KR20170142797A - Methods of Treating Women for Hypoactive Sexual Desire Disorder (HSDD) with Bupropion and Trazodone Combination Treatment - Google Patents

Abstract

The present invention relates to a method for treating female hypoactive sexual desire disorder (HSDD) using daily oral administration of low dose and high dose trazodone and bupropion combinations. The method comprises: (a) perform daily administration of a first drug at a dose concentration of 150 mg to a female patient in need of HSDD treatment, wherein the first drug is bupropion; and (b) perform daily administration of a second drug at a dose concentration of 75 mg to the female patient, wherein the second drug is trazodone.

Description

(HSDD) with Bupropion and Trazodone Combination Therapy for the Treatment of Sexual Loss Induced Disorder (HSDD)

Cross reference of related patent application

The present application is related to U.S. Patent Application No. 14 / 045,677 entitled "Treatment Regimens", filed October 3, 2013, and U.S. Patent Application No. 14 / 120,112, filed August 6, "Treatment Regimens"), each of which is incorporated herein by reference in its entirety as if fully set forth herein.

Background technology

Sexual desensitization disorder (HSDD) is one of or the most common sexual dysfunction problem presented today for clinicians to diagnose and treat. HSDD occurs in men and women of all ages. According to myVMC, it is estimated that approximately 20% of men and 33% of women develop low or no sex drive. See the material "Hypoactive Sexual Desire Disorder (HSDD)" reported at http://www.myvmc.com/diseases/hypoactive-sexual-desire-disorder-hsdd/.

HSDD is defined as "a lack of sexual fantasy and a lack of desire for sexual activity". The harm caused by this necessarily causes a significant discomfort or interpersonal difficulty. 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 adverse effects on women's overall health, their quality of life, and their well-being. Without sexual desire for women, in some cases they can have a negative impact on their relationships, quality of life, and well-being, as well as being able to cause a variety of psychological, emotional, and / have. HSDD can be a major obstacle to life satisfaction and happiness.

Therefore, clinicians need to understand these effects and address their concerns.

Unlike other disabilities, HSDD diagnoses are generally subjective diagnoses by health care providers. Thus, HSDD diagnosis typically depends on clinical judgment based on individual characteristics, interpersonal relationships such as relationships, routine and family life, and cultural environment. Women with HSDD typically have reduced sexuality, reduced interest in sexual intercourse, and reduced acceptance of partner attempts.

Although HSDD is the most common sexual disorder in women of all ages, it is difficult to address until now and its prevalence varies from study to study as illustrated above and below. For example, Segraves and Woodard have reported that HSDD occurs in about 5.4% to about 13.6% of women. Segraves R, Woodard T: Female hypoactive sexual desire disorder: history and current status. J Sex Med, 3 (3): 408-418 (2006). West reported that HSDD occurred in about 8.3% of women. 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 study of prevalence and disinhibition of women with disabilities (PRESIDE study) found that HSDD accounts for about 8.9% of women aged 18 to 44 years, 45 to 64 years (12.3% of women of three years of age and 7.4% of women of 65 years of age or older) (Shifren JL, Monz BU, Russo PA, Segretia A, Johannes CB: Sexual problems and distress in United States women: prevalence and correlates The International Society for Sexual Medicine reports that HSDD occurs in about 10% of all women. (See Obstet Gynecol., 112 (5): 970-978 (2008)). See the material "Hypoactive Sexual Desire Disorder In Women" reported at http://www.issm.info/who-we-are/public-policy/hypoactive-sexual-desire-disorder-in-women/. Prevalence of low sexual desire and hypoactive sexual desire disorder in a nationally representative sample of US women. Arch Intern Med., 168 (13): 1441-9 (July 14, 2008). Variations in the prevalence for each study may be due to, for example, differences in the definition of HSDD used, differences in data collection methods used, differences in age groups studied, and other selection criteria used.

On August 18, 2015, the FDA approved Addyi® (flibanserin) for the treatment of pre-menopausal women with acquired systemic libido (HSDD). [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm]. So far, ADDI® (flibanserin) was the first and only treatment for HSDD treatment approved by the FDA. Unfortunately, ADDI® (flibanserin) has apparently not achieved the same level of success as Viagra® or other phosphodiesterase (PDE) inhibitors for the treatment of erectile dysfunction in men until now. Rather, the sales of ADDI® (flibanserin) have shown a level of disappointment since launch. For example, "Selling 'Female Viagra': Agreement" reported at [http://www.ibtimes.com/selling-female-viagra-agreement-fda-forces-sprout-pharmaceuticals-market-its-low-2147020] With FDA Forces Sprout Pharmaceuticals To Market Its Low Sexual Desire Pill In New Ways "; "Why Sales of 'Female Viagra' Addyi Have Been So Anticlimactic" reported at [http://time.com/money/4116171/female-viagra-addyi-sales/]; [http://www.bloomberg.com/news/articles/2015-11-17/valeant-s-newest-problem-the-female-libido-pill-isn-t-selling] "The Female Libido Pill Is No Viagra "; "Female Sex Drug Addyi Not Sprouting Sales for Valeant (VRX)" reported in [http://www.biospace.com/News/female-sex-drug-addyi-not-sprouting-sales-for/399895]; See "Pill for Low Libido in Women on Sale on Saturday" reported at [https://www.nlm.nih.gov/medlineplus/news/fullstory_155191.html].

According to an article entitled "Five Studies: Does Flibanserin Provide Real Sexual Benefits for Women?" Reported in the Pacific Standard, the ADDY® (flibanserin) placebo-controlled trial in HSDD resulted in approximately 7 % Improvement. More specifically, the test confirmed the tendency among the results: women who took flibanserin achieved an average of one more "satisfactory sex" per month. These could include any type of genital stimulation. More than 23 percent of women who took flibanserin felt "very much" or "much" improved compared to the 16.2 percent who took the placebo. See [http://www.psmag.com/health-and-behavior/is-flibanserin-the-real-deal-or-a-pharmaceutical-ploy]. In the same Pacific Standard article above, "The study suggested that the current FDA-approved female libido-booster - at least in part - suggests ploy." See [http://www.psmag.com/health-and-behavior/is-flibanserin-the-real-deal-or-a-pharmaceutical-ploy].

Thus, despite the overwhelming and growing need for effective treatment of women with HSDD and the approval of ADI® (flibanserin) by the FDA, these treatments remain difficult to find and unmet. In conclusion, it is clear that HSDD requires a higher level of attention from professional staff to clinical training. It is also clear that there is still a need for effective HSDD treatment that can be prescribed to women to achieve therapeutic confidence and to treat HSDD in women.

The present invention overcomes the drawbacks and shortcomings of the current state of treatment of female HSDD through the discovery of new and effective combination therapies for treating HSDD in women.

Generally speaking, the novel combination therapies of the present invention include treating HSDD in a woman in need of HSDD treatment in combination with two drugs, bupropion and trazodone, according to a particular therapeutic regimen. Specifically, the combination treatment of the present invention comprises administering to a female bupropion once or twice a day, and in an amount effective to treat trazodone once a day in a female HSDD. More specifically, according to the present invention, bupropion is administered to the female in the morning, or in about two to eight hours later in the morning and late afternoon, again in two equal doses, and the trazodone is administered at night, Dose. More specifically, the bupropion dose concentration used in accordance with the present invention to treat female HSDD is 150 mg, whether administered once a day or twice a day, to treat female HSDD The concentration of trazodon dose used according to the invention is 75 mg or 150 mg. Preferably, both bupropion and trazodone are in the form of oral extended release (ER) or sustained release (SR) administration, and the woman whose HSDD is treated is a premenopausal woman.

Medicament therapy according to the present invention, that is, oral bupropion 150 mg twice a day (preferably ER or SR), wherein the first bupropion administration is administered in the morning and the second bupropion administration is administered in about 8 hours thereafter ), Oral trazodone 150 mg once daily (preferably ER or SR) (where the trazodone is administered once daily at bedtime) is referred to herein as " Lorexys at intermediate dose ". The present invention provides a low dose treatment regimen, i.e. oral bupropion 150 mg once a day (preferably ER or SR) wherein bupropion is administered once a day in the morning, oral trazodone 75 mg once daily (ER) or SR (where TRAJODON is administered once a day at bedtime) is referred to as a " Lexis " Accordingly, the present invention contemplates a daily treatment combination dosage range of about 75 mg to about 150 mg of trazodone and about 150 mg to 300 mg of bupropion administered daily. Although the trazodone is preferably administered at night, most preferably at bedtime, and bupropion is preferably administered in the morning and / or night, more preferably in the morning, the present invention provides both trazodone and bupropion It is contemplated that the compounds may be administered in separate dosage forms or in a single dosage form containing both drugs at any time of the day.

Specifically, the novel combination therapies of the present invention exhibit unexpected excellence in that they have little or no effect on efficacy and / or side effects compared to heretofore available female HSDD therapies. Lexis in moderate doses using standard scales of sexual desire and sexual dysfunction and Lexis's test safety and efficacy in premenopausal women In HSDD clinical trials, Lexis and Intermediate doses with low doses meeting the responder criteria The percentage of women treated with SSRIs was about 76% and about 88%, respectively. In contrast, only 36% and 45% of the same females treated with bupropion SR alone according to the same dose level and the same treatment regimen met the response criteria.

The advantage of the present invention is that it is not statistically significant (p " 0.01) and is very unexpected. Percentage of women who meet the relaxation criteria for low doses of Lexis and intermediate doses of Lexis exhibit similar advantages over bupropion treatment.

In addition, Lexis therapy with the low dose of the present invention with Lexis and intermediate dose is also advantageous over the prior treatment in that the patient responds rapidly. While other treatments typically take at least three months to relieve, approximately 58% of women treated with the low doses of Lexis and intermediate doses of the present invention in the case of Lexis treatment met the palliative criteria within about 4 weeks.

Regarding side effects, the main adverse effects that FDA worries about drugs in this area are over-sedation, ie, drowsiness, fatigue, dizziness, depression, accidents and fainting (all of which are exacerbated by alcohol). However, surprisingly and unexpectedly, it has been rigorously evaluated that there are no sedative-type side effects during clinical trials for women treated with Lexis at low doses and Lexis at intermediate doses. Also, very surprisingly and unexpectedly, during the clinical trials, treatment of women with low doses of Lexis and intermediate doses of Lexis in the present invention did not lead to discontinuity syndrome, and depression, syncope, or accident was not observed.

"Reactor" as used herein means an improved sexual desire response to 2 points for a standard scale of 2-10. The respondents were female subscales of desire for sexual function tests; From 2 (with very low or no sexual desire, and with little or no sexual desire) to 10 (sexual desire is very high and almost always or always present).

As used herein, "remitter" is a person with a score of 5 or more.

Alternatively, the sexual dysfunctional responders are those who are improved by one point on a standard scale of 0-4. The measure is the item "annoyance due to low libido" of female sexual dysfunction scale - revised, which ranges from 4 (always) to 0 (none at all), and the mitigator is a person whose score is sometimes less than 2.

In one aspect, the invention provides a method of treating a sexual disorder or a symptom thereof (e.g., HSDD, erectile dysfunction, sexual arousal disorder, FSD, ≪ / RTI > MSD, and the like).

In one aspect, the invention provides a composition comprising a 5-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier. In another aspect, the composition is a composition wherein the 5-HT _2A antagonist is also a 5-HT _1A receptor agonist. In another aspect, the composition is a composition comprising trazodone and bupropion. In another aspect, the composition is a composition 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 a composition 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 comprises bupropion or comprises bupropion in a dosage range of 200-450 mg; Bupropion in a dosage range of 225-300 mg; Or bupropion in a dosage range of 200-275 mg; Bupropion in a dosage range of 100-450 mg; Bupropion in a dosage range of 100-275 mg; Bupropion in a dosage range of 25-275 mg; Wherein the bupropion is in the dosage range of XX-YY mg, wherein XX is an integer from 5 to 400 and YY is an integer from 50 to 450. [

In one embodiment, the composition comprises trazodone, or comprises trazodone in a dosage range of 25-450 mg; Containing trazodone in a dosage range of 75-150 mg; Or trazodone in a dosage range of 50-100 mg; Trasadon as a dose range of XX-YY mg, wherein XX is an integer from 25 to 400 and YY is an integer from 50 to 450. [

In one aspect, the invention provides a method of treating or preventing sexual desire disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a 5-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor and a pharmaceutically acceptable carrier, (HSDD) in a subject suffering from or susceptible to the disease. In one aspect, one compound is both a 5-HT _2A antagonist and a 5-HT _1A receptor agonist (eg, trazodone). In another aspect, the norepinephrine-dopamine reuptake inhibitor is also an alpha adrenergic blocker (e. G., Bupropion).

In one aspect, the invention provides a method for treating sexual desire disorder, comprising administering to a subject in need of treatment a therapeutically effective amount of a composition comprising a 5-HT _1A receptor agonist, a 5-HT _2A antagonist and a pharmaceutically acceptable carrier, (HSDD) in a subject suffering from or susceptible to the disease. In one aspect, one compound is both a 5-HT _1A receptor agonist and a 5-HT _2A antagonist (for example, trazodone).

In many ways, the method is that the Sexual Disability (SD) is a female sexual disorder (FSD). In many aspects, the method is that the SD is a female extremity disorder (FOD); SD is female sexual arousal disorder (FSAD); Or SD is a dyspareunia or dysfunction. In various aspects, the method is a method wherein the FSD comprises at least one of simultaneous dysfunctions of sexual desire, sexual arousal, sexual exaggeration, and / or dyspareunia. In many respects, the method is that SD is male sexual dysfunction (MSD).

Yet another aspect is a method of treating a disease, disorder or symptom 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.

Yet another aspect is a method of treating erectile dysfunction (ED) in a subject, comprising administering to the subject a compound or composition herein.

Yet 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-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier.

In one aspect, the invention provides a composition comprising a 5-HT _1A receptor agonist and a 5-HT _2A antagonist nepalozone and a pharmaceutically acceptable carrier.

In one aspect, the invention provides a composition comprising a 5-HT _1A receptor agonist and a 5-HT _2A antagonist, mirtazapine, and a pharmaceutically acceptable carrier.

Another aspect is that the composition is administered orally; The composition is administered locally; The subject is diagnosed with depression and is being treated; The subject is not being treated for depression; The subject is co-administered with an additional therapeutic agent; Or the subject is not co-prescribed with an additional therapeutic agent; The subject is co-administered with an additional therapeutic agent; Or that the subject is not co-administered with the additional therapeutic agent.

In one aspect, the invention provides a composition comprising a 5-HT _1A receptor agonist, a 5-HT _2A antagonist, and a pharmaceutically acceptable carrier.

In one embodiment, the composition comprises bupropion; Bupropion in a dosage range of 100-450 mg / day; Bupropion in a dosage range of 200-450 mg daily; Bupropion in a dosage range of 100-300 mg / day; Bupropion in a dosage range of 225-300 mg / day; Bupropion in a dosage range of 100-275 mg / day; Bupropion in a dosage range of 200-275 mg / day; Or bupropion in the dosage range of XX-YY mg daily (where XX is an integer from 5 to 400 and YY is an integer from 50 to 450).

In one embodiment, the composition comprises trazodone; Trazodone in a dosage range of 25-450 mg / day; Trazodone in a dosage range of 75-150 mg / day; Trazodone in a dosage range of 50-100 mg daily; Or trazodone in a dosage range of daily XX-YY mg (where XX is an integer from 25 to 400 and YY is an integer from 50 to 450).

In one embodiment, the composition comprises bupropion and trazodone; Bupropion in a dosage range of 50-450 mg and trazodone in a dosage range of 25-450 mg; Bupropion in a dose range of 200-450 mg and trazodone in a dosage range of 25-450 mg; Bupropion in a dosage range of 100-300 mg daily and containing trazodone in a dosage range of 75-150 mg daily; Bupropion in a dosage range of 225-300 mg daily and containing trazodone in a dosage range of 75-150 mg daily; Bupropion in a dosage range of 100-275 mg daily and containing trazodone in a dosage range of 50-100 mg daily; Or bupropion in a dosage range of 200-275 mg per day and a dosage range of 50-100 mg daily in trazodone.

In one aspect, the invention provides a method of making a composition comprising a combination of a 5-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising a combination of a 5-HT _1A receptor agonist, a 5-HT _2A antagonist, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising a combination of a 5-HT _1A receptor agonist, and a pharmaceutically acceptable carrier. In one aspect, the invention provides a method of making a composition comprising a combination of a 5-HT _1A antagonist, and a pharmaceutically acceptable carrier.

In one aspect, a method of making a composition comprises combining a 5-HT _1A receptor agonist, a norepinephrine-dopamine reuptake inhibitor, and a pharmaceutically acceptable carrier such that the composition comprises a 5-HT _1A receptor agonist in the range of 25-450 . In another aspect, the method of manufacture comprises combining a 5-HT _2A antagonist and a pharmaceutically acceptable carrier such that the composition comprises a 5-HT _2A antagonist and a norepinephrine-dopamine reuptake inhibitor in the range of 25-450 mg.

In one embodiment, the method comprises combining bupropion, trazodone, and a pharmaceutically acceptable carrier.

In one aspect, the invention provides a kit comprising the composition described herein, and a label that provides instructions for administering the composition to a subject to treat or ameliorate HSDD or its symptoms in the subject.

In another aspect, the invention provides a method of treating sexual desire disorder (HSDD) in a subject, comprising administering to the subject a 5-HT _1A receptor agonist and a 5-HT _2A antagonist. The methods herein may further comprise a method wherein the subject is identified as requiring such treatment, and a method wherein the subject is treated by administration of the compounds and / or compositions herein. The method is such that the subject has not previously received the compound and / or composition of the present invention, or that the subject has not previously been administered the compound and / or composition of the present invention at the stated dosage level or dosage regimen May be included.

In another embodiment, the invention provides a method of treating a person suffering from sexual desire disorder (HSDD) comprising administering to a subject in need thereof a therapeutically effective amount of a 5-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HT _1A receptor agonist, The present invention provides a method of treating a subject suffering from or susceptible to libido-lowering disorder (HSDD) comprising administering a therapeutically effective amount of a composition comprising one or any combination thereof and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of treating a subject by administering to the subject a therapeutically effective amount of a 5-HT _2A antagonist, a norepinephrine-dopamine reuptake inhibitor, a 5-HT _1A receptor agonist, an endocrine activator, (HSDD) in a subject suffering from sexual desire disorder (HSDD).

In one aspect, the endocrine agent is testosterone, and the dosage can range from 25 to 1000 mg.

In one aspect, the subject is a subject not being treated with a selective serotonin reuptake inhibitor (SSRI) agonist.

In one aspect, the subject is a subject being treated with a selective serotonin reuptake inhibitor (SSRI) agonist.

In one aspect, the subject is a subject identified as having a selective serotonin reuptake inhibitor (SSRI) agonist-induced HSDD.

In one aspect, the subject is a subject being treated with a PDE-5 inhibitor compound (i.e., sildenafil, tadalafil, etc.).

In one aspect, the subject is a subject not simultaneously being treated with a PDE-5 inhibitor compound (i.e., sildenafil, tadalafil, etc.).

In one aspect, the subject is a subject being treated with an endocrine agent (e. G., Testosterone).

In one aspect, the subject is a subject not simultaneously being treated with an endocrine agent (e. G., Testosterone).

In another aspect, the methods of the present invention take samples (i.e., fluids, blood, urine, saliva, tissue, etc.) and determine the presence of biological markers (ie, liver enzymes, CYP3A4, and / or transport gene markers, , Receptor affinity, metabolism, or serotonin activity, serotonin 1A or 2A subtype, dopamine, or receptor subtype of dopamine) to determine the health status of the subject before, during, or after administration of the composition of the present invention .

These and other objects, advantages and features of the present invention and the manner of accomplishing it will be more readily apparent when taken in conjunction with the accompanying drawings and embodiments which illustrate the following detailed description and embodiments of the invention.
Figure 1 summarizes the results of an IIa-phase 3-way open-label crossover study in which a combination of the present invention of trazodone and bupropion is used to treat pre-menopausal women's sexual desire disorder (HSDD).
Figure 2 summarizes the design and capacity of an IIa phase 3-way open-label crossover study.
Figure 3 summarizes the inclusion criteria of IIa-phase 3-way open-label crossover study.
Figure 4 summarizes the participation criteria of the IIa 3-way open-label crossover study: exclusion.
Figure 5 shows a sample size of 30, which is able to detect more than 80% delta 35% between low dose of rolexis and intermediate dose of rolexis in the control (bupropion) and IIa phase 3-way open-label crossover study FIG.
Figure 6 summarizes the patient placement in an IIa phase 3-way open cross-over study.
Figure 7 summarizes the% response of intermediate dose Rochex versus bupropion in the IIa phase 3-mode open cross-over study.
Figure 8 summarizes the percentage of patients who reached relaxation for low dose of Rochex versus bupropion in the IIa phase 3-mode open-label crossover study.
Figure 9 summarizes the low dose of the Rochex mid-efficacy in terms of overall patient satisfaction with the patient's overall change of satisfaction in the end point evaluation of the IIa phase 3-way open-label crossover study, i.
Figure 10 summarizes the adverse events of the IIa phase 3-way open-label crossover study.
Figure 11 summarizes the conclusions of the IIa-phase 3-way open-label crossover study.

The present inventors have now found a therapeutic strategy for the treatment of desensitization disorders (HSDD) in women, especially premenopausal women.

The present invention also relates to a pharmaceutical composition comprising at least in part a combination of a 5-HT _2A antagonist (optionally a 5-HT _1A receptor agonist), a norepinephrine-dopamine reuptake inhibitor (and optionally an endocrine active agent) And provide superior and synergistic results.

1. Definitions

Prior to further description of the present invention, and for the purpose of making the present invention easier to understand, certain terms are first defined and collected for convenience.

The terms "administering" or "administering" include introducing the compound (s) of the invention into a subject to effectuate its intended function. Examples of routes of administration that may be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intraspinal), oral, buccal, sublingual, inhalation, rectal and transdermal. Pharmaceutical formulations may be given in a form suitable for each route of administration. For example, these agents may be administered in the form of tablets or capsules, such as by injection, inhalation, eye lotion, ointment, injection, suppository by inhalation or inhalation; Locally by lotion or ointment; And suppository to the rectum. Oral administration is preferred. The injection may be bolus or it may be continuous infusion. Depending on the route of administration, the compounds of the invention may be coated with or placed within a selected material to protect against the natural conditions that may adversely affect its ability to perform its intended function. The compounds of the present invention may be administered alone or in combination with other agents or pharmaceutically acceptable carriers as described above, or both. The compounds of the present invention may be administered prior to, concurrently with, or after administration of another agent. In addition, the compounds of the present invention may also be administered in the form of their active metabolites, or prodrugs that are converted in vivo to more active metabolites.

Language "Biological activity" of a compound of the present invention encompasses all activities derived by a compound of the present invention in a reactive cell. This includes genomic and non-genomic activities derived by these compounds.

"Biological composition" or "biological sample" refers to a composition that contains or is derived from a cell or biopolymer. The cell-containing composition may be formulated for administration to a mammal such as a mammalian blood, a red blood cell concentrate, a platelet concentrate, a leukocyte concentrate, a blood cell protein, a plasma, a platelet-rich plasma, a plasma concentrate, a precipitate from any fractionation of plasma, A supernatant from any fractionation of plasma, a blood plasma protein fraction, a purified or partially purified blood protein or other component, a serum, a semen, a mammalian colostrum, a milk solution, a saliva, a placenta extract, a frozen precipitate, (For example, through recombinant DNA or monoclonal antibody technology) cells, such as yeast, mammalian cell culture or culture medium, fermentation products, multiple liquids, proteins derived in blood cells, and normal or transformed cells And the product produced in the culture. The biological composition may be cell-free and uniquely. In a preferred embodiment, a suitable biological composition or biological sample is a red blood cell suspension. In some embodiments, the blood cell suspension comprises mammalian blood cells. Preferably, the blood cells are obtained from human, non-human primates, dogs, cats, horses, cows, goats, sheep or pigs. In a preferred embodiment, the blood cell suspension comprises red blood cells and / or platelet and / or white blood cells and / or bone marrow cells.

The term "effective amount" encompasses an amount effective, for example, sufficient to treat a desquamation disorder in a subject, in order to achieve the desired result at the required dosage and for a period of time. An effective amount of a compound of the present invention may vary depending on factors such as the disease state of the subject, age and body weight, and the ability of the compound of the present invention to elicit the desired response in the subject. The dosage regimen may be adjusted to provide optimal therapeutic response. An effective amount is also one in which the therapeutically beneficial effect outweighs any toxic or deleterious effects (e. G., Side effects) of the compounds of the present invention.

A therapeutically effective amount (i.e., an effective dosage) of a compound of the invention is 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 More preferably from about 1 to 10 mg / kg, from 2 to 9 mg / kg, from 3 to 8 mg / kg, from 4 to 7 mg / kg, or from 5 to 6 mg / kg body weight. The skilled artisan will appreciate that certain factors, including, but not limited to, the severity of the disease or disorder of the subject, previous treatment, overall health and / or age, and other conditions present, affect the dosage required to effectively treat the subject Will be aware of the possibility. Moreover, treating a subject with a therapeutically effective amount of a compound of the present invention may comprise a single treatment, or, preferably, may comprise a series of treatments. In one example, the subject is treated with a compound of the present invention in a range of about 0.1 to 20 mg / kg body weight for about 1 to 10 weeks, preferably 2 to 8 weeks, more preferably about 3 to 7 weeks, Is treated for 1 hour per week for about 4, 5 or 6 weeks. It will also be understood that the effective dosage of the compounds of the present invention used in therapy may be increased or decreased over a particular treatment period. The dosing regimens of the present application are given by the following abbreviations when specified: SID or QD = once daily; BID = 2 times a day, TID = 3 times a day; QID = 4 times a day; q.h.s = every night.

The term " homeostatic "is perceived in the relevant art to mean maintaining static or constant conditions in the internal environment.

The language "improved biological properties" refers to any inherent activity that enhances the in vivo efficacy of the compounds of the present invention. In a preferred embodiment, this term refers to any qualitative or quantitative improved therapeutic properties of the compounds of the invention, such as reduced toxicity.

The term "adjusting" refers to an objective end result, for example an increase or decrease, e.g. a change, of a sexual desire disorder and / or its symptoms in a subject in which the treatment outcome is achieved.

The term "obtaining " as in" obtaining a compound useful in the treatment of sexual desire disorder "is intended to include purchasing, synthesizing or otherwise obtaining the compound.

As used herein, the terms "parenteral administration" and "parenterally administered " refer to modes of administration other than injectable, enteral, and topical administration, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, Intramuscular, intraperitoneal, intraperitoneal, femoral, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

A "prophylactically effective amount " of a language compound refers to an amount of a compound of the invention described herein, at or in any combination ratio of the subject effective to prevent or treat a sexual disorder in a single or multi-dose administration to a patient.

The language "reduced toxicity" is intended to include the reduction of any undesirable side effects caused by the compounds of the present invention in vivo.

The term "subject" includes organisms, such as humans (male or female) and non-human animals (male or female), which may be suffering from sexual disorders or otherwise be beneficial due to administration of the compounds or compositions of the present invention . Preferred humans include human patients suffering from or susceptible to loss of libido or an associated condition as described herein. The term "non-human animal" of the present invention encompasses all vertebrate animals such as mammals such as rodents such as mice and non-mammals such as non-human primates, Cattle, chickens, amphibians, reptiles, and the like.

The term " susceptibility to lethargy disorder "is intended to include subjects who have been previously diagnosed with or have a family history of a person at risk of developing a sexual desire disorder, for example, a family history of sexual desire disorder or history.

As used herein, the phrase "systemic administration," systemically administered ", "peripheral administration ", and" peripheral administered " Administration of a drug or other substance, e. G., Subcutaneous administration.

"Therapeutically effective amount" of the compounds of the present invention refers to a compound that modulates the symptoms of loss of libido and / or loss of libido in a single or multiple dose administration to a patient, (Either objectively or objectively, depending on the patient or healthcare provider).

2. Compounds of the present invention

In one aspect, the invention provides compounds that are capable of modulating sexual desire disorder in a subject. Such compounds include 5-HT _2A antagonists, 5-HT _1A receptor agonists, norepinephrine-dopamine reuptake inhibitors, and endocrine activators. The composition of the present invention further comprises a pharmaceutically acceptable carrier.

The compounds, 5-HT _2A compound is a 5-HT _2A antagonist to demonstrate antagonistic activity on the receptors described herein; A norepinephrine-dopamine reuptake inhibitor, a compound that exhibits inhibitory activity in norepinephrine-dopamine reabsorption; A 5-HT _1A receptor agonist that is a compound that demonstrates agonist activity on 5-HT _1A receptors; And an endocrine activator that is an agent that is active in regulating the endocrine system.

In one embodiment, the invention encompasses a compound capable of modulating loss of libido (e. G., A compound of the invention); And their pharmaceutically acceptable esters, salts, hydrates, solvates, isomers and prodrugs thereof.

The naturally occurring or synthetic isomers can be separated in a number of ways known in the art. Methods for separating the racemic mixture of the two enantiomers include chromatography using a chiral stationary phase (see, e.g., Chiral Liquid Chromatography, WJ Lough, Ed. Chapman and Hall, New York 1989). Enantiomers can also be separated by conventional resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate the enantiomers. For separation of enantiomers of carboxylic acids, diastereoisomeric salts may be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like. Alternatively, diastereoisomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to provide enantiomerically enriched free carboxylic acids. For the resolution of optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can lead to the formation of diastereomeric salts.

3. Use of the compounds of the invention

In one embodiment, the invention provides a method of treating sexual desire disorder (HSDD) in a subject, comprising administering to the subject a composition as described herein. In certain embodiments, the subject is a mammal, such as a primate, such as a human. In terms of the compounds, compositions and methods of treatment thereof, the diseases, disorders or symptoms thereof are described in the document " Diagnostic and Statistical Manual of Mental Disorders 4th Edition - Text Revision, (DSM-I-TRV), American Psychiatric Association & .

In certain embodiments, the methods of the invention comprise administering to a subject a therapeutically effective amount of a compound of the invention in combination with another pharmaceutical active compound. Examples of pharmaceutically active compounds include those compounds known to treat sexual desensitization disorder (HSDD) in a subject. Other pharmaceutical active compounds that can be used are described 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 entire contents of which are expressly incorporated herein by reference. The compounds and pharmaceutical active compounds of the present invention may be administered to a subject (either simultaneously or at different times) with the same pharmaceutical composition or with different pharmaceutical compositions.

Determination of a therapeutically effective amount of a compound of the present invention for the treatment of sexual desire loss (HSDD), a preventive effective amount of sexual desire disorder, can be determined by the use of known techniques and by observing the results obtained under similar circumstances, ("Clinician in charge"). The dose should be determined by the patient's needs within the judgment of the clinician; The severity of the condition being treated and the particular compound being employed. An effective amount or dose of treatment for sexual desire disorder, and a specific sexual desire disorder experienced in determining an effective amount or dose for the prevention of sexual desire disorder; The pharmacokinetic characteristics of a particular agonist and its mode and route of administration; The desired time course of treatment; Species of mammals; His size, age, and overall health; Specific disease involved; Degree or severity of disease; Individual patient response; The particular compound administered; Mode of administration; Bioavailability characteristics of the agent to be administered; Selected dose regimen; The type of co-treatment (i. E., The interaction of a compound of the invention with other co-administered therapeutic agents); And other related circumstances, are contemplated by the attending clinician.

Dosage administration may be in a single dosage form or in multiple dosage forms. The doses may be administered jointly, simultaneously or sequentially. The dosage can be a single dose just prior to sex, or it can be one or more doses daily, regardless of time before sexual activity. The treatment may be initiated at a lower dose which is less than the optimal dose of the compound. Thereafter, the dosage can be increased in small increments until the optimum effect is achieved under the given circumstances. For convenience, the total daily dose may be administered in divided portions during the day if desired. A therapeutically effective amount and a prophylactically effective amount of a compound of the present invention is expected to vary from about 0.1 milligram (mg / kg / day) to about 100 mg / kg / day per kilogram body weight per day.

Identification of patients in need of prophylactic treatment for loss of libido is well within the skill and knowledge of those of ordinary skill in the relevant arts. Any of the methods for the identification of patients at risk of developing loss of libido, which can be treated by the method of the present invention, such as the presence of a family history and a risk factor associated with the development of such a disease state in a subject, Use of depressed drugs, hormone contraceptives, antihormonal and / or cytotoxic chemotherapy, sedatives, antipsychotic drugs, antiepileptic drugs, mood stabilizers drugs, opioid drugs, alcohols, or narcotic drugs) are well known in the medical arts . Conventional clinicians in the relevant art can readily identify such candidate patients by, for example, clinical trials, physical examinations and use of history / family history.

As used herein, "obtaining a biological sample from a subject" includes obtaining a sample for use in the methods described herein. Biological samples are described above.

In another aspect, the compounds of the invention are packaged with a therapeutically effective amount of a pharmaceutically acceptable carrier or diluent. The composition may be formulated to treat a subject suffering from or susceptible to loss of libido, and may be packaged with instructions for treating a subject suffering from or susceptible to loss of libido.

The subject may be at risk for loss of libido, and / or may be symptomatic of loss of libido, and / or may be susceptible to loss of libido and / or diagnosed with sexual desire disorder.

If the conditioning of the condition indicates that the subject can have a beneficial clinical response to treatment, the subject may be treated with the compound. For example, a subject may be administered a compound of a therapeutically effective dose or dosage.

The kit of the present invention comprises a kit for treating a loss of libido in a subject. The kit may comprise a compound of the present invention, for example, a compound described herein, its pharmaceutically acceptable esters, salts and prodrugs, and instructions for use. Usage guidelines may include information on dosage, delivery method, storage of the kit, and the like. In terms of the kit (and method of using it), the composition and / or method of treatment comprises (i) requiring and / or taking CYP3A4, CYP2B6-, or CYP 2D6-metabolism drugs; (ii) taking any sex hormone other than an approved hormone contraceptive; (or not administered to) those who drink more than one alcoholic beverage per day (iii) (e.g., 12-oz beer, 4-oz wine, etc.) per day .

Alternatively, the effects of the compounds of the present invention can be characterized in vivo using animal models.

4. Pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising an effective amount of a compound described herein and a pharmaceutically acceptable carrier. In a further embodiment, an effective amount is effective in treating a sexual desire disorder as previously described.

In one embodiment, a compound of the invention is administered to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, 1 week, 2 weeks, 3 weeks after administration of a pharmaceutically acceptable agent, Week, or four weeks to a subject using a pharmaceutically acceptable agent that provides sustained delivery of a compound of the present invention to the subject.

In certain embodiments, these pharmaceutical compositions are suitable for topical or oral, buccal, or sublingual administration to a subject. In another embodiment, the pharmaceutical compositions of the present invention, as described in detail below, can be formulated specifically for administration in solid or liquid form, including those adapted for: (1) oral administration, For example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example as a sterile solution or suspension, for example by subcutaneous, intramuscular or intravenous injection; (3) topical application, for example as cream, ointment or spray applied to the skin; (4) into the vagina or rectum as, for example, pessaries, creams or foams; Or (5) aerosols as aqueous aerosols, liposomes, or solid particles, for example, containing the compounds or compositions herein.

The phrase " pharmacologically acceptable "refers to a pharmacological agent suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, or other problem or complication within the scope of reasonable medical judgment, Refers to compounds, compositions of the present invention that contain compatible compounds and / or dosage forms.

The phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, which is involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body , Diluents, excipients, solvents or encapsulating materials. Each carrier is "tolerated" in the sense of being compatible with the other ingredients of the formulation and not harming the patient. Some examples of materials that 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 derivatives thereof 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 wax; (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) a phosphate buffer solution; And (21) Other non-toxic compatible materials used in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, emollients, coatings, sweeteners, flavors and perfumes, preservatives and antioxidants may also be present in the composition.

Examples of pharmaceutically acceptable antioxidants are: (1) water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) Availability 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, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

Compositions containing the compounds of the present invention 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 of the methods well known in the pharmaceutical art. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated, the particular mode of administration. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, in 100 percent, this amount will range from about 1 percent to about 99 percent, preferably from about 5 percent to about 70 percent, and more preferably from about 10 percent to about 30 percent of the active ingredient.

Methods of making these compositions comprise bringing the compound of the invention (s) into association with a carrier, and, optionally, one or more accessory ingredients.

Generally, formulations are prepared by causing the compounds of the present invention to associate uniformly and intimately with a liquid carrier or a finely divided solid carrier, or both, and then molding the product as required.

Compositions of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavoring substrate, typically sucrose and acacia or tragacanth), powders, in the form of granules or in aqueous or non- May be present as a solution or suspension, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using inert substrates such as gelatin and glycerin, or sucrose and acacia) and / Each containing a predetermined amount of a compound of the present invention (s) as an active ingredient. The compound may also be administered as a bolus, soft or paste.

In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, etc.) of the invention for oral administration, the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, specific silicates, and sodium carbonate; (5) dissolution retardants 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 as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; And (10) a colorant. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or lactose as well as high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by conventional means including, but not limited to, binding agents (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants such as sodium starch glycollate or crosslinked sodium carboxymethylcellulose, surface- . ≪ / RTI > Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered active ingredient that has been wetted with an inert liquid diluent.

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 may be scored or coated and shells such as enteric coatings and other coatings well known in the pharmaceutical- . ≪ / RTI > They may also be formulated to provide slow or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes and / or microspheres to provide the desired release profile . They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating the sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium just prior to use. These compositions may also optionally contain opacifying agents and may be compositions that release only the active ingredient (s), or, preferentially, in a particular part of the gastrointestinal tract, optionally in a delayed manner. Examples of embolic compositions that may be used include polymeric materials and waxes. The active ingredient may also be in microencapsulated form, if appropriate, with one or more of the excipients described above.

Liquid dosage forms for oral administration of the compounds of the present invention 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 (Especially cottonseed, peanut, corn, embryo, olive, castor and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and sorbitol, such as benzyl alcohol, benzyl benzoate, propylene glycol, Fatty acid esters of bitumen, and mixtures thereof.

In addition to inert diluents, the oral compositions may include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfumes, and preservatives.

The suspension may contain, in addition to the active compound of the present invention (s), suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- Agar and tragacanth, and mixtures thereof.

The pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as a suppository, which may contain one or more compounds of the present invention (s), for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate By mixing with one or more suitable non-polar excipients or carriers which will be solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vagina to release the active.

Compositions of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers known to be appropriate in the art.

Dosage forms for topical or transdermal administration of a compound of the present invention (s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound of the present invention (s) may be mixed with a pharmaceutically acceptable carrier under sterile conditions, and any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to the compounds of the present invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, , Talc and zinc oxide, or mixtures thereof.

Powders and sprays may contain, in addition to the compound (s) of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. The spray may additionally contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

The compounds of the present invention (s) may alternatively be administered by an aerosol. This is achieved by preparing aqueous aerosols, liposomal formulations or solid particles containing the compound. Suspensions of non-aqueous (e. G., Fluorocarbon propellants) may be used. An acoustic nebulizer is preferred because it minimizes exposure of the agent to shear, which can lead to decomposition of the compound.

Typically, aqueous aerosols are prepared by formulating aqueous solutions or suspensions of the agents together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers will typically depend on the requirements of the particular compound but are typically selected from nonionic surfactants (Tween, pluronics or polyethylene glycols), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids, Such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally made from isotonic solutions.

The transdermal patch has the additional advantage of providing controlled delivery of the compounds of the invention (s) to the body. Such dosage forms can be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancing agents may also be used to increase the flow of the active ingredient through the skin. This flow rate can be controlled by providing a rate controlling membrane or by dispersing the active ingredient in a polymer matrix or gel.

Ophthalmic formulations, ointments, powders, solutions and the like are also considered to be within the scope of the present invention.

Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into a sterile injectable solution or dispersion immediately prior to use (S) of the invention (s) in combination with an antioxidant, a buffering agent, a bactericide, a solubilizing agent that makes the formulation isotonic with the blood of the intended recipient, or a suspending or thickening agent have.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) 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 preserving agents, wetting agents, emulsifying agents and dispersing agents. Prevention of microbial action can be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the composition. In addition, sustained absorption of the injectable pharmaceutical form may be achieved by including an agonist that slows the absorption, such as aluminum monostearate and gelatin.

In some cases, to sustain the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution, which may also vary depending on the crystal size and crystalline form. Alternatively, delayed absorption of the parenterally-administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are prepared by forming a microencapsulated matrix of the compound (s) of the present invention in a biodegradable polymer, such as a polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the properties of the particular polymer used, 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 microemulsions compatible with body tissues.

When the compound (s) of the present invention is administered as a pharmaceutical to humans and animals, it may be provided as such or may contain, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient In combination with a pharmaceutically acceptable carrier.

The compounds of the present invention (s) and / or the pharmaceutical compositions of the present invention, which may be used in a suitable hydration form, regardless of the route of administration selected, may be administered by a conventional method known to those of ordinary skill in the art ≪ / RTI >

The actual dosage level and time course of the active ingredient in the pharmaceutical compositions of the present invention will be adjusted so as to obtain the amount of active ingredient effective to achieve the desired therapeutic response in a particular patient, It can be different. An exemplary dose range is 0.1 to 10 mg per day.

In the present invention, the preferred dose of the compound of the present invention is the maximum that the patient can withstand and does not cause serious side effects. Preferably, the compounds of the invention are administered at a concentration of from about 0.001 mg to about 100 mg per kilogram body weight, from about 0.001 to about 10 mg / kg, or from about 0.001 mg to about 100 mg / kg body weight. The range of intermediate to above-mentioned values is also intended to be part of the present invention.

5. Example

The present invention is further illustrated by the following examples, which are intended to illustrate, but not to limit, the scope of the invention.

Lexis HSDD clinical trials with low dose of Lexis and high dose in premenopausal women

The present inventors focused on the menopausal status of American women and tried to estimate the prevalence of low sexual desire and libido (HSDD) in US women.

Way:

Open cross-over study. From a probabilistic sample of households, we interviewed 2207 US women over the age of 30 to 70 and in a stable relationship (> or = 3 months) by telephone. The analysis focused on 755 premenopausal women and 552 natural menopausal women and 637 surgical menopausal women. Low sexual desire was defined using the desire domain of the Female Sexual Function Profile, and HSDD was defined using the Female Sexual Function Profile and the Personal Distress Scale.

result:

The prevalence of low sexuality ranged from 26.7% of premenopausal women to 52.4% of natural postmenopausal women. The prevalence of HSDD was the highest among surgical postmenopausal women (12.5%). Compared to premenopausal women, adjusting for age, race / ethnicity, education level and smoking status, the prevalence rate for HSDD was 2.3 (95% confidence interval, 1.2-4.5) for surgical postmenopausal women, Was about 1.2 (0.5-2.8); The prevalence rates for low sexual desire were 1.3 (0.9-1.9) and 1.5 (1.0-2.2) for postmenopausal women, respectively.

conclusion:

The prevalence of low sexual desire was higher among postmenopausal women than among premenopausal women. The pain associated with low demand (HSDD) seemed to be more than twice as common as surgical postmenopausal women, although estimates were fairly inaccurate, compared to premenopausal women.

Desensitization disorder (HSDD) is one type of CNS agonist, bupropion, which is recommended, but without approved drug therapy. This study examined the efficacy and safety of roflexis, an exclusive combination of bupropion and trazodone in premenopausal women.

Clinical studies were performed using Rochexis to treat premenopausal women with HSDD. The primary objective of the study was to evaluate the safety, tolerability and pre-sexual efficacy of rolexis compared to bupropion, one of the constituents of rolexis. Other objectives included exploring the onset and duration of the action of Rochexis.

The study has an adaptive three-way cross-open-label design. We enrolled 30 premenopausal women who met the DSM-IV-TR criteria for HSDD and also evaluated patients for the newly defined DSM-5 Sexual Interest and Arousal Disorder. Each subject was given a daily dose of bupropion as an active control for 4 weeks followed by a 1 week-long withdrawal period, followed by a daily low dose of roxith for 4 weeks followed by another withdrawal period, Finally, four doses of Lorycis intermediate doses were administered daily followed by another withdrawal period.

Administration and therapeutic regimens for the study were as follows:

Active Control: Bupropion SR 300 mg was administered once daily for four weeks in the morning.

Lexis at low dosage: Lexis at low dosage is a combination therapy consisting of two drugs, buproprion and trazodone. For four weeks each, bupropion SR 150 mg was administered once daily in the morning and 75 mg of trazodone ER was administered at bedtime once daily.

Intermediate dose of Lexis: With an intermediate dose, Lexis is also a combination therapy consisting of two drugs, buproprion and trazodone. For each 4 weeks, bupropion SR 150 mg was administered twice a day in the morning once, and once after eight (8) hours, and 150 mg of trazodone ER was administered at bedtime once a day.

Patients were self-assessed weekly using questionnaires and evaluated during 8 clinical visits. Outcome measures for efficacy included a proven self-rating scale of sexual functioning and sexual pain and overall change. Results of safety measurements included standard laboratory studies and a comprehensive assessment of electrocardiograms in addition to symptom and vital signs. The study was conducted in two clinical sites in the United States.

Materials and methods:

This was an open-label crossover study using four weeks per treatment in a 25-50 year old non-depressive or healthy patient with DSM-IV-TR HSDD. In the case of responders with n = 30 and 33% more than bupropion SR, the effect at α = 0.05 was 80%. Four weeks of bupropion SR at 300 mg / day and the abortion period followed by a low dose of Lecithin (LOR-low), ie 4 weeks of Bupropion SR + TRAzodone ER with a lower dose than the labeled dose, Four weeks of rheexis medium-dose (LOR medium; 2x LOR-low) were performed. The primary efficacy endpoint was the female sexual desire index domain (FSFI-d); The main secondary efficacy endpoint was the female sexual pain scale-revision (FSDS-R). The analysis included% responders and% relaxation from the first baseline using the standard definition for FSFI-d and FSDS-R item 13 (FSDS-R-i13) + patient overall satisfaction rating (PGIC) Reference). See Figure 1-11.

result

Five patients (17%) for the LOR-intermediate were discontinued for administrative reasons; One patient (4%) discontinued as a hazardous case. Table 1 below shows the reactant and relaxor ratios when the LOR-intermediate is used; The above ratio in the case of using LOR-low was intermediate compared to bupropion and not significant.

conclusion

Rochex was superior to bupropion in pre-menopausal HSDD, or to bupropion SR alone in the treatment of premenopausal women against HSDD. See Table 1 and Figures 1-11.

<Table 1> Results

The disclosures of each and every patent, patent application, and publication cited herein are incorporated herein by reference in their entirety.

Reference to a chemical group listing in any definition of a variable herein includes the definition of such variable as any single group of the listed groups or a combination thereof. Reference herein to an embodiment of a variable includes any embodiment as such or in combination with any other embodiment or portion thereof. Reference herein to an embodiment encompasses such embodiments in any single embodiment or in combination with any other embodiment or portion thereof.

Although the present invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments of the invention may be devised by those skilled in the art without departing from the true spirit and scope of the invention. It is intended that the claims be construed as including all such modifications and equivalent arrangements.

Claims (35)

(a) daily administration of a first drug at a dose concentration of 150 mg to a woman in need of HSDD treatment wherein the first drug is bupropion;
(b) administering to said female a second drug at a dose concentration of 75 mg daily, wherein said second drug is trazodone
Lt; / RTI &gt;
(c) HSDD treatment using combination therapies comprising at least two different drugs, wherein said administration of said first drug and said second drug is in accordance with a prescribed therapeutic regimen for the treatment of said female HSDD How to treat HSDD in women who need it. 2. The method of claim 1, wherein said administration of said first drug and said second drug occurs on the same day during a prescribed therapy. 2. The method of claim 1, wherein the prescribed therapeutic regimen occurs for at least about 30 days. 2. The method of claim 1, wherein the prescribed therapeutic regimen occurs for at least about one month. 2. The method of claim 1, wherein the prescribed therapeutic regimen occurs for about one year. 2. The method of claim 1, wherein the prescribed therapeutic regimen occurs for at least about one year. 3. The method of claim 1, wherein the bupropion is in an oral extended or sustained release dosage form. 2. The method of claim 1, wherein the trazodone is in an oral extended or sustained release dosage form. 2. The method of claim 1, wherein the bupropion is an oral extended or sustained release dosage form, wherein the trazodone is in an oral extended release dosage form. The method of claim 1, wherein the female is a premenopausal female. 2. The method of claim 1, wherein administration of the first medication comprises administering to the female a first medication in the morning. 3. The method of claim 1, wherein administering the second drug comprises administering to the woman a second drug in the evening. 3. The method of claim 1, wherein administering the second drug comprises administering to the woman a second drug at bedtime. (a) administering to a female in need of HSDD treatment a first drug at a dosage level of 300 mg daily, wherein the first drug is bupropion;
(b) administering to said female a second drug at a dosage level of 150 mg daily, wherein said second drug is a trazodone-
Lt; / RTI &gt;
(c) HSDD treatment using combination therapies comprising at least two different drugs, wherein said administration of said first drug and said second drug is in accordance with a prescribed therapeutic regimen for the treatment of said female HSDD How to treat HSDD in women who need it. 15. The method of claim 14, wherein said administration of said first drug and said second drug occurs on the same day during a prescribed therapy. 15. The method of claim 14, wherein the prescribed treatment regimen occurs for at least about 30 days. 15. The method of claim 14, wherein the prescribed treatment regimen occurs for at least about one month. 15. The method of claim 14, wherein the prescribed treatment regimen occurs for about one year. 15. The method of claim 14, wherein the prescribed therapeutic regimen occurs for at least about one year. 15. The method of claim 14, wherein the bupropion is in an oral extended release dosage form. 15. The method of claim 14, wherein the trazodone is in an oral extended or sustained release dosage form. 15. The method of claim 14, wherein the bupropion is an oral extended or sustained release dosage form, wherein the trazodone is in an oral extended release dosage form. 15. The method of claim 14, wherein the female is a premenopausal female. 15. The method of claim 14, wherein administration of the first drug comprises administering to the female a first drug in the morning at a first dose of 150 mg and in the evening at a second dose of 150 mg. 15. The method of claim 14, wherein administration of the second drug comprises administering to the female a second drug in the evening. 3. The method of claim 1, wherein administering the second drug comprises administering to the woman a second drug at bedtime. The method comprising administering to a female in need of HSDD treatment a daily low dose of Lorexys wherein said administration of said first drug and said second drug is a prescribed treatment for treating said female & A method of treating HSDD in a woman in need of HSDD treatment using combination therapy comprising at least two different drugs, wherein the treatment is according to a regimen. The method comprising administering an intermediate dose of rolexis daily to a woman in need of HSDD treatment wherein said administration of said first drug and said second drug is administered to a prescribable therapeutic regimen for treating said female & A method of treating HSDD in a woman in need of HSDD treatment using combination therapy comprising at least two different drugs. (a) administering to a woman in need of HSDD treatment a daily dose of a first drug in a dosage concentration ranging from about 150 mg to 300 mg, wherein the first drug is bupropion;
(b) administering to said female a second drug at a dosage concentration in the range of about 75 mg to about 150 mg daily, wherein said second drug is trazodone
Lt; / RTI &gt;
(c) HSDD treatment using combination therapies comprising at least two different drugs, wherein said administration of said first drug and said second drug is in accordance with a prescribed therapeutic regimen for the treatment of said female HSDD How to treat HSDD in women who need it. 29. The method of claim 28, wherein the trazodone and bupropion are in an oral extended or sustained release dosage form and the trazodone is in an oral extended release dosage form. 29. The method of claim 28, wherein the trazodone and bupropion are formulated in one oral single dose form. 29. The method of claim 28, wherein one oral single dose form is a tablet. 29. The method of claim 28, wherein one oral single dose form is a caplet. 29. The method of claim 28 wherein one oral single dose form is encapsulated. 34. The method according to any one of claims 1 to 33, wherein bupropion and trazodone comprise their respective pharmaceutically acceptable salts, esters, hydrates, solvates, isomers and prodrug forms.

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