily at bedtime, each for four weeks.

Moderate Dose Lorexys: Moderate dose Lorexys is also combination therapy that consist of two drugs: buproprion and trazadone. burpropion SR 150 mg was administered twice daily, once in the morning and once eight (8) hours later, and trazadone ER
150 mg was administered once daily at bedtime, each for four weeks.
Patients self-evaluated weekly with questionnaires and were assessed during eight clinic visits.
Outcome measures for efficacy included validated self-rated scales of Sexual Function and Sexual Distress and global change. Outcome measures for safety included comprehensive evaluations of symptoms and vital signs, plus standard laboratory studies and electrocardiograms. The study was conducted at two clinical sites in the U.S.
Materials and Methods:
This was an open-label crossover study in non-depressed, otherwise healthy patients with DSM-IV-TR HSDD, aged 25-50 years, with four weeks per treatment. With n=30 and 33%
more Lorexys responders vs. Bupropion SR, the power at a =0.05 was 80%. Four weeks of Bupropion SR at 300 mg/day and a washout was followed by four weeks of Lorexys low-dose (LOR-low), i.e, Bupropion SR plus Trazodone ER at doses lower than the labeled doses, followed by another washout and four weeks of Lorexys moderate-dose (LORmod; 2x LOR-low).The primary efficacy endpoint was Female Sexual Function Index Desire domain (FSFI-d); the key secondary was Female Sexual Distress Scale-Revised (FSDS-R). Analyses included %
responders and %
remitters from the first baseline, using standard definitions (see Table 1) for FSFI-d and FSDS-R
item 13 (FSDS-R-i13), plus Patient's Global Impression of Change (PGIC). See FIGS. 1-11.
Results Five patients (17%) discontinued for administrative reasons; one (4%) discontinued for adverse events, on LOR-mod. Table 1 below shows responder and remitter rates with LOR-mod; rates with LOR-low were intermediate and non-significant vs. bupropion.
Conclusion Lorexys was highly superior to bupropion in non-depressed, otherwise healthy, premenopausal HSDD to Bupropion SR alone in the treatment of premenopausal women for HSDD. See Table 1 and FIGS. 1-11.
Table 1. Results Measure Definition LOR-mod Bupropion p-value on Fisher's Exact test, 2-tailed Responders FSFI-d 2-point increase 76% 38% <0.01 FSDS-R-i13 1-point decrease 88% 45% <0.01 PGIC >=Moderately 58% 24% <0.05 Improved Remitters FSFI-d >=5 58% 24% <0.05 FSDS-R-i13 <=2 75% 32% <0.01 The disclosures of each and every patent, patent application and publication cited herein are hereby incorporated herein by reference in their entireties.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
Although the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of the invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

Having describe my invention, I claim:
(1) A method of treating a woman for HSDD with a combination treatment comprising at least two different drugs, wherein the woman is need of HSDD treatment, said method comprising:
(a) administering to the woman daily a first drug having a dosage strength of 150 mg, wherein the first drug is bupropion;
(b) administering to the woman daily a second drug having a dosage strength of 75 mg, wherein the second drug is trazodone; and (c) wherein said administration of said first drug and said second drug is in accordance with a prescribed treatment regimen for treating the woman for HSDD.
(2) A method of claim 1, wherein said administrations of said first drug and said second drug is on the same day during the prescribed treatment regimen.
(3) A method of claim 1, wherein said prescribed treatment regimen is for at least about 30 days.
(4) A method of claim 1, wherein said prescribed treatment regimen is for about one or more months.
(5) A method of claim 1, wherein said prescribed treatment regimen is for about one year.
(6) A method of claim 1, wherein said prescribed treatment regimen is for about one or more years.
(7) A method of claim 1, wherein the bupropion is in an oral extended or sustained released dosage form.

(8) A method of claim 1, wherein the trazodone is in an oral extended or sustained release dosage form.
(9) A method of claim 1, wherein the bupropion is in an oral extended or sustained released dosage form and the trazodone is in an oral extended release dosage form.
(10) A method of claim 1, wherein the woman is a premenopausal woman.
(11) A method of claim 1, wherein said administration of the first drug comprises administering the first drug to the woman in the morning.
(12) A method of claim 1, wherein said administration of the second drug comprises administering the second drug to the woman in the evening.
(13) A method of claim 1, wherein said administration of the second drug comprises administering the second drug to the woman at bedtime.
(14) A method of treating a woman for HSDD with a combination treatment comprising at least two different drugs, wherein the woman is need of HSDD treatment, said method comprising:
(a) administering to the woman daily a first drug in a dosage strength of 300 mg, wherein the first drug is bupropion; and (b) administering to the woman daily a second drug in a dosage strength of 150 mg, wherein the second drug is trazodone;
(c) wherein said administration of said first drug and said second drug is in accordance with a prescribed treatment regimen for treating the woman for HSDD.
(15) A method of claim 14, wherein said administrations of said first drug and said second drug is on the same day during the prescribed treatment regimen.

(16) A method of claim 14, wherein said prescribed treatment regimen is for at least about 30 days.
(17) A method of claim 14, wherein said prescribed treatment regimen is for about one or more months.
(18) A method of claim 14, wherein said prescribed treatment regimen is for about one year.
(19) A method of claim 14, wherein said prescribed treatment regimen is for about one or more years (20) A method of claim 14, wherein the bupropion is in an oral extended released dosage form.
(21) A method of claim 14, wherein the trazodone is in an oral extended or sustained release dosage form.
(22) A method of claim 14, wherein the bupropion is in an oral extended or sustained released dosage form and the trazodone is in an oral extended release dosage form.
(23) A method of claim 14, wherein the woman is a premenopausal woman.
(24) A method of claim 14, wherein said administration of the first drug comprises administering the first drug to the woman in a first dose of 150 mg the morning, and a second dose of 150 mg in the evening.
(25) A method of claim 14, wherein said administration of the second drug comprises administering the second drug to the woman in the evening.
(26) A method of claim 1, wherein said administration of the second drug comprises administering the second drug to the woman at bedtime.

(27) A method of treating a woman for HSDD with a combination treatment comprising at least two different drugs, wherein the woman is need of HSDD treatment, said method comprising:
administering to the woman daily Low Dose Lorexys, wherein said administration of said first drug and said second drug is in accordance with a prescribed treatment regimen for treating the woman for HSDD.
(28) A method of treating a woman for HSDD with a combination treatment comprising at least two different drugs, wherein the woman is need of HSDD treatment, said method comprising:
administering to the woman daily Moderate Dose Lorexys, wherein said administration of said first drug and said second drug is in accordance with a prescribed treatment regimen for treating the woman for HSDD.
(29) A method of treating a woman for HSDD with a combination treatment comprising at least two different drugs, wherein the woman is need of HSDD treatment, said method comprising:
(a) administering to the woman daily a first drug having a dosage strength in the range of between about 150 mg and 300 mg, wherein the first drug is bupropion;
(b) administering to the woman daily a second drug having a dosage strength in the range of between about 75 mg and 150 mg, wherein the second drug is trazodone;

and (c) wherein said administration of said first drug and said second drug is in accordance with a prescribed treatment regimen for treating the woman for HSDD.
(30) A method of claim 29, wherein the trazodone and the bupropion are in an oral extended or sustained released dosage form and the trazodone is in an oral extended release dosage form.

(31) A method of claim 29, wherein the trazodone and the bupropion are formulated into a single oral unitary dosage form.
(32) A method of claim 29, wherein the single oral unitary dosage form is a tablet.
(33) A method of claim 29, wherein the single oral unitary dosage form is a caplet.
(34) A method of claim 29, wherein the single oral unitary dosage form is a capsule.
(35) A method of anyone of claims 1-34, wherein the bupropion and the trazodone include their respective pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug forms.
(36) The use of trazadone and bupropion in the manufacture of a medicament for the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone is in an amount of about 75 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion is in an amount of about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, wherein the medicament is to be administered orally, and wherein the treatment is to be daily and continued in accordance with a prescribed treatment regimen.
(37) The use of claim 36, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.
(38) The use of claim 36, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.
(39) The use of claim 36, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.

(40) The use of claims 36, 37, 38 or 39, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(41) The use of claim 40, wherein the single oral unitary dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(42) The use of claims 36, 37, 38 or 39, wherein the trazadone and bupropion are each in a separate oral dosage form.
(43) The use of claim 47, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(44) Trazadone in an amount of about 75 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion in an amount of between about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, for combination use in the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone and bupropion are to be administered orally, and wherein the treatment is to be daily and continued in accordance with a prescribed treatment regimen.
(45) The combination use of claim 44, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.
(46) The combination use of claim 44, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.
(47) The combination use of claim 44, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.
(48) The combination use of claims 44, 45,46 or 47, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(49) The combination use of claim 48, wherein the single oral unitary dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(50) The combination use of claims 44, 45, 46 or 47, wherein the trazadone and bupropion are each in a separate oral dosage form.
(51) The combination use of claim 50, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(52) The use of trazadone and bupropion in the manufacture of a medicament for the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone is in an amount of about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion is in an amount of about 300 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, wherein the medicament is to be administered orally, and wherein the treatment is to be daily and continued in accordance with a prescribed treatment regimen.
(53) The use of claim 52, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.
(54) The use of claim 52, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.

(55) The use of claim 52, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.
(56) The use of claims 52, 53, 54 or 55, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(57) The use of claim 56, wherein the single oral unitary dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(58) The use of claims 52, 53, 54 or 55, wherein the trazadone and bupropion are each in a separate oral dosage form.
(59) The use of claim 58, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(60) Trazadone in an amount of about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion in an amount of between about 300 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, for combination use in the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone and bupropion are to be administered orally, and wherein the treatment is to be daily and continued in accordance with a prescribed treatment regimen.
(61) The combination use of claim 60, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.

(62) The combination use of claim 60, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.
(63) The combination use of claim 60, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.
(64) The combination use of claims 60, 61, 62, or 63, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(65) The combination use of claim 64, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(66) The combination use of claims 60, 61, 62, or 63, wherein the trazadone and bupropion are each in separate oral dosage forms.
(67) The combination use of claim 66, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(68) The use of trazadone and bupropion in the manufacture of a medicament for the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone is in an amount of between about 75 mg and about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion is in an amount of between about 150 mg and about 300 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, wherein the medicament is to be administered orally, and wherein the treatment is to be daily and continued in accordance with a prescribed treatment regimen.
(69) The use of claim 68, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.

(70) The use of claim 68, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.
(71) The use of claim 68, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.
(72) The use of claims 68, 69, 70, or 71, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(73) The use of claim 72, wherein the single oral unitary dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(74) The use of claims 68, 69, 70, or 71, wherein the trazadone and bupropion are each in a separate oral dosage form.
(75) The use of claim 74, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(76) Trazadone in an amount of between about 75 mg and about 150 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer or prodrug thereof, and bupropion in an amount of between about 150 mg and about 300 mg, and any pharmaceutically acceptable salt, ester, hydrate, solvate, isomer and prodrug thereof, for combination use in the treatment of hypoactive sexual desire disorder (HSDD), wherein the trazodone and bupropion are to be administered orally, and wherein the treatment is to daily and be continued in accordance with a prescribed treatment regimen.

(77) The cornbination use of claim 76, wherein the trazodone is in an oral extended or sustained release dosage form and the bupropion is in an oral extended or sustained release dosage form.
(78) The combination use of claim 76, wherein the trazodone and the bupropion are each in an oral immediate release dosage form.
(79) The combination use of claim 76, wherein the trazodone and the bupropion are in the same or different oral dosage forms, wherein the oral dosage forms are selected from a group of oral dosage forms consisting of an oral immediate release dosage form, an oral extended release dosage form and an oral sustained release dosage form.
(80) The combination use of claims 76, 77, 78 or 79, wherein the medicament is a single oral unitary dosage form comprised of both the trazodone and the bupropion.
(81) The combination use of claim 80, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.
(82) The combination use of claims 76, 77, 78 or 79, wherein the trazadone and bupropion are each in separate oral dosage forms.
(83) The combination use of claim 82, wherein the separate oral dosage form is selected from a group consisting of a tablet, a caplet, a capsule, a gel cap, a pill, a cachet, a lozenge, a powder and granules.