Cyclobenzaprine treatment of sexual dysfunction

Abstract

The present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of cyclobenzaprine and one or more agents, and methods for treating and / or preventing sexual dysfunction. In one embodiment of the present disclosure, a method is provided for treating or preventing sexual dysfunction and its associated symptoms, the method comprising administering to a female subject in need of or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 007,251, filed April 8, 2020, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] background There is growing evidence of the comorbidity of sexual dysfunction (SD) and posttraumatic stress disorder (PTSD) among veterans (Letica-Crepulja et al., 2019). Compared with those without any mental health diagnosis or with a mental health diagnosis other than PTSD, veterans with PTSD are at higher risk for SD. This is true regardless of symptom chronicity, age, or other health concerns, suggesting that the underlying mechanisms of such dysfunction are directly related to PTSD (Hirsch, 2009). Common types of SD in men include erectile dysfunction, sexual apathy, and premature ejaculation; whereas common types of SD in women include fear of intercourse, arousal problems, orgasm problems, sexual apathy, and vaginal pain. Furthermore, the relationship between sexual functioning and psychological well-being is stronger for women than for men (Rosen & Bauchman, 2008).

[0003] Despite the importance of addressing comorbid symptoms, the topic of SD is often clinically overlooked and remains underexplored in the research literature (Tran et al., 2015). Regarding treatment, experts recommend that evidence-based treatment for PTSD should be a top priority. However, treatment for PTSD does not necessarily resolve SD symptoms. For example, compared with a no-treatment control group, women who participated in cognitive behavioral therapy for PTSD showed a significant reduction in PTSD symptoms but no significant improvement in sexual function (Cohen & Hien, 2006). Furthermore, serotonin reuptake inhibitors (SSRIs) and benzodiazepines (psychiatric medications commonly prescribed for the treatment of PTSD) have been shown to exacerbate existing SD and contribute to poor compliance and refusal of medication (Keller, McGarvey, Clayton, 2006).

[0004] Cyclobenzaprine and its pharmaceutically acceptable salts are serotonin-2A, alpha-1-adrenergic, histamine-1 receptor antagonists currently being developed for the treatment of PTSD to target sleep disturbances and hyperarousal in PTSD. A Phase 2 trial of cyclobenzaprine HCl in military-related PTSD showed very low rates of adverse events related to sexual function in both the drug and placebo groups. Therefore, in a subsequent Phase 3 trial in military-related PTSD, a systematic study was conducted to evaluate the effects of treatment on sexual function in women and men. Summary of the Invention [Means for solving the problem]

[0005] Summary of disclosure Some embodiments of the present disclosure are as follows: 1. A method for treating or preventing sexual dysfunction and its associated symptoms, said method comprising administering to a female subject in need of or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier. 2. The method of embodiment 1, wherein said cyclobenzaprine is the free base or a pharmaceutically acceptable salt thereof. 3. The method of embodiment 1 or 2, wherein said pharmaceutically acceptable salt of cyclobenzaprine is an acid salt of cyclobenzaprine. 4. The method of embodiment 3, wherein said acid salt of cyclobenzaprine is cyclobenzaprine-HCl. 5. The method of any one of embodiments 1-4, wherein said cyclobenzaprine or a pharmaceutically acceptable salt thereof is in the form of a eutectic. 6. The method of embodiment 5, wherein the eutectic is a mannitol eutectic. 7. The method of embodiment 6, wherein the mannitol eutectic is selected from the group consisting of a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol with a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, and granules comprising an outer layer of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. 8. The method of any one of embodiments 1-7, wherein the composition comprising a pharmaceutically acceptable salt of cyclobenzaprine further comprises a basifying agent. 9. The method of embodiment 8, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate, and trisodium citrate. 10. The method of embodiment 9, wherein the basifying agent is dipotassium hydrogen phosphate. 11. The method of embodiment 1, wherein the composition comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 12. The method of embodiment 11, wherein the composition comprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 13. The method of embodiment 12, wherein the composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 14. The method of embodiment 12, wherein the composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 15. The method of embodiment 13, wherein the composition comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 16. The method of embodiment 15, wherein the composition comprises about 5.6 mg of cyclobenzaprine-HCl. 17. The method of embodiment 13, wherein the composition comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 18. The method of embodiment 17, wherein the composition comprises about 2.8 mg of cyclobenzaprine-HCl. 19. The method of embodiment 17 or 18, wherein the composition is administered simultaneously or sequentially in two dosage units, and the combined amount of the composition in the two dosage units is about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 20. The method of embodiment 19, wherein the composition is administered simultaneously in two dosage units, each dosage unit containing about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 21. The method of embodiment 19, wherein the composition is administered sequentially in two dosage units, each dosage unit containing about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 22. The method of any one of embodiments 1-21, wherein the pharmaceutical composition is administered daily. 23. The method of any one of embodiments 1-22, wherein the composition is administered once a day. 24. The method of embodiment 23, wherein said pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, thin film, transdermal, parenteral, rectal, or vaginal administration. 25. The method of embodiment 24, wherein the pharmaceutical composition is formulated for sublingual administration. 26. The method of embodiment 25, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a thin film, transdermally, parenterally, rectally, or vaginally. 27. The method of embodiment 26, wherein the pharmaceutical composition is administered sublingually. 28. The method further comprises administering to a subject a subject, the subject being a subject, an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 1A ) receptor agonist, 5-hydroxytryptamine 2A (5-HT 2A) antagonists, synthetic or gonadal steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, anxiolytics, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensive agents, antilipid agents, hormones, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergic agents, amphetamines, dopaminergic receptor agonists, anorexic agents, and narcotics 27. The method of any one of embodiments 1-26, further comprising administering, sequentially or simultaneously, one or more therapeutic agents selected from the group consisting of: 29. The method of embodiment 28, wherein the estrogen receptor modulator is ospemifene. 30. 5-HT 1A Receptor agonists or the 5-HT 2A 29. The method of embodiment 28, wherein the receptor agonist is flibanserin. 31. The method of embodiment 28, wherein said dopaminergic receptor agonist is apomorphine. 32. The method of embodiment 28, wherein the steroidal agent is tibolone, estrogen, or testosterone. 33. The method of embodiment 28, wherein the phosphodiesterase inhibitor is sildenafil or tadalafil. 34. The method of embodiment 28, wherein said melanocortin receptor agonist is bremelanotide. 35. The method of embodiment 28, wherein said alpha-1-adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin, or tamsulosin. 36. The method of embodiment 28, wherein the beta adrenergic receptor antagonist is propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, or nebivolol. 37. The method of embodiment 28, wherein said anticonvulsant or mood stabilizer is carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topimarate, or valproate. 38. The method of embodiment 28, wherein said selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. 39. The method of embodiment 28, wherein said serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. 40. The method of embodiment 28, wherein said antidepressant is citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, or nortriptyline. 41. The method of embodiment 28, wherein the anti-anxiety agent is lorazepam, oxazepam, or buspirone. 42. The method of embodiment 28, wherein said antipsychotic is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. 43. The antihistamine is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, barbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate 29. The method of embodiment 28, wherein the active ingredient is dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, and VUF-6002. 44. The method of embodiment 28, wherein the benzodiazepine is quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, and midazolam. 45. The method of embodiment 28, wherein the hormonal agent is oxytocin, estrogen, or testosterone. 46. ​​A therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof, and optionally an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 1A) A combination comprising one or more therapeutic agents selected from the group consisting of receptor agonists, steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, antianxiety agents, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensive agents, antilipid agents, hormones, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorectics, and anesthetics. 47. The combination of embodiment 46, wherein the cyclobenzaprine or salt thereof and the one or more therapeutic agents are in the same dosage form or in separate dosage forms that are packaged together or separately, and wherein the cyclobenzaprine or salt thereof and the one or more therapeutic agents are administered simultaneously or sequentially. 48. The one or more therapeutic agents are ospemifene, flibanserin, tibolone, estrogen, or testosterone, sildenafil, tadalafil, bremelanotide, prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, nebivolol, carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, venlafaxine, citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine loxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, nortriptyline, lorazepam, oxazepam, buspirone, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, risperidone, acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate Dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ The combination of embodiment 41, wherein the compound is 7777120, VUF-6002, quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, midazolam, or oxytocin. 49. The combination according to embodiment 46, wherein said cyclobenzaprine is the free base or a pharmaceutically acceptable salt thereof. 50. A combination according to any one of embodiments 47-49, wherein said pharmaceutically acceptable salt of cyclobenzaprine is an acid salt of cyclobenzaprine. 51. The combination according to embodiment 50, wherein the acid salt of cyclobenzaprine is cyclobenzaprine-HCl. 52. A combination according to any one of embodiments 47-51, wherein the cyclobenzaprine or a pharmaceutical salt thereof is in the form of a eutectic. 53. A combination according to embodiment 52, wherein the eutectic is a mannitol eutectic. 54. A combination according to embodiment 53, wherein said eutectic is selected from the group consisting of a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol with a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, and granules comprising an outer phase of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. 55. A combination according to any one of embodiments 47 to 54, wherein the combination comprises a pharmaceutically acceptable salt of cyclobenzaprine and a basifying agent. 56. The combination of embodiment 55, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 57. The combination according to embodiment 56, wherein the basifying agent is dipotassium hydrogen phosphate. 58. The combination according to embodiment 47, wherein the combination comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 59. The combination according to embodiment 58, wherein the combination comprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 60. The combination according to embodiment 59, wherein the combination comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 61. The combination according to embodiment 59, wherein the combination comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 62. The combination according to embodiment 60, wherein the combination comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 63. The combination according to embodiment 62, wherein the composition comprises about 5.6 mg of cyclobenzaprine-HCl. 64. The combination according to embodiment 60, wherein the combination comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. 65. The combination according to embodiment 64, wherein the combination comprises about 2.8 mg of cyclobenzaprine. 66. The method of embodiment 1, wherein the female subject has female genitalia by birth, reconstructive surgery, or sex reassignment surgery. 67. The method of embodiment 66, wherein the female subject is premenopausal, perimenopausal, or postmenopausal. 68. The method of any one of embodiments 1-45 and 66-67, wherein said sexual dysfunction is associated with the use of one or more medications selected from the group consisting of antidepressants, anxiolytics, antihypertensives, chemotherapeutic agents, hormones, corticosteroids, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorexiants, and anesthetics. 69. The method of any one of embodiments 1-45 and 66-67, wherein the sexual dysfunction is associated with a medical or mental health condition. 70. The method of embodiment 69, wherein said sexual dysfunction is a desire disorder, an arousal disorder, an orgasm disorder, or a sexual pain disorder. 71. The method of embodiment 70, wherein the sexual dysfunction is associated with one or more of the following symptoms: sexual aversion, low sexual desire or interest, fear of sexual intercourse, difficulty with arousal, inability to become or remain aroused during sexual activity, persistent or recurring difficulty in achieving orgasm after sufficient sexual arousal and continued stimulation, and pain associated with sexual stimulation or vaginal contact. 72. The method of embodiment 69, wherein the medical condition is selected from the group consisting of cardiovascular disease, obesity, cancer, a pulmonary condition, a renal condition, a bladder condition, a rectal condition, an intestinal condition, a liver condition, a gynecological condition, an autoimmune disorder, a hormonal condition, a viral infection, a bacterial infection, a parasitic infection, and a prion infection. 73. The method of embodiment 72, wherein the cardiovascular disease is selected from the group consisting of heart disease, hypertension, and peripheral vascular disease. 74. The method of embodiment 72, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gestational trophoblastic disease, uterine sarcoma, vaginal cancer, vulvar cancer, pancreatic cancer, rectal cancer, renal cell carcinoma, skin cancer, brain cancer, head and neck cancer, lung cancer, thyroid cancer, bladder cancer, esophageal cancer, mesothelioma, glioblastoma, thymic carcinoma, lymphoma, leukemia, myeloma, hematological malignancies, and colon or gastrointestinal cancer. 75. The method of embodiment 72, wherein said pulmonary condition is selected from the group consisting of pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax, and mesothelioma. 76. The method of embodiment 72, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjogren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease. 77. The method of embodiment 72, wherein the liver condition is selected from the group consisting of hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease. 78. The method of embodiment 72, wherein said gynecological condition is selected from the group consisting of menopause, peritonitis, uterine retrogression, fibroids, endometritis, uterine cyst, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy, and hormonal fluctuations. 79. The method of embodiment 72, wherein the bladder condition is selected from the group consisting of urethritis, interstitial cystitis, and urinary tract infection. 80. The method of embodiment 72, wherein said renal condition is selected from the group consisting of chronic kidney disease (CKD), diabetes, anorexia nervosa, high blood pressure, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome. 81. The method of embodiment 72, wherein the hormonal condition is associated with menopause, perimenopause, pregnancy, or childbirth. 82. The method of embodiment 72, wherein the viral infection is caused by human papillomavirus, hepatitis C virus, or herpes simplex virus. 83. The method of embodiment 72, wherein the bacterial infection is caused by Gardnerella vaginalis. 84. The method of embodiment 69, wherein the mental health condition is one or more conditions selected from the group consisting of psychological conditions, mood disorders, trauma and stressor related disorders, neurodegenerative disorders, and anxiety disorders. 85. The method of embodiment 84, wherein the psychological condition is sexual, emotional, or physical trauma or abuse. 86. The method of embodiment 84, wherein the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. 87. The method of embodiment 84, wherein the trauma- and stressor-related disorder is post-traumatic stress disorder, acute stress disorder, adjustment disorder, or reactive attachment disorder. 88. The method of embodiment 84, wherein the neurodegenerative disorder is mild cognitive impairment, amnestic mild cognitive impairment, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, amyotrophic lateral sclerosis, or motor neuron disease. 89. The method of embodiment 84, wherein the anxiety disorder is panic, generalized anxiety disorder, specific phobia, or social phobia. DETAILED DESCRIPTION OF THE INVENTION

[0006] Detailed Description The present disclosure provides, in some embodiments, methods and pharmaceutical compositions for treating sexual dysfunction and related symptoms in a subject in need of or at risk, wherein the pharmaceutical composition comprises a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier, optionally in combination with one or more therapeutic or non-therapeutic agents.

[0007] definition The term "herein" means the entire application.

[0008] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. In case of conflict, the present application, including definitions, will control.

[0009] It should be understood that any of the embodiments described herein may be combined with one or more other embodiments of the present disclosure, including those described under different aspects and portions of the present disclosure, unless expressly disclaimed or inappropriate, and that the combination of embodiments is not limited to those specific combinations claimed via multiple dependent claims.

[0010] All publications, patents, and patent publications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0011] Throughout this specification, the words "comprise" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0012] The term "including," as used herein, means "including but not limited to." "Including" and "including but not limited to" are used interchangeably. Thus, it is understood that these terms imply the inclusion of a stated integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0013] As used herein, the term "about" refers to (and describes) a value or parameter itself, including embodiments relating to that value or parameter itself. For example, a statement referring to "about X" includes the statement "X." As used herein, the term "about" allows for a ±10% variation within the range of significant figures. Numerical ranges are inclusive of the numbers defining the range.

[0014] Any examples following the term "eg" or "for example" are not meant to be exhaustive or limiting.

[0015] Unless otherwise required by context, singular terms shall include plural terms and plural terms shall include the singular term.

[0016] The articles "a", "an" and "the" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0017] When aspects or embodiments are described in terms of Markush groups or other groupings of alternatives, the application encompasses not only the entire group recited as a whole, but also each member of the group individually and all possible subgroups of that main group, as well as the main group lacking one or more of its group members.

[0018] Although exemplary methods and materials are described herein, materials and methods similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments of the present disclosure. The above materials, methods, and examples are illustrative only and are not intended to be limiting.

[0019] In order that this disclosure may be more readily understood, certain terms are first defined. These definitions should be read and understood in light of the remainder of the disclosure as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Additional definitions are provided throughout the entire disclosure.

[0020] As used herein, the term "treat" and its cognate terms refer to the complete or partial amelioration, improvement, or modulation of sexual dysfunction or at least one discernible symptom thereof. In some embodiments, "treating at least one discernible symptom" refers to an improvement in desire and / or interest. In some embodiments, "treating" refers to an improvement in pleasure. In some embodiments, "treating at least one discernible symptom" refers to an improvement in desire and / or frequency. In some embodiments, "treating" refers to an improvement in arousal and / or excitement. In some embodiments, "treating at least one discernible symptom" refers to an improvement in orgasm and / or consummation. In some embodiments, "treating at least one discernible symptom" refers to an improvement in sexual desire disorder. In some embodiments, "treating at least one discernible symptom" refers to an improvement in arousal disorder. In some embodiments, "treating at least one discernible symptom" refers to an improvement in orgasmic disorder. In some embodiments, "treating at least one discernible symptom" refers to the amelioration of dyspareunia.

[0021] In some embodiments of the present disclosure, the cyclobenzaprine is an acid salt of cyclobenzaprine. In other embodiments, the acid salt is cyclobenzaprine-HCl.

[0022] In other embodiments, the acid salt is combined with a basifying agent. In some embodiments, the basifying agent is an ingredient (and excipient) in a tablet or other formulation, and the basifying agent exerts its effect while the formulation is dispersed in mucus substances, including the oral and sublingual tissues, while a portion of the formulation dissolves in the mucus substances and over a period of time after the tablet has dissolved in the mucus substances.

[0023] In some embodiments of the present disclosure, the "basifying agent" is selected from the group consisting of potassium dihydrogen phosphate (monopotassium phosphate, monobasic potassium phosphate, KHPO), dipotassium hydrogen phosphate (dipotassium phosphate, dibasic potassium phosphate, KHPO), tripotassium phosphate (KPO), sodium dihydrogen phosphate (monosodium phosphate, monobasic sodium phosphate, NaHPO), disodium hydrogen phosphate (disodium phosphate, dibasic sodium phosphate, NaHPO), trisodium phosphate (NaPO), bicarbonate or carbonate salts, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borates, hydroxides, silicates, nitrates, dissolved ammonia, conjugate bases of some organic acids (including bicarbonates), and sulfides. In some embodiments, the basifying agent is dipotassium hydrogen phosphate (K2HPO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), tripotassium citrate, or trisodium citrate. A basifying agent particularly useful in combination with cyclobenzaprine-HCl is dipotassium hydrogen phosphate (K2HPO4). Another basifying agent particularly useful in combination with cyclobenzaprine-HCl is potassium dihydrogen phosphate (KH2PO4). Another basifying agent particularly useful in combination with cyclobenzaprine-HCl is disodium hydrogen phosphate (Na2HPO4). Another basifying agent particularly useful in combination with cyclobenzaprine-HCl is tripotassium citrate. Another basifying agent particularly useful in combination with cyclobenzaprine-HCl is trisodium citrate.

[0024] In some embodiments of the present disclosure, the cyclobenzaprine or acid salt thereof is present in a eutectic. In some embodiments, the eutectic includes mannitol. In some aspects, the mannitol is β-mannitol. In other embodiments, the mannitol is δ-mannitol. In some aspects, the eutectic is a eutectic of cyclobenzaprine-HCl and mannitol, and is selected from the group consisting of a eutectic of 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol, a eutectic of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol, a mixture of a eutectic of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol with a eutectic of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol, and granules comprising an outer layer of a eutectic of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol and an inner layer of β-mannitol. See, for example, WO2014 / 145156 and WO2016 / 044796 (both of which are incorporated herein by reference). It should be understood that the "cyclobenzaprine-HCl" eutectic of the present disclosure refers to either these eutectic or granules. In some aspects, the eutectic is combined with a basifying agent. See, for example, WO2013 / 188847 (incorporated herein by reference).

[0025] As used herein, the term "eutectic" or "in the form of a eutectic" refers to a mixture of compounds or elements having a single chemical composition that melts at a lower temperature than any other composition made from the same components. A composition containing a eutectic is known as a eutectic composition, and its melting temperature is known as the eutectic temperature. Eutectic compositions often have higher stability and / or dissolution rates than their non-eutectic counterparts. Because eutectics enhance dissolution, they can be used to increase the permeability in solid dispersions and dispersed systems.

[0026] Methods for Treatment In some embodiments, the present disclosure provides methods for treating, ameliorating, and / or preventing sexual dysfunction and its associated symptoms, the method comprising administering to a female subject in need of or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier.

[0027] In some embodiments, the method for treating, ameliorating, and / or preventing sexual dysfunction comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable acid salt of cyclobenzaprine and a basifying agent. In some embodiments, the pharmaceutical composition comprises a cocrystal of a pharmaceutically acceptable salt of cyclobenzaprine and mannitol, optionally combined with a basifying agent. The compositions of the present disclosure may be administered in one, two, or more daily doses. In some embodiments, the method for treating and / or preventing sexual dysfunction comprises administering a daily dose of between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose comprises about 5.6 mg of cyclobenzaprine-HCl. In some embodiments, the daily dose comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose comprises about 2.8 mg of cyclobenzaprine-HCl. In some embodiments, the method for treating and / or preventing sexual dysfunction comprises simultaneously or sequentially administering two dosage units of cyclobenzaprine, wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, each of the two dosage units comprises about 2.8 mg of cyclobenzaprine-HCl. In some embodiments, the method for treating and / or preventing sexual dysfunction comprises daily administering a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof.In some embodiments, the method for treating and / or preventing sexual dysfunction comprises administering a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof once daily.

[0028] In some embodiments, a method for treating and / or preventing sexual dysfunction comprises administering a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, thin film, transdermal, parenteral, rectal, or vaginal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration. In some embodiments, the pharmaceutical composition is formulated for buccal administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for suppository administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for intramuscular administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intranasal administration. In some embodiments, the pharmaceutical composition is formulated for transdermal administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for rectal administration. In some embodiments, the pharmaceutical composition is formulated for vaginal administration.

[0029] In some embodiments, the methods of the disclosure comprise administering an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 2+ ), in combination with a composition of the disclosure comprising cyclobenzaprine or a pharmaceutically acceptable salt thereof. 1A ) receptor agonist, 5-hydroxytryptamine 2A (5-HT 2AIn some embodiments, the method further comprises administering, sequentially or simultaneously, one or more therapeutic agents selected from the group consisting of: steroid hormone receptor antagonists, synthetic or gonadal steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, antianxiety agents, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensive agents, antilipid agents, hormonal agents, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergic agents, amphetamines, dopaminergic receptor agonists, anorectics, and anesthetics. In some embodiments, the one or more therapeutic agents are administered sequentially or simultaneously with a composition of the present disclosure comprising cyclobenzaprine-HCl.

[0030] In some embodiments, the sexual dysfunction or risk thereof is in a female subject. In some embodiments, the subject has female genitalia by birth, reconstructive surgery, or sex reassignment surgery. In some embodiments, the female subject is premenopausal, perimenopausal, or postmenopausal.

[0031] In some embodiments, the sexual dysfunction may be associated with the use of one or more medications selected from the group consisting of antidepressants, anxiolytics, antihypertensives, chemotherapeutic agents, hormones, corticosteroids, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorectics, and anesthetics.

[0032] In some embodiments, the sexual dysfunction may be associated with a medical condition or a mental health condition. In some embodiments, the sexual dysfunction is associated with a medical condition, wherein the medical condition is selected from the group consisting of cardiovascular disease, obesity, cancer, lung conditions, kidney conditions, bladder conditions, rectal conditions, intestinal conditions, liver conditions, gynecological conditions, autoimmune disorders, hormonal conditions, viral infections, bacterial infections, parasitic infections, and prion infections. In some embodiments, the cardiovascular disease is selected from the group consisting of heart disease, hypertension, and peripheral vascular disease. In some embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gestational trophoblastic disease, uterine sarcoma, vaginal cancer, vulvar cancer, pancreatic cancer, rectal cancer, renal cell carcinoma, skin cancer, brain cancer, head and neck cancer, lung cancer, thyroid cancer, bladder cancer, esophageal cancer, mesothelioma, glioblastoma, thymic carcinoma, lymphoma, leukemia, myeloma, hematological malignancies, and colon or gastrointestinal cancer. In some embodiments, the pulmonary condition is selected from the group consisting of pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax, and mesothelioma. In some embodiments, the autoimmune disease is selected from the group consisting of multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjogren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease. In some embodiments, the liver condition is selected from the group consisting of hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease. In some embodiments, the gynecological condition is selected from the group consisting of menopause, peritonitis, uterine involution, fibroids, endometritis, uterine cyst, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy, and hormonal fluctuations. In some embodiments, the bladder condition is selected from the group consisting of urethritis, interstitial cystitis, and urinary tract infection. In some embodiments, the kidney condition is selected from the group consisting of chronic kidney disease (CKD), diabetes, anorexia nervosa, high blood pressure, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome. In some embodiments, the hormonal condition is associated with menopause, perimenopause, pregnancy, or childbirth.In some embodiments, the viral infection is caused by human papillomavirus, hepatitis C virus, or herpes simplex virus. In some embodiments, the bacterial infection is caused by Gardnerella vaginalis.

[0033] In some embodiments, the mental health condition is one or more conditions selected from the group consisting of psychological conditions, mood disorders, trauma and stressor-related disorders, neurodegenerative disorders, and anxiety disorders. In some embodiments, the psychological condition is sexual, emotional, or physical trauma or abuse. In some embodiments, the mood disorder is depressive disorder, bipolar disorder, or substance-induced disorder. In some embodiments, the trauma and stressor-related disorder is post-traumatic stress disorder, acute stress disorder, adjustment disorder, or reactive attachment disorder. In some embodiments, the neurodegenerative disorder is mild cognitive impairment, amnestic mild cognitive impairment, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, amyotrophic lateral sclerosis, or motor neuron disease. In some embodiments, the anxiety disorder is panic, generalized anxiety disorder, specific phobia, or social phobia.

[0034] In some embodiments, the sexual dysfunction is a sexual desire disorder, an arousal disorder, an orgasmic disorder, or a dyspareunia disorder.

[0035] In some embodiments, the sexual dysfunction is associated with one or more of the following symptoms: sexual aversion, low sexual desire or interest, fear of sexual intercourse, difficulty with arousal, inability to become or remain aroused during sexual activity, persistent or recurring difficulty in achieving orgasm after sufficient sexual arousal and continued stimulation, and pain associated with sexual stimulation or vaginal contact.

[0036] Changes in Sexual Function Questionnaire-14 (CSFQ-14) The Changes in Sexual Functioning Questionnaire (CSFQ) is a 36-item clinical and research instrument that identifies five scales of sexual function. The CSFQ has been abbreviated to a factor structure of a 14-item version (CSFQ-14), which captures scores on three scales corresponding to phases of the sexual response cycle (e.g., desire, excitement, and orgasm) as well as the five scales of the original CSFQ (e.g., desire / frequency, desire / interest, arousal / excitement, orgasm / completion, and pleasure). Factor analysis confirms the construct validity of the CSFQ-14 as a comprehensive measure of sexual dysfunction.

[0037] DSM-5 Diagnostic Criteria for PTSD and CAPS-5 The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) is a diagnostic tool published by the American Psychiatric Association. DSM-5 includes descriptions, symptoms, and criteria for diagnosing mental disorders. It also includes a common language for clinicians to communicate about their patients in order to establish consistent and reliable diagnoses that can be used in the study of mental disorders. DSM-5 also provides researchers with a common language to study criteria for potential future revisions and to aid in the development of medications and other interventions.

[0038] The Clinician-Administered PTSD Scale (CAPS) is a semi-structured diagnostic interview that assesses the essential features of PTSD as defined by the DSM-5 diagnostic criteria for PTSD (Weathers et al., 2017). It can also be used to assess associated features of the diagnostic syndrome (e.g., survivor guilt). The interview is designed to accommodate various post-traumatic time periods as a reference point for diagnosis. CAPS allows clinicians the flexibility to ask questions about symptoms and diagnostic status over the past week, past month, and / or lifetime diagnosis. Any one or all three of these time frames can be used depending on the nature of the task at hand. Other diagnostic scales or tools based on the DSM-5 diagnostic criteria for diagnosing PTSD are also known. These include, for example, the PTSD Checklist for DSM-5 (PCL-5), symptom severity, intensity and / or frequency rating scales completed by clinicians, and symptom severity, intensity and / or intensity rating scales completed by patients.

[0039] In some embodiments, the assessment of change in one or more of the DSM-5 diagnostic criteria for PTSD is based on one or more of the Clinical Diagnostic Interview for PTSD (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), a clinician-administered symptom severity, intensity, and / or frequency rating scale, or a patient-administered symptom severity, intensity, and / or frequency rating scale. The Clinical Diagnostic Interview for PTSD (CAPS-5) is a 30-item questionnaire corresponding to the DSM-5 diagnosis of PTSD. The CAPS-5 requires the identification of a single-index trauma, which serves as the basis for the symptom questions. The CAPS-5 asks questions relevant to assessing the dissociative subtype of PTSD (depersonalization and derealization), but no longer includes other associated symptoms (e.g., gaps in awareness). The CAPS-5 symptom severity rating is based on symptom frequency and intensity. However, CAPS-5 items are rated with a single severity score, in contrast to previous versions of CAPS which required separate frequency and intensity scores.

[0040] Pharmaceutical Compositions In some embodiments, the present disclosure provides a therapeutically effective amount of the disclosed cyclobenzaprine or a pharmaceutically acceptable salt thereof and optionally an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 1AIn some embodiments, the estrogen receptor modulator is ospemifene. ... 1A Receptor agonists or the above 5-HT 2AIn some embodiments, the receptor agonist is flibanserin. In some embodiments, the dopaminergic receptor agonist is apomorphine. In some embodiments, the steroid is tibolone, estrogen, or testosterone. In some embodiments, the phosphodiesterase inhibitor is sildenafil or tadalafil. In some embodiments, the melanocortin receptor agonist is bremelanotide. In some embodiments, the alpha-1-adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin, or tamsulosin. In some embodiments, the beta adrenergic receptor antagonist is propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, or nebivolol. In some embodiments, the anticonvulsant or mood stabilizer is carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, or valproate. In some embodiments, the selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. In some embodiments, the serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. In some embodiments, the antidepressant is citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, or nortriptyline.In some embodiments, the anti-anxiety agent is lorazepam, oxazepam, or buspirone. In some embodiments, the antipsychotic is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone. In some embodiments, the antihistamine is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate. Dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, and VUF-6002. In some embodiments, the benzodiazepine is quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, and midazolam. In some embodiments, the hormonal agent is oxytocin, estrogen, or testosterone.

[0041] In some embodiments, the cyclobenzaprine or pharmaceutically acceptable salt thereof of the present disclosure and the one or more optional therapeutic agents are in the same dosage form or in separate dosage forms packaged together or separately, wherein the cyclobenzaprine or pharmaceutically acceptable salt thereof and the one or more optional therapeutic agents are administered simultaneously or sequentially. In some embodiments, the cyclobenzaprine or salt and the one or more optional therapeutic agents are in the same dosage form. In some embodiments, the cyclobenzaprine and the one or more optional therapeutic agents are in separate dosage forms. In some embodiments, the cyclobenzaprine or salt and the one or more optional therapeutic agents are packaged together. In some embodiments, the cyclobenzaprine or salt and the one or more optional therapeutic agents are packaged separately. In some embodiments, the cyclobenzaprine or salt and the one or more optional therapeutic agents are administered simultaneously. In some embodiments, the cyclobenzaprine or salt and the one or more optional therapeutic agents are administered sequentially.

[0042] In some embodiments, the one or more optional therapeutic agents are: ospemifene, flibanserin, tibolone, estrogen or testosterone, sildenafil, bremelanotide, prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, nebivolol, carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, venlafaxine, citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine loxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, nortriptyline, lorazepam, oxazepam, buspirone, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, risperidone, acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate Dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, VUF-6002, quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, midazolam, or oxytocin.

[0043] In some embodiments, the cyclobenzaprine is a free base or a pharmaceutically acceptable salt of the free base. In some embodiments, the cyclobenzaprine is a free base. In some embodiments, the cyclobenzaprine is a pharmaceutically acceptable salt. In some embodiments, the cyclobenzaprine is an acid salt. In some embodiments, the acid salt of cyclobenzaprine is cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine and a basifying agent.

[0044] In some embodiments, the compositions of the present disclosure contain between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the compositions contain about 5.6 mg of cyclobenzaprine-HCl. In some embodiments, the compositions contain about 2.8 mg of cyclobenzaprine-HCl.

[0045] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, thin film, transdermal, parenteral, rectal, or vaginal administration. In some embodiments, the pharmaceutical composition is formulated for sublingual administration. In some embodiments, the pharmaceutical composition is formulated for buccal administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for suppository administration. In some embodiments, the pharmaceutical composition is formulated for intravenous administration. In some embodiments, the pharmaceutical composition is formulated for intramuscular administration. In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for inhalation administration. In some embodiments, the pharmaceutical composition is formulated for intranasal administration. In some embodiments, the pharmaceutical composition is formulated for transdermal administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration. In some embodiments, the pharmaceutical composition is formulated for rectal administration. In some embodiments, the pharmaceutical composition is formulated for vaginal administration.

[0046] In some embodiments, the dosage form of the composition of the present disclosure is a tablet, film, thin film, liquid, powder, or spray solution. In some embodiments, the dosage form is a tablet. In some embodiments, the dosage form is a film. In some embodiments, the dosage form is a thin film. In some embodiments, the dosage form is a liquid. In some embodiments, the dosage form is a powder. In some embodiments, the dosage form is a spray solution. In some embodiments, the dosage form is a sublingual tablet, sublingual film, sublingual liquid, sublingual powder, or sublingual spray solution. In some embodiments, the dosage form is a sublingual tablet. In some embodiments, the dosage form is a sublingual film. In some embodiments, the dosage form is a sublingual liquid. In some embodiments, the dosage form is a sublingual powder. In some embodiments, the dosage form is a sublingual spray solution. [Example]

[0047] Example 1 Effects of a low-dose sublingual formulation of cyclobenzaprine on female sexual function in subjects with military-related PTSD after 12 weeks of treatment

[0048] In this 12-week, multicenter, adaptive-design, randomized, fixed-dose controlled trial, 5.6 mg cyclobenzaprine HCl (2 × 2.8 mg sublingual tablets containing 75% ± 2% cyclobenzaprine HCl and 25% ± 2% mannitol eutectic and anhydrous dibasic calcium phosphate (basifying agent)) taken once daily at bedtime was compared with placebo for the treatment of PTSD at 45 US sites. Eligible participants (men and women) were 18–75 years of age, had experienced a traumatic event during military service since 2001 that met DSM-5 PTSD Criterion A, met DSM-5-defined PTSD criteria as defined by the Clinical Diagnostic Interview for PTSD (CAPS-5), had a baseline CAPS-5 severity score of ≥33, and were antidepressant-naive and naive or on washout from other psychotropic medications. A preplanned interim analysis was performed when approximately half of the originally planned sample of 550 participants had outcome data.

[0049] The study was terminated early after an interim analysis indicated a low probability of achieving significant separation between treatment groups for the CAPS-5 primary endpoint. Therefore, all analyses were performed on the interim analysis sample of 274 participants. The modified intention-to-treat (mITT) population, including all randomized subjects with at least one post-baseline CAPS-5, included 125 participants treated with the above-mentioned cyclobenzaprine-HCl sublingual formulation at a dose of 5.6 mg / day and 127 participants given a placebo. The female subgroup of the study, including 10 participants treated with the above-mentioned cyclobenzaprine-HCl sublingual formulation at a dose of 5.6 mg / day and 17 participants given a placebo, showed a significant mean improvement in CAPS-5 compared to placebo (-9.1 units after 12 weeks of treatment).

[0050] Sexual function was measured by the Changes in Sexual Function Questionnaire-Short Form (CSFQ-14), a validated 14-item scale (Keller, McGarvey, Clayton, 2006). Similar gender-specific versions were administered to men (CSFQ-14-M) and women (CSFQ-14-F), and each gender was analyzed separately. In addition to a total sexual function score, there are five subscales: desire / frequency, desire / interest, arousal / excitement, orgasm / completion, and pleasure. The scales range from (never) to (every day), with higher scores reflecting higher levels of sexual function.

[0051] Medium effect sizes were found for the CSFQ-14-F total score and four of the five subscales among women treated with the 5.6 mg dose (N=8) and placebo (N=16). Due to sample size differences between the active treatment and placebo groups, results are better characterized by Hedge's g effect size. Specifically, there were moderate effects on the total score, g = 0.49 (95% CI -1.34, 0.37), desire / interest subscale, g = 0.63 (95% CI -1.49, 0.25), pleasure subscale, g = 0.54 (95% CI -1.40, 0.33), desire / frequency subscale, g = 0.46 (95% CI -1.31, 0.40), and arousal / excitement subscale, g = 0.55 (95% CI -1.41, 0.32). No effect was found on the orgasm / completion scale. Overall, adverse events (AEs) in this study were comparable to previous studies with a similar 5.6 mg cyclobenzaprine-HCl dose. The most common AE was oral hypoaesthesia (tongue / mouth numbness), which was administration site-related, was generally transient (<60 minutes after administration), and was never rated as serious. The most common systemic AE was somnolence, which was also never rated as serious. Two participants who received placebo and eight participants who received the 5.6 mg cyclobenzaprine-HCl dose had at least one AE leading to study discontinuation.

[0052] Results in the female cohort suggest that a 5.6 mg daily dose of the cyclobenzaprine-HCl composition has clinically meaningful effects over placebo in improving overall sexual function, frequency of sexual activity, interest in sexual experiences, arousability, and pleasure of current intercourse in women with military-related PTSD. This effect was strongest for arousal / excitement, a major form of female sexual dysfunction for which effective and safe available treatment options are limited (Goldstein, 2000).

[0053] Example 2 Effects of a Sublingual Cyclobenzaprine-HCl Formulation on Female Sexual Function in a Military and Civilian Phase 3 PTSD Trial: Preliminary Evidence of Female-Specific Improvements in Sexual Function After 12 Weeks

[0054] Three randomized, placebo-controlled, and double-blind clinical trials of the 5.6 mg cyclobenzaprine-HCl sublingual formulation (2 × 2.8 mg tablets) described above were conducted (Phase 2 and 3 trials in military-related PTSD and a Phase 3 trial in primarily civilian PTSD). All three trials demonstrated promising activity using the 5.6 mg cyclobenzaprine-HCl dose with respect to clinician- and patient-assessed overall PTSD symptoms (Clinician Global Impression [CGI] and Patient Global Impression of Change [PGIC]). Given the very low rates of adverse events related to sexual function in both the drug and placebo groups in the Phase 2 trial, a systematic review was conducted to evaluate the effects of treatment on female sexual function in a subsequent Phase 3 trial. This retrospective analysis examined the activity of the cyclobenzaprine-HCl sublingual formulation on the Short Form of the Sexual Function Change Questionnaire (CSFQ-14) in two Phase 3 trials.

[0055] In a phase 3 trial in military-related PTSD, eligible participants (men and women) were 18–75 years of age, had experienced a traumatic event during military service since 2001 that met DSM-5 PTSD criteria A, met DSM-5-defined PTSD criteria as measured by CAPS-5, had a baseline CAPS-5 severity score of ≥33, and were not using antidepressants or were not using or were on or off other psychotropic medications. In a phase 3 trial in primarily civilian PTSD, the inclusion criteria were expanded to include civilian participants with current PTSD, as determined by CAPS-5. Thus, this trial included 94% civilian traumatic events with a minimal baseline severity score of ≥33 on CAPS-5. Both trials were stopped early after interim analyses indicated a low probability of achieving significant separation between treatment groups for the CAPS-5 primary endpoint. Thus, analyses were conducted on the interim analysis sample of 252 participants (89% male [n=225 M; n=27 F]; 100% military-related PTSD) in the military-related Phase 3 trial and 143 subjects (79% female [n=129 F; n=34 M]; ​​94% civilian PTSD) in the civilian Phase 3 trial.

[0056] The CSFQ-14 is a validated 14-item scale (Keller, McGarvey, Clayton, 2006) with separate male and female versions, which were analyzed separately. In addition to a total sexual function score, there are five subscales: desire / frequency, desire / interest, arousal / excitement, orgasm / completion, and pleasure. The items range from (never) to (every day) on a 5-point Likert scale. Higher scores reflect higher levels of sexual function.

[0057] In a Phase 3 trial of predominantly male and all military-related PTSD, the sample size of female completers (N=24) was small, and the trial was not powered to detect differences in subgroups. Thus, effect sizes (as characterized by Hedge's g) are reported for the CSFQ-14 total score and for four of the five subscales for women treated with the 5.6 cyclobenzaprine-HCl dose (N=8) compared with placebo (N=16): total score g=0.49 (95% CI -1.34, 0.37), desire / interest subscale g=0.63 (95% CI -1.49, 0.25), pleasure subscale g=0.54 (95% CI -1.40, 0.33), desire / frequency subscale g=0.46 (95% CI -1.31, 0.40), and arousal / excitement subscale g=0.55 (95% CI -1.41, 0.32). No effect was found for the orgasm / completion scale.

[0058] In a phase 3 trial of primarily civilian PTSD subjects, female completers (N=58) in the 5.6 mg cyclobenzaprine-HCl dose group showed a trend toward improvement in CSFQ-14-F total scores versus placebo (N=55), with a medium effect size (p=0.07, Hedge's g=0.37 [95% CI 0.00, 0.74]). Although the study was not powered to detect differences in subgroups, small to medium effect sizes were observed for each of the subscales, including: desire / interest g=0.23 (95% CI -0.14, 0.60), desire / frequency g=0.21 (95% CI -0.16, 0.57), pleasure g=0.19 (95% CI -0.17, 0.56), arousal / excitement g=0.33 (95% CI -0.04, 0.70), and orgasm / completion g=0.29 (95% CI -0.08, 0.66).

[0059] Adverse events (AEs) in both Phase 3 studies were comparable to previous studies with the 5.6 mg cyclobenzaprine-HCl dose. The most frequent AE was oral hypoesthesia (tongue / mouth numbness), which was administration site-related, was generally transient (<60 minutes after administration), and was never rated as serious. The most common systemic AE was somnolence, which was also never rated as serious.

[0060] Results from two Phase 3 trials in the female population suggest a trend toward clinically meaningful improvement in overall sexual function in women with PTSD. Results from both trials showed strong effects on female arousal / excitement, a major form of female sexual dysfunction for which available treatment options are limited. The effect size was larger in the military Phase 3 trial, but there were relatively few women in that trial. The civilian Phase 3 trial had a larger female sample, and proportionally more female participants in that trial reported indicator trauma related to sexual trauma.

[0061] These above examples demonstrate that the 5.6 mg cyclobenzaprine-HCl dose of the composition of the present disclosure has activity in military-related PTSD and civilian PTSD, in female SD. The present invention provides, for example, the following items. (Item 1) 1. A method for treating or preventing sexual dysfunction and its associated symptoms, said method comprising administering to a female subject in need of or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier. (Item 2) 2. The method of claim 1, wherein the cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof. (Item 3) 3. The method according to item 1 or 2, wherein the pharmaceutically acceptable salt of cyclobenzaprine is an acid salt of cyclobenzaprine. (Item 4) 4. The method of claim 3, wherein the acid salt of cyclobenzaprine is cyclobenzaprine-HCl. (Item 5) 5. The method according to any one of items 1 to 4, wherein the cyclobenzaprine or a pharmaceutically acceptable salt thereof is in the form of a eutectic. (Item 6) 6. The method according to item 5, wherein the eutectic is a mannitol eutectic. (Item 7) The mannitol eutectic was a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic, 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol co-crystal, 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol and 65%±2% cyclobenzaprine-HCl and 35%±2% 7. The method according to item 6, wherein the β-mannitol is selected from the group consisting of a mixture of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and a granule comprising an outer layer of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. (Item 8) 8. The method according to any one of items 1 to 7, wherein the composition comprising a pharmaceutically acceptable salt of cyclobenzaprine further comprises a basifying agent. (Item 9) 9. The method of claim 8, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. (Item 10) 10. The method according to item 9, wherein the basifying agent is dipotassium hydrogen phosphate. (Item 11) 2. The method of claim 1, wherein the composition comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 12) 12. The method of claim 11, wherein the composition comprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 13) 13. The method of claim 12, wherein the composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 14) 13. The method of claim 12, wherein the composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 15) 14. The method of claim 13, wherein the composition comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 16) 16. The method of claim 15, wherein the composition comprises about 5.6 mg of cyclobenzaprine-HCl. (Item 17) 14. The method of claim 13, wherein the composition comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 18) 18. The method of claim 17, wherein the composition comprises about 2.8 mg of cyclobenzaprine-HCl. (Item 19) 19. The method of claim 17 or 18, wherein the composition is administered simultaneously or sequentially in two dosage units, and the combined amount of the composition in the two dosage units is about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 20) 20. The method of claim 19, wherein the composition is administered simultaneously in two dosage units, each dosage unit containing about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 21) 20. The method of claim 19, wherein the composition is administered sequentially in two dosage units, each dosage unit containing about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 22) 22. The method according to any one of items 1 to 21, wherein the pharmaceutical composition is administered daily. (Item 23) 23. The method of any one of items 1 to 22, wherein the composition is administered once a day. (Item 24) 24. The method of item 23, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, thin film, transdermal, parenteral, rectal, or vaginal administration. (Item 25) 25. The method of claim 24, wherein the pharmaceutical composition is formulated for sublingual administration. (Item 26) 26. The method of item 25, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in a thin film, transdermally, parenterally, rectally, or vaginally. (Item 27) 27. The method of claim 26, wherein the pharmaceutical composition is administered sublingually. (Item 28) The method includes administering an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 1A ) receptor agonist, 5-hydroxytryptamine 2A (5-HT 2A 27. The method of any one of items 1 to 26, further comprising administering, sequentially or simultaneously, one or more therapeutic agents selected from the group consisting of: α-1-adrenergic receptor antagonists, synthetic or gonadal steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, antianxiety agents, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensive agents, antilipid agents, hormonal agents, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergic agents, amphetamines, dopaminergic receptor agonists, anorectics, and anesthetics. (Item 29) 29. The method of claim 28, wherein the estrogen receptor modulator is ospemifene. (Item 30) 5-HT 1A Receptor agonists or the 5-HT 2A 29. The method of item 28, wherein the receptor agonist is flibanserin. (Item 31) 29. The method of claim 28, wherein the dopaminergic receptor agonist is apomorphine. (Item 32) 29. The method of claim 28, wherein the steroid agent is tibolone, estrogen, or testosterone. (Item 33) 29. The method of claim 28, wherein the phosphodiesterase inhibitor is sildenafil or tadalafil. (Item 34) 29. The method of claim 28, wherein the melanocortin receptor agonist is bremelanotide. (Item 35) 29. The method of item 28, wherein the alpha-1-adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin, or tamsulosin. (Item 36) 29. The method of item 28, wherein the beta adrenergic receptor antagonist is propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, or nebivolol. (Item 37) 29. The method of item 28, wherein the anticonvulsant or mood stabilizer is carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, or valproate. (Item 38) 29. The method of claim 28, wherein the selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. (Item 39) 29. The method of item 28, wherein the serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. (Item 40) 29. The method of item 28, wherein the antidepressant is citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, or nortriptyline. (Item 41) 29. The method of claim 28, wherein the anti-anxiety agent is lorazepam, oxazepam, or buspirone. (Item 42) 29. The method of claim 28, wherein the antipsychotic drug is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine or risperidone. (Item 43) The antihistamines include acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, and dimenhydrinate. 29. The method of item 28, wherein the active ingredient is dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, or VUF-6002. (Item 44) 29. The method of claim 28, wherein the benzodiazepine is quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, or midazolam. (Item 45) 29. The method of claim 28, wherein the hormonal agent is oxytocin, estrogen, or testosterone. (Item 46) A therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof, and optionally an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT 1A ) A combination comprising one or more therapeutic agents selected from the group consisting of receptor agonists, steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, antianxiety agents, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensive agents, antilipid agents, hormones, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorectics, and anesthetics. (Item 47) 47. The combination of item 46, wherein the cyclobenzaprine or salt thereof and the one or more therapeutic agents are in the same dosage form or in separate dosage forms that are packaged together or separately, and wherein the cyclobenzaprine or salt thereof and the one or more therapeutic agents are administered simultaneously or sequentially. (Item 48) The one or more therapeutic agents may be ospemifene, flibanserin, tibolone, estrogen, or testosterone, sildenafil, tadalafil, bremelanotide, prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, nebivolol, carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, venlafaxine, citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine loxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, nortriptyline, lorazepam, oxazepam, buspirone, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, risperidone, acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate Dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, VUF-6002, quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, midazolam, or oxytocin. (Item 49) 47. The combination according to item 46, wherein the cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof. (Item 50) 50. The combination according to any one of items 47 to 49, wherein the pharmaceutically acceptable salt of cyclobenzaprine is an acid salt of cyclobenzaprine. (Item 51) 51. The combination according to item 50, wherein the acid salt of cyclobenzaprine is cyclobenzaprine-HCl. (Item 52) 52. The combination according to any one of items 47 to 51, wherein the cyclobenzaprine or a pharmaceutical salt thereof is in the form of a eutectic. (Item 53) 53. The combination according to item 52, wherein the eutectic is a mannitol eutectic. (Item 54) 54. The combination according to item 53, wherein the eutectic is selected from the group consisting of a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol with a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, and granules comprising an outer phase of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol. (Item 55) 55. The combination according to any one of items 47 to 54, wherein the combination comprises a pharmaceutically acceptable salt of cyclobenzaprine and a basifying agent. (Item 56) 56. The combination according to item 55, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. (Item 57) 57. The combination according to item 56, wherein the basifying agent is dipotassium hydrogen phosphate. (Item 58) Item 48. The combination according to item 47, wherein the combination comprises between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 59) 59. The combination according to item 58, wherein the combination comprises between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 60) 60. The combination according to item 59, wherein the combination comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 61) 60. The combination according to item 59, wherein the combination comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 62) 61. The combination according to item 60, wherein the combination comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 63) 63. The combination according to item 62, wherein the composition comprises about 5.6 mg of cyclobenzaprine-HCl. (Item 64) 61. The combination according to item 60, wherein the combination comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. (Item 65) 65. The combination according to item 64, wherein the combination comprises about 2.8 mg of cyclobenzaprine. (Item 66) 10. The method of claim 1, wherein the female subject has female genitalia by birth, reconstructive surgery, or sex reassignment surgery. (Item 67) 67. The method of item 66, wherein the female subject is premenopausal, perimenopausal, or postmenopausal. (Item 68) 68. The method of any one of items 1-45 and 66-67, wherein the sexual dysfunction is associated with the use of one or more medications selected from the group consisting of antidepressants, anxiolytics, antihypertensives, chemotherapeutic agents, hormones, corticosteroids, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorexiants, and anesthetics. (Item 69) 68. The method of any one of items 1-45 and 66-67, wherein the sexual dysfunction is associated with a medical or mental health condition. (Item 70) 70. The method of claim 69, wherein the sexual dysfunction is sexual desire disorder, arousal disorder, orgasmic disorder, or dyspareunia disorder. (Item 71) 71. The method of claim 70, wherein the sexual dysfunction is associated with one or more of the following symptoms: sexual aversion, low sexual desire or interest, fear of sexual intercourse, difficulty with arousal, inability to become or maintain arousal during sexual activity, persistent or recurring difficulty in achieving orgasm after sufficient sexual arousal and continued stimulation, and pain associated with sexual stimulation or vaginal contact. (Item 72) 70. The method of claim 69, wherein the medical condition is selected from the group consisting of cardiovascular disease, obesity, cancer, a pulmonary condition, a renal condition, a bladder condition, a rectal condition, an intestinal condition, a liver condition, a gynecological condition, an autoimmune disorder, a hormonal condition, a viral infection, a bacterial infection, a parasitic infection, and a prion infection. (Item 73) 73. The method of claim 72, wherein the cardiovascular disease is selected from the group consisting of heart disease, hypertension, and peripheral vascular disease. (Item 74) 73. The method of item 72, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gestational trophoblastic disease, uterine sarcoma, vaginal cancer, vulvar cancer, pancreatic cancer, rectal cancer, renal cell carcinoma, skin cancer, brain cancer, head and neck cancer, lung cancer, thyroid cancer, bladder cancer, esophageal cancer, mesothelioma, glioblastoma, thymic carcinoma, lymphoma, leukemia, myeloma, hematological malignancies, and colon or digestive cancer. (Item 75) 73. The method of claim 72, wherein the pulmonary condition is selected from the group consisting of pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax, and mesothelioma. (Item 76) 73. The method of item 72, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjogren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease. (Item 77) 73. The method of claim 72, wherein the liver condition is selected from the group consisting of hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease. (Item 78) 73. The method of claim 72, wherein the gynecological condition is selected from the group consisting of menopause, peritonitis, uterine involution, fibroids, endometritis, uterine cyst, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy, and hormonal fluctuations. (Item 79) 73. The method of claim 72, wherein the bladder condition is selected from the group consisting of urethritis, interstitial cystitis, and urinary tract infection. (Item 80) 73. The method of claim 72, wherein the renal condition is selected from the group consisting of chronic kidney disease (CKD), diabetes, anorexia nervosa, high blood pressure, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome. (Item 81) 73. The method of item 72, wherein the hormonal condition is associated with menopause, perimenopause, pregnancy, or childbirth. (Item 82) 73. The method of item 72, wherein the viral infection is caused by human papillomavirus, hepatitis C virus, or herpes simplex virus. (Item 83) The bacterial infection is caused by Gardnerella vaginalis Item 72. The method according to item 72. (Item 84) 70. The method of item 69, wherein the mental health condition is one or more conditions selected from the group consisting of psychological conditions, mood disorders, trauma and stressor-related disorders, neurodegenerative disorders, and anxiety disorders. (Item 85) 85. The method of claim 84, wherein the psychological condition is sexual, emotional, or physical trauma or abuse. (Item 86) 85. The method of item 84, wherein the mood disorder is a depressive disorder, a bipolar disorder, or a substance-induced disorder. (Item 87) Item 85. The method of item 84, wherein the trauma- and stressor-related disorder is post-traumatic stress disorder, acute stress disorder, adjustment disorder, or reactive attachment disorder. (Item 88) 85. The method of claim 84, wherein the neurodegenerative disorder is mild cognitive impairment, amnestic mild cognitive impairment, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, amyotrophic lateral sclerosis, or motor neuron disease. (Item 89) Item 85. The method of item 84, wherein the anxiety disorder is panic, generalized anxiety disorder, specific phobia, or social phobia.

Claims

1. A pharmaceutical composition for treating or preventing sexual dysfunction and its associated symptoms in a female subject in need of or at risk of treating or preventing sexual dysfunction and its associated symptoms, comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier.

2. 10. The pharmaceutical composition of claim 1, wherein the cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof.

3. 3. The pharmaceutical composition of claim 2, wherein the pharmaceutically acceptable salt of cyclobenzaprine is cyclobenzaprine-HCl.

4. 4. The pharmaceutical composition of claim 3, wherein the cyclobenzaprine-HCl is in the form of a mannitol co-crystal.

5. 5. The pharmaceutical composition of claim 4, wherein the mannitol eutectic is selected from the group consisting of a 75%±2% by weight cyclobenzaprine-HCl and 25%±2% by weight β-mannitol eutectic, a 65%±2% by weight cyclobenzaprine-HCl and 35%±2% by weight δ-mannitol eutectic, a mixture of 75%±2% by weight cyclobenzaprine-HCl and 25%±2% by weight β-mannitol with a 65%±2% by weight cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic, and a granule comprising an outer layer of a 65%±2% by weight cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic and an inner layer of β-mannitol.

6. 3. The pharmaceutical composition of claim 2, wherein the composition comprising a pharmaceutically acceptable salt of cyclobenzaprine further comprises a basifying agent.

7. 5. The pharmaceutical composition of claim 4, wherein the composition comprising cyclobenzaprine-HCl-mannitol cocrystal further comprises a basifying agent.

8. 8. The pharmaceutical composition of claim 6 or 7, wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

9. 9. The pharmaceutical composition of claim 8, wherein the basifying agent is dipotassium hydrogen phosphate.

10. The composition comprises: (a) between 0.1 mg and 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof; (b) between 1 mg and 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof; (c) less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof; or (d) less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof 2. The pharmaceutical composition of claim 1, comprising:

11. The pharmaceutically acceptable salt is cyclobenzaprine-HCl and the composition comprises: (a) 5.6 mg of cyclobenzaprine-HCl; or (b) 2.8 mg of cyclobenzaprine-HCl 5. The pharmaceutical composition of claim 3 or 4, comprising:

12. The composition is administered simultaneously or sequentially in two dosage units, wherein: (a) the combined amount of the composition in the two dosage units is 5.6 mg of cyclobenzaprine-HCl; or (b) each dosage unit contains 2.8 mg of cyclobenzaprine-HCl; 12. The pharmaceutical composition of claim 11.

13. The pharmaceutical composition of any one of claims 1 to 7, wherein the pharmaceutical composition is formulated for daily administration.

14. 14. The pharmaceutical composition of claim 13, wherein the composition is formulated for once-daily administration.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, intravenous, intramuscular, subcutaneous, inhalation, intranasal, transdermal, parenteral, rectal, or vaginal administration.

16. 16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated for sublingual administration.

17. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in the dosage form of a tablet, suppository, film, thin film, liquid, powder, or spray liquid.

18. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is in the form of a sublingual tablet.

19. The pharmaceutical composition comprises an estrogen receptor modulator, 5-hydroxytryptamine 1A (5-HT １Ａ ) receptor agonist, 5-hydroxytryptamine 2A (5-HT ２Ａ 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated for sequential or simultaneous administration with one or more therapeutic agents selected from the group consisting of: α-1-adrenergic receptor antagonists, steroids, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha-1-adrenergic receptor antagonists, beta-adrenergic antagonists, anticonvulsants or mood stabilizers, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antidepressants, anxiolytics, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensives, antilipidemic agents, hormones, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergic agents, amphetamines, dopaminergic receptor agonists, anorectics, and anesthetics.

20. (a) the estrogen receptor modulator is ospemifene; (b) the 5-HT １Ａ receptor agonist or the 5-HT ２Ａ The receptor agonist is flibanserin; (c) the dopaminergic receptor agonist is apomorphine; (d) the steroidal agent is tibolone, estrogen, or testosterone; (e) the phosphodiesterase inhibitor is sildenafil or tadalafil; (f) the melanocortin receptor agonist is bremelanotide; (g) the alpha-1-adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin, or tamsulosin; (h) the β-adrenergic receptor antagonist is propranolol, bucindolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butoxamine, ICI-118,551, SR 59230A, or nebivolol; (i) the anticonvulsant or mood stabilizer is carbamazepine, divalproex, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, or valproate; (j) the selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline; (k) the serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine; (l) the antidepressant is citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, or nortriptyline; (m) the anti-anxiety agent is lorazepam, oxazepam, or buspirone; (n) the antipsychotic is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone; (o) The antihistamine is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate dimethindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, tiotidine, clobenpropit, ABT-239, ciproxifan, conessine, A-349,821, thioperamide, thioperamide, JNJ 7777120, or VUF-6002; (p) the benzodiazepine is quazepam, chlordiazepoxide, flurazepam, alprazolam, clorazepate, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, or midazolam; or 20. The pharmaceutical composition of claim 19, wherein (q) the hormonal agent is oxytocin, estrogen, or testosterone.

21. 10. The pharmaceutical composition of claim 1, wherein the female subject has female genitalia by birth, reconstructive surgery, or sex reassignment surgery.

22. 22. The pharmaceutical composition of claim 21, wherein the female subject is premenopausal, perimenopausal, or postmenopausal.

23. 10. The pharmaceutical composition of claim 1, wherein the sexual dysfunction is associated with the use of one or more medications selected from the group consisting of antidepressants, anxiolytics, antihypertensives, chemotherapeutic agents, hormones, corticosteroids, antipsychotics, antihistamines, benzodiazepines, psychotropic agents, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRh) agonists, contraceptives, anticholinergics, amphetamines, anorexiants, and anesthetics.

24. The sexual dysfunction is: (a) associated with a medical or mental health condition; (b) sexual desire disorder, arousal disorder, orgasmic disorder, or dyspareunia disorder; or (c) associated with one or more of the following symptoms: sexual aversion, low sexual desire or interest, fear of sexual intercourse, difficulty with arousal, inability to become or remain aroused during sexual activity, persistent or recurrent difficulty in achieving orgasm after sufficient sexual arousal and continued stimulation, and pain associated with sexual stimulation or vaginal contact. The pharmaceutical composition of claim 1.

25. The medical condition is: (a) a cardiovascular disease selected from the group consisting of heart disease, hypertension, and peripheral vascular disease; (b) obesity; (c) a cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, endometrial cancer, gestational trophoblastic disease, uterine sarcoma, vaginal cancer, vulvar cancer, pancreatic cancer, rectal cancer, renal cell carcinoma, skin cancer, brain cancer, head and neck cancer, lung cancer, thyroid cancer, bladder cancer, esophageal cancer, mesothelioma, glioblastoma, thymic carcinoma, lymphoma, leukemia, myeloma, hematological malignancies, and colon or gastrointestinal cancer; (d) a pulmonary condition selected from the group consisting of pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax, and mesothelioma; (e) a renal condition selected from the group consisting of chronic kidney disease (CKD), diabetes, anorexia nervosa, high blood pressure, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome; (f) a bladder condition selected from the group consisting of urethritis, interstitial cystitis, and urinary tract infection; (g) rectal condition; (h) bowel condition; (i) a liver condition selected from the group consisting of hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease; (j) a gynecological condition selected from the group consisting of menopause, peritonitis, uterine involution, fibroids, endometritis, uterine cyst, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy, and hormonal fluctuations; (k) an autoimmune disorder selected from the group consisting of multiple sclerosis, type 1 diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjogren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease; (l) hormonal conditions associated with menopause, perimenopause, pregnancy, or childbirth; (m) viral infection; (n) Bacterial infection; (o) parasitic infection; and (p) Prion infection 25. The pharmaceutical composition of claim 24, wherein the pharmaceutical composition is selected from the group consisting of:

26. The mental health condition is: (a) a psychological condition selected from the group consisting of sexual trauma or abuse, emotional trauma or abuse, and physical trauma and abuse; (b) a mood disorder selected from the group consisting of depressive disorder, bipolar disorder, and substance-induced disorder; (c) a trauma- and stressor-related disorder selected from the group consisting of post-traumatic stress disorder, acute stress disorder, adjustment disorder, and reactive attachment disorder; (d) a neurodegenerative disorder selected from the group consisting of mild cognitive impairment, amnestic mild cognitive impairment, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, amyotrophic lateral sclerosis, and motor neuron disease; and (e) An anxiety disorder selected from the group consisting of panic disorder, generalized anxiety disorder, specific phobia, and social phobia.

25. The pharmaceutical composition of claim 24, wherein the condition is one or more conditions selected from the group consisting of: