Cyclobenzaprine for the treatment of sexual dysfunction

Abstract

The present disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of cyclobenzaprine and one or more pharmaceutical agents, and methods of treating and / or preventing sexual dysfunction.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 007,251, filed on April 8, 2020, the contents of which are incorporated by reference in their entirety into this application.

[0003] background

[0004] There is a growing body of literature demonstrating the comorbidity of sexual dysfunction (SD) and post-traumatic stress disorder (PTSD) among veterans (Letica-Crepulja et al., 2019). Veterans with PTSD are at higher risk for SD compared to those without any mental health diagnosis or with a mental health diagnosis other than PTSD. This is true regardless of the chronicity of symptoms, age, or other health problems, suggesting that the mechanisms underlying this dysfunction are directly related to PTSD (Hirsch, 2009). Common types of SD in men include erectile dysfunction, lack of interest in sex, and premature ejaculation; whereas common types of SD in women include sexual fear, arousal problems, orgasm problems, lack of interest in sex, and vaginal pain. In addition, the correlation between sexual function and mental health is stronger in women than in men (Rosen & Bauchman, 2008).

[0005] Despite the importance of addressing comorbid symptoms, the topic of SD is often clinically overlooked and underexplored in the research literature (Tran et al., 2015). In terms of treatment, experts recommend that evidence-based treatments for PTSD should be the first priority. However, treating PTSD does not necessarily address the symptoms of SD. For example, when compared to a no-treatment control group, women who participated in cognitive behavioral therapy for PTSD showed significant reductions in PTSD symptoms but no significant improvements in sexual function (Cohen & Hien, 2006). In addition, serotonin reuptake inhibitors (SSRIs) and benzodiazepines have been shown to reduce PTSD symptoms. (Psychotropic medications commonly prescribed to treat PTSD) have been shown to exacerbate pre-existing SD, as well as leading to poor adherence and medication refusal (Keller, McGarvey, Clayton, 2006).

[0006] Cyclobenzaprine and its pharmaceutically acceptable salts are serotonin-2A, alpha-1-adrenergic, and histamine-1 receptor antagonists that are being developed to target sleep disturbances and hyperarousal in PTSD as a treatment for PTSD. A phase 2 study of cyclobenzaprine-HCl in military-related PTSD had very low rates of adverse events related to sexual function in both the drug and placebo groups. Therefore, in a subsequent phase 3 study in military-related PTSD, a systematic study was conducted to evaluate the effect of treatment on sexual function in women and men.

[0007] Overview of the Disclosure

[0008] Some embodiments of the present disclosure are:

[0009] A method for treating or preventing sexual dysfunction and its related symptoms, comprising administering to a female subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier.

[0010] The method of embodiment 1, wherein cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof.

[0011] The method of embodiment 1 or 2, wherein the pharmaceutically acceptable salt of cyclobenzaprine is cyclobenzaprine salt.

[0012] The method of Embodiment 3, wherein the cyclobenzaprine salt is cyclobenzaprine-HCl.

[0013] The method of any one of embodiments 1-4, wherein the cyclobenzaprine or a pharmaceutically acceptable salt thereof is in the form of a eutectic mixture.

[0014] The method of Embodiment 5, wherein the eutectic mixture is a mannitol eutectic mixture.

[0015] The method of embodiment 6, wherein the mannitol eutectic mixture is selected from a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic mixture, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol, and a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, and particles comprising an outer layer of a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture and an inner layer of β-mannitol.

[0016] The method of any of embodiments 1-7, wherein the composition comprising a pharmaceutically acceptable salt of cyclobenzaprine further comprises an alkalizing agent.

[0017] The method of embodiment 8, wherein the alkalizing agent is selected from 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.

[0018] The method according to embodiment 9, wherein the alkalizing agent is dipotassium hydrogen phosphate.

[0019] The method of embodiment 1, wherein the composition comprises 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0020] The method of embodiment 11, wherein the composition comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0021] The method of embodiment 12, wherein the composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0022] The method of embodiment 12, wherein the composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0023] The method of embodiment 13, wherein the composition comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0024] The method of Embodiment 15, wherein the composition comprises about 5.6 mg of Cyclobenzaprine-HCl.

[0025] The method of embodiment 13, wherein the composition comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0026] The method of Embodiment 17, wherein the composition comprises about 2.8 mg of Cyclobenzaprine-HCl.

[0027] The method of embodiment 17 or 18, wherein the composition is administered simultaneously or sequentially in two dosage units, and wherein the combined amount of the composition in the two dosage units is about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0028] The method of embodiment 19, wherein the composition is administered simultaneously in two dosage units, and wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0029] The method of embodiment 19, wherein the composition is administered sequentially in two dosage units, and wherein each dosage unit comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0030] The method of any one of embodiments 1-21, wherein the pharmaceutical composition is administered daily.

[0031] The method of any one of embodiments 1-22, wherein the composition is administered once daily.

[0032] The method of embodiment 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.

[0033] The method of embodiment 24, wherein the pharmaceutical composition is formulated for sublingual administration.

[0034] The method of embodiment 25, wherein the pharmaceutical composition is administered sublingually, buccally, orally, in the form of a suppository, intravenously, intramuscularly, subcutaneously, by inhalation, intranasally, in the form of a thin film, transdermally, parenterally, rectally, or vaginally.

[0035] The method of embodiment 26, wherein the pharmaceutical composition is administered sublingually.

[0036] The method of any one of embodiments 1-26, wherein the method further comprises sequentially or simultaneously administering one or more therapeutic agents selected from the group consisting of: estrogen receptor modulators, 5-hydroxytryptamine 1A (5-HT 1A ) receptor agonists, 5-hydroxytryptamine 2A (5-HT 2A ) antagonists, synthetic or gonadal steroid agents, 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 drugs, psychoactive drugs, barbiturates, lithium, antihypertensives, antilipids, hormonal drugs, gonadotropin-releasing hormone (GnRH) agonists, birth control pills, anticholinergics, amphetamines, dopamine receptor agonists, anorectics, and anesthetics.

[0037] The method of embodiment 28, wherein the estrogen receptor modulator is ospemifene.

[0038] The method of embodiment 28, wherein 5-HT 1A 5-HT receptor agonists 2A The receptor agonist is flibanserin.

[0039] The method of embodiment 28, wherein the dopaminergic receptor agonist is apomorphine.

[0040] The method of embodiment 28, wherein the steroid agent is tibolone, estrogen, or testosterone.

[0041] The method of embodiment 28, wherein the phosphodiesterase inhibitor is sildenafil or tadalafil.

[0042] The method of embodiment 28, wherein the melanocortin receptor agonist is bumelatide.

[0043] The method of embodiment 28, wherein the alpha-1-adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin, or tamsulosin.

[0044] The method of embodiment 28, wherein the beta adrenergic receptor antagonist is propranolol, bucinolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butaxamine, ICI-118,551, SR 59230A, or nebivolol.

[0045] The method of embodiment 28, wherein the anticonvulsant or mood stabilizer is carbamazepine, divalproex sodium, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate, or valproate.

[0046] The method of embodiment 28, wherein the selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline.

[0047] The method of embodiment 28, wherein the serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine.

[0048] The method of embodiment 28, wherein the antidepressant is citalopram, fluoxetine, paroxetine, sertraline, escitalopram, trazodone, venlafaxine, bupropion, duloxetine, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, or nortriptyline.

[0049] The method of embodiment 28, wherein the antianxiety agent is lorazepam, oxazepam, or buspirone.

[0050] The method of embodiment 28, wherein the antipsychotic drug is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, or risperidone.

[0051] The method of embodiment 28, wherein the antihistamine is acrivastine, Sting, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindane, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine doxycycline, orphenadrine, phenindrine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, thiotidine, clofenac, ABT-239, ciprofloxacin, kenesin, A-349,821, thioperamide, thioperamide, JNJ 7777120, and VUF-6002.

[0052] The method of embodiment 28, wherein the benzodiazepine The drugs are quazepam, chlordiazepoxide, flurazepam, alprazolam, chlordiazepoxide , diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, and midazolam.

[0053] The method of embodiment 28, wherein the hormonal drug is oxytocin, estrogen, or testosterone.

[0054] A combination comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof and optionally one or more therapeutic agents selected from the group consisting of an estrogen receptor modulator, a 5-hydroxytryptamine 1A (5-HT 1A ) receptor agonists, steroid agents, 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 drugs, psychoactive drugs, barbiturates, lithium, antihypertensives, antilipids, hormonal drugs, gonadotropin-releasing hormone (GnRH) agonists, birth control pills, anticholinergics, amphetamines, anorectics, and narcotics.

[0055] The combination of embodiment 46, wherein the cyclobenzaprine or its salt and the one or more therapeutic agents are in the same dosage form or in separate dosage forms packaged together or separately, wherein the cyclobenzaprine or its salt and the one or more therapeutic agents are administered simultaneously or sequentially.

[0056] The combination of embodiment 41, wherein the one or more therapeutic agents are ospemifene, flibanserin, tibolone, estrogen or testosterone, sildenafil, tadalafil, bumelatide, prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, propranolol, bucinolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butaxamine, ICI-118,551, SR 59230A, nebivolol, carbamazepine, divalproex sodium, 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, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, nortriptyline, lorazepam, oxazepam, buspirone, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, risperidone, acrivastine, nitrogen Sting, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindane, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltro Salmin, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, thiotidine, clofenac, ABT-239, ciprofloxacin, kenesin, A-349,821, thioperamide, thioperamide, JNJ7777120, VUF-6002, quazepam, chlordiazepoxide, flurazepam, alprazolam, chlordiazepoxide , diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, midazolam, or oxytocin.

[0057] The combination of embodiment 46, wherein cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof.

[0058] The combination of any one of embodiments 47-49, wherein the pharmaceutically acceptable salt of cyclobenzaprine is cyclobenzaprine salt.

[0059] The combination of embodiment 50 wherein the cyclobenzaprine salt is cyclobenzaprine-HCl.

[0060] The combination of any one of Embodiments 47-51, wherein cyclobenzaprine or a pharmaceutically acceptable salt thereof is in the form of a eutectic mixture.

[0061] The combination of embodiment 52, wherein the eutectic mixture is a mannitol eutectic mixture.

[0062] The combination of embodiment 53, wherein the eutectic mixture is selected from a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic mixture, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol, and a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, and particles comprising an outer layer of 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol and an inner layer of β-mannitol.

[0063] The combination of any one of embodiments 47-54, wherein the combination comprises a pharmaceutically acceptable salt of cyclobenzaprine and an alkalizing agent.

[0064] The combination of embodiment 55, wherein the alkalizing agent is selected from 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.

[0065] The combination of embodiment 56, wherein the alkalizing agent is dipotassium hydrogen phosphate.

[0066] The combination of embodiment 47, wherein the combination comprises 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0067] The combination of embodiment 58, wherein the combination comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0068] The combination of Embodiment 59, wherein the combination comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0069] The combination of Embodiment 59, wherein the combination comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0070] The combination of embodiment 60, wherein the combination comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0071] The combination of embodiment 62, wherein the composition comprises about 5.6 mg of cyclobenzaprine-HCl.

[0072] The combination of embodiment 60, wherein the combination comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

[0073] The combination of embodiment 64, wherein the combination comprises about 2.8 mg of cyclobenzaprine.

[0074] The method of embodiment 1, wherein the female subject has female reproductive organs by birth, plastic surgery, or sex reassignment surgery.

[0075] The method of embodiment 66, wherein the female subject is premenopausal, perimenopausal, or postmenopausal.

[0076] The method of any one of embodiments 1-45 and 66-67, wherein the sexual dysfunction is associated with the use of one or more agents selected from the group consisting of antidepressants, antianxiety agents, antihypertensive agents, chemotherapeutic agents, hormonal agents, corticosteroids, antipsychotics, antihistamines, benzodiazepines, drugs, psychoactive drugs, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRH) agonists, birth control pills, anticholinergics, amphetamines, anorectics, and narcotics.

[0077] The method of any of embodiments 1-45 and 66-67, wherein the sexual dysfunction is associated with a medical condition or a mental health condition.

[0078] The method of embodiment 69, wherein the sexual dysfunction is sexual desire disorder, sexual arousal disorder, orgasmic disorder, or dyspareunia disorder.

[0079] 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, sexual fear, difficulty with sexual arousal, inability to become aroused or maintain arousal during sexual activity, difficulty achieving sustained or recurring orgasm after adequate sexual arousal and sustained stimulation, and pain associated with sexual stimulation or vaginal contact.

[0080] The method of embodiment 69, wherein the medical condition is selected from cardiovascular disease, obesity, cancer, lung disorders, kidney disorders, bladder disorders, rectal disorders, intestinal disorders, liver disorders, gynecological disorders, autoimmune diseases, hormonal disorders, viral infections, bacterial infections, parasitic infections, and prion infections.

[0081] The method of embodiment 72, wherein the cardiovascular disease is selected from the group consisting of heart disease, hypertension, and peripheral vascular disease.

[0082] The method of embodiment 72, wherein the cancer is selected from 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 cancer, lymphoma, leukemia, myeloma, hematological malignancies, and colon cancer or gastrointestinal cancer.

[0083] The method of embodiment 72, wherein the pulmonary condition is selected from pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax, and mesothelioma.

[0084] The method of embodiment 72, wherein the autoimmune disease is selected from multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjögren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease.

[0085] The method of embodiment 72, wherein the liver disorder is selected from hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease.

[0086] The method of embodiment 72, wherein the gynecological condition is selected from the group consisting of menopause, peritonitis, uterine degeneration, fibroids, endometritis, uterine cysts, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy, and hormonal fluctuations.

[0087] The method of embodiment 72, wherein the bladder disorder is selected from the group consisting of urethritis, interstitial cystitis, and urinary tract infection.

[0088] The method of embodiment 72, wherein the renal disorder is selected from chronic kidney disease (CKD), diabetes, anorexia nervosa, hypertension, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome.

[0089] The method of embodiment 72, wherein the hormonal disorder is associated with menopause, perimenopause, pregnancy, or childbirth.

[0090] The method of embodiment 72, wherein the viral infection is caused by human papillomavirus, hepatitis C virus, or herpes simplex virus.

[0091] The method of embodiment 72, wherein the bacterial infection is caused by Gardnerella vaginalis.

[0092] 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.

[0093] The method of embodiment 84, wherein the psychological condition is sexual, emotional, or physical trauma or abuse.

[0094] The method of embodiment 84, wherein the mood disorder is depression, bipolar disorder, or a substance-induced disorder.

[0095] 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.

[0096] 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.

[0097] The method of embodiment 84, wherein the anxiety disorder is panic, generalized anxiety disorder, specific phobia, or social phobia.

[0098] Detailed Description

[0099] In some embodiments, the present disclosure provides methods and pharmaceutical compositions for treating sexual dysfunction and related symptoms in a subject in need thereof or at risk thereof, 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.

[0100] definition

[0101] The term "this application" refers to the entire application.

[0102] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by one of ordinary skill in the art. In the event of a conflict, the present specification, including definitions, will control.

[0103] It should be understood that any embodiment described in this application, including those described under different aspects of the disclosure and different parts of the specification, can be combined with one or more other embodiments of the disclosure, except where expressly disclaimed or inappropriate. The combination of embodiments is not limited to those specific combinations claimed through multiple dependent claims.

[0104] All publications, patents, and published patent applications referred to in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0105] Throughout the specification, the word "comprise" or variations such as "include" or "comprising" will be understood to imply the inclusion of a stated integer (or element) or group of integers (or elements) but not the exclusion of any other integer (or element) or group of integers (or elements).

[0106] The term "comprising" as used in this application means "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. Therefore, these terms will be understood to imply the inclusion of the stated integers (or elements) or groups of integers (or elements), but not the exclusion of any other integers (or elements) or groups of integers (or elements).

[0107] As used in this application, the term "about" refers to a value or parameter that includes (and describes) embodiments for that value or parameter itself. For example, a description involving "about X" includes a description of "X". As used in this application, the term "about" allows for a variation of ±10% within the range of significant figures. Numerical ranges include the numbers at both ends that define the range.

[0108] The term "for example" or any examples following "for example" is not meant to be exhaustive or limiting.

[0109] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0110] As used in this application, the articles "a," "an," and "the" refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0111] When aspects or embodiments are described in terms of Markush groups or other alternative groups, the application includes not only the entire group listed as a whole, but also each member of the individual group and all possible subgroups of the main group, including the main group lacking one or more of the group members.

[0112] Exemplary methods and materials are described in this application, however, methods and materials similar or equivalent to those described in this application can also be used to implement or test various aspects and embodiments of the present disclosure. The materials, methods, and examples are illustrative only and not limiting.

[0113] In order to more easily understand the present disclosure, some terms are first defined. These definitions should be read in light of the remainder of the present disclosure as understood by those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those generally understood by those of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0114] As used in this application, the terms "treat", "treat", "treat" and their cognates refer to the complete or partial improvement, amelioration or regulation of a sexual dysfunction or at least one discernible symptom thereof. In some embodiments, "treat at least one discernible symptom" refers to an improvement in desire and / or interest. In some embodiments, "treat" refers to an improvement in pleasure. In some embodiments, "treat at least one discernible symptom" refers to an improvement in desire and / or frequency. In some embodiments, "treat" refers to an improvement in arousal and / or excitement. In some embodiments, "treat at least one discernible symptom" refers to an improvement in orgasm and / or complete. In some embodiments, "treat at least one discernible symptom" refers to an improvement in sexual desire disorder. In some embodiments, "treat at least one discernible symptom" refers to an improvement in arousal disorder. In some embodiments, "treat at least one discernible symptom" refers to an improvement in orgasm disorder. In some embodiments, "treat at least one discernible symptom" refers to an improvement in dyspareunia disorder.

[0115] In some embodiments of the present disclosure, cyclobenzaprine is an acid salt of cyclobenzaprine. In other embodiments, the acid salt is cyclobenzaprine-HCl.

[0116] In other embodiments, the acid salt is combined with an alkalizing agent. In some embodiments, the alkalizing agent is an ingredient (and excipient) in a tablet or other formulation, and the alkalizing agent exerts its effect during the time that the formulation is dispersed in the mucus material (including buccal mucosa and sublingual tissue) and a portion of the formulation is dissolved in the mucus material and continues for a period of time after the tablet is dissolved in the mucus material.

[0117] In some embodiments of the present disclosure, the "alkalizing agent" included is selected from potassium dihydrogen phosphate (monopotassium phosphate, potassium dihydrogen phosphate, KH2PO4), dipotassium hydrogen phosphate (dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, K2HPO4), tripotassium phosphate (K3PO4), sodium dihydrogen phosphate (monosodium phosphate, sodium dihydrogen phosphate, NaH2PO4), disodium hydrogen phosphate (disodium hydrogen phosphate, disodium hydrogen phosphate, Na2HPO4), trisodium phosphate (Na3PO4), bicarbonate or carbonate, dipotassium citrate, tripotassium citrate, disodium citrate, trisodium citrate, borate, hydroxide, silicate, nitrate, dissolved ammonia, conjugate bases of some organic acids (including bicarbonate) and sulfide. In some embodiments, the alkalizing agent is dipotassium hydrogen phosphate (K2HPO4), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), tripotassium citrate or trisodium citrate. An alkalizing agent that is particularly useful in combination with cyclobenzaprine-HCl is dipotassium hydrogen phosphate (K2HPO4). Another alkalizing agent that is particularly useful in combination with cyclobenzaprine-HCl is monopotassium hydrogen phosphate (KH2PO4). Another alkalizing agent that is particularly useful in combination with cyclobenzaprine-HCl is disodium hydrogen phosphate (Na2HPO4). Another alkalizing agent that is particularly useful in combination with cyclobenzaprine-HCl is tripotassium citrate. Another alkalizing agent that is particularly useful in combination with cyclobenzaprine-HCl is trisodium citrate.

[0118] In some embodiments of the present disclosure, cyclobenzaprine or an acid salt thereof is present in a eutectic mixture. In some embodiments, the eutectic mixture includes mannitol. In some aspects, the mannitol is beta mannitol. In other embodiments, the mannitol is delta mannitol. In some aspects, the eutectic mixture is a eutectic mixture of cyclobenzaprine-HCl and mannitol, selected from a 75%±2% cyclobenzaprine-HCl and 25%±2% mannitol eutectic mixture, a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, a mixture of 75%±2% cyclobenzaprine-HCl and 25%±2% β-mannitol, and a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture, and particles having an outer layer of a 65%±2% cyclobenzaprine-HCl and 35%±2% δ-mannitol eutectic mixture 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 mixture of the present disclosure refers to any of these eutectic mixtures or particles. In some aspects, the eutectic mixture is combined with an alkalizing agent. See, for example, WO2013 / 188847, which is incorporated herein by reference.

[0119] As used in this application, the term "eutectic mixture" or "form of a eutectic mixture" refers to a mixture of compounds or elements having a single chemical composition that melts at a lower temperature than any other composition composed of the same ingredients. A composition comprising a eutectic mixture is called a eutectic composition, and its melting temperature is called the eutectic temperature. Eutectic compositions generally have higher stability and / or dissolution rates than their non-eutectic counterparts. Because eutectic mixtures enhance dissolution, they can be used to increase permeability in solid dispersions and dispersed systems.

[0120] Treatment

[0121] In some embodiments, the present disclosure provides a method for treating, improving and / or preventing sexual dysfunction and symptoms related thereto, comprising administering to a female subject in need thereof or at risk thereof a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier.

[0122] In some embodiments, the method for treating, improving and / or preventing sexual dysfunction comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable acid salt of cyclobenzaprine and an alkalizing agent. In some embodiments, the pharmaceutical composition comprises a eutectic mixture of a pharmaceutically acceptable salt of cyclobenzaprine and mannitol, which is optionally combined with an alkalizing agent. The composition 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 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose is 1 mg to 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 contains about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the daily dose contains about 2.8 mg of cyclobenzaprine-HCl. In some embodiments, the method of treating and / or preventing sexual dysfunction comprises administering two dosage units of cyclobenzaprine simultaneously or sequentially, and wherein each dosage unit contains about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, each of the two dosage units contains about 2.8 mg of cyclobenzaprine-HCl. In some embodiments, the method of treating and / or preventing sexual dysfunction comprises administering a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof daily. In some embodiments, the method of treating and / or preventing sexual dysfunction comprises administering a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof once a day.

[0123] In some embodiments, the method of 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, 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 compositions are formulated for vaginal administration.

[0124] In some embodiments, the methods of the present disclosure further comprise administering one or more therapeutic agents selected from the group consisting of estrogen receptor modulators, 5-hydroxytryptamine 1A (5-HT 1A ) receptor agonists, 5-hydroxytryptamine 2A (5-HT 2A ) antagonists, synthetic or gonadal steroid agents, 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 In some embodiments, the one or more therapeutic agents are administered sequentially or simultaneously with the composition of the present disclosure comprising cyclobenzaprine-HCl.

[0125] In some embodiments, the sexual dysfunction or risk thereof is in a female subject. In some embodiments, the subject has female reproductive organs by birth, plastic surgery, or sex reassignment surgery.

[0126] In some embodiments, the sexual dysfunction is associated with the use of one or more agents selected from the group consisting of antidepressants, antianxiety agents, antihypertensive agents, chemotherapeutic agents, hormonal drugs, corticosteroid drugs, antipsychotic drugs, antihistamines, benzodiazepines, drugs, psychoactive drugs, barbiturates, lithium, antihypertensives, antilipids, gonadotropin-releasing hormone (GnRH) agonists, birth control pills, anticholinergics, amphetamines, anorectics, and narcotics.

[0127] In some embodiments, the sexual dysfunction is 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 cardiovascular disease, obesity, cancer, lung disease, kidney disease, bladder disease, rectal disease, intestinal disease, liver disease, gynecological disease, autoimmune disease, hormonal disease, viral infection, bacterial infection, parasitic infection and prion infection. In some embodiments, the cardiovascular disease is selected from heart disease, hypertension and peripheral vascular disease. In some embodiments, the cancer is selected from 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 cancer, lymphoma, leukemia, myeloma, hematological malignancies and colon cancer or gastrointestinal cancer. In some embodiments, the pulmonary condition is selected from 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 multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjögren's syndrome, myasthenia gravis, pernicious anemia and celiac disease. In some embodiments, the liver condition is selected from hepatitis, fatty liver disease, liver cancer, hemochromatosis and Wilson's disease. In some embodiments, the gynecological condition is selected from menopause, peritonitis, uterine degeneration, fibroids, endometritis, uterine cysts, cystocele, rectocele, uterine prolapse, hysterectomy, oophorectomy, salpingectomy and hormone fluctuations. In some embodiments, the bladder condition is selected from urethritis, interstitial cystitis and urinary tract infection. In some embodiments, the renal disorder is selected from chronic kidney disease (CKD), diabetes, anorexia nervosa, hypertension, high cholesterol, lupus, multiple myeloma and hemolytic uremic syndrome. In some embodiments, the hormonal disorder 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.

[0128] In some embodiments, the mental health condition is one or more conditions selected from the group consisting of a psychological condition, a mood disorder, a trauma and stressor-related disorder, a neurodegenerative disorder, and an anxiety disorder. In some embodiments, the psychological condition is sexual, emotional, or physical trauma or abuse. In some embodiments, the mood disorder is depression, bipolar disorder, or a 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. The anxiety disorder is panic, generalized anxiety disorder, specific phobia, or social phobia.

[0129] In some embodiments, the sexual dysfunction is sexual desire disorder, sexual arousal disorder, orgasmic disorder, or dyspareunia disorder.

[0130] In some embodiments, the sexual dysfunction is associated with one or more of the following symptoms: sexual aversion, low sexual desire or interest, sexual fear, difficulty becoming sexually aroused, inability to become aroused or maintain arousal during sexual activity, difficulty achieving sustained or recurring orgasm after adequate arousal and sustained stimulation, and pain associated with sexual stimulation or vaginal contact.

[0131] Sexual Function Change Questionnaire-14 (CSFQ-14)

[0132] The Changes in Sexual Function Questionnaire (CSFQ) is a 36-item clinical and research instrument that identifies sexual function on five scales. The CSFQ has been shortened to a factor structure of a 14-item version (CSFQ-14), which produces scores for three scales equivalent to the stages of the sexual response cycle (e.g., desire, arousal, and orgasm) and five scales of the original CSFQ (e.g., desire / frequency, desire / interest, arousal / excitement, orgasm / fullness, and pleasure). Factor analysis confirmed the construct validity of the CSFQ-14 as a comprehensive measure of sexual dysfunction.

[0133] DSM-5 Diagnostic Criteria for PTSD and CAPS-5

[0134] The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is a diagnostic tool published by the American Psychiatric Association. DSM-5 contains descriptions, symptoms, and criteria for diagnosing mental disorders. It also contains common language for clinicians to communicate with their patients to establish consistent and reliable diagnoses that can be used in the study of mental disorders. DSM-5 also provides researchers with common language to study potential future revisions to the criteria and aids in the development of medications and other interventions.

[0135] The Clinician Administered PTSD Scale (CAPS) is a semi-structured diagnostic interview that assesses the basic features of PTSD as defined by the DSM-5 diagnostic criteria for PTSD (Weathers et al., 2017). It can also be used to assess relevant features of diagnostic syndromes (e.g., survivor guilt). Interviews are designed to accommodate different time spans after trauma as reference points for diagnosis. CAPS provides clinicians with the flexibility to query symptoms and diagnostic status for the past week, the last month, and / or lifetime diagnosis. Depending on the nature of the task at hand, any one or all three time structures can be used. Other diagnostic scales or tools based on the DSM-5 diagnostic criteria for diagnosing PTSD are also well known. They include, for example, the PTSD Checklist (PCL-5) for DSM-5, symptom severity, intensity, and / or frequency rating scales completed by clinicians, and symptom severity, intensity, and / or intensity rating scales completed by patients.

[0136] In some embodiments, the changes in one or more of the DSM-5 diagnostic criteria items for assessing PTSD are based on one or more of the PTSD scale (CAPS-5) of DSM-5 administered by a clinician, the PTSD checklist (PCL-5) of DSM-5, the symptom severity, intensity and / or frequency rating scale completed by a clinician, or the symptom severity, intensity and / or frequency rating scale completed by a patient. The PTSD scale (CAPS-5) of DSM-5 administered by a clinician is a 30-item questionnaire equivalent to the DSM-5 diagnosis of PTSD. CAPS-5 requires the identification of a single index trauma to be used as the basis for a symptom survey. CAPS-5 asks questions related to the assessment of the dissociative subtypes (depersonalization and derealization) of PTSD, but no longer includes other related symptoms (e.g., consciousness gap). CAPS-5 symptom severity ratings are based on symptom frequency and intensity. However, in contrast to previous versions of CAPS that required separate frequency and intensity scores, CAPS-5 projects are rated with a single severity score.

[0137] Pharmaceutical composition

[0138] In some embodiments, the present disclosure provides a combination comprising a therapeutically effective amount of cyclobenzaprine or a pharmaceutically acceptable salt thereof of the present disclosure and optionally one or more therapeutic agents selected from estrogen receptor modulators, 5-hydroxytryptamine 1A (5-HT 1A) receptor agonists, steroid agents, 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 In some embodiments, the estrogen receptor modulator is ospemifene. In some embodiments, the 5-HT 1A 5-HT receptor agonists 2AIn some embodiments, the dopaminergic receptor agonist is flibanserin. In some embodiments, the dopaminergic receptor agonist is apomorphine. In some embodiments, the steroid agent is tibolone, estrogen or testosterone. In some embodiments, the phosphodiesterase inhibitor is sildenafil or tadalafil. In some embodiments, the melanocortin receptor agonist is bumelatide. 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, bucinolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butaxamine, ICI-118,551, SR 59230A or nebivolol. In some embodiments, the anticonvulsant or mood stabilizer is carbamazepine, divalproex sodium, 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, levamisole, 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 antianxiety 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, nitrosamine, Sting, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindane, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine In some embodiments, the benzodiazepine is The drugs are quazepam, chlordiazepoxide, flurazepam, alprazolam, chlordiazepoxide , diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam and midazolam. In some embodiments, the hormone drug is oxytocin, estrogen or testosterone.

[0139] In some embodiments, the cyclobenzaprine or a pharmaceutically acceptable salt thereof and one or more optional therapeutic agents of the present disclosure are in the same dosage form or in separate dosage forms packaged together or separately, wherein the cyclobenzaprine or a pharmaceutically acceptable salt thereof and the optional 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 or salt 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.

[0140] In some embodiments, the one or more optional therapeutic agents are ospemifene, flibanserin, tibolone, estrogen or testosterone, sildenafil, bumelatide, prazosin, terazosin, doxazosin, silodosin, alfuzosin, tamsulosin, propranolol, bucinolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butaxamine, ICI-118,551, SR 59230A, nebivolol, carbamazepine, divalproex sodium, 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, amitriptyline, venlafaxine, mirtazapine, desvenlafaxine, nortriptyline, lorazepam, oxazepam, buspirone, quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine, risperidone, acrivastine, nitrogen Sting, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindane, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine , orphenadrine, phenindrine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripeliramine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, thiotidine, clofenac, ABT-239, ciprofloxacin, kenesin, A-349,821, thioperamide, thioperamide, JNJ 7777120, VUF-6002, quazepam, chlordiazepoxide, flurazepam, alprazolam, chlordiazepoxide , diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam, midazolam, or oxytocin.

[0141] In some embodiments, cyclobenzaprine is a free base or a pharmaceutically acceptable salt of the free base. In some embodiments, cyclobenzaprine is a free base. In some embodiments, cyclobenzaprine is a pharmaceutically acceptable salt. In some embodiments, cyclobenzaprine is an acid salt. In some embodiments, the cyclobenzaprine acid salt is cyclobenzaprine hydrochloride. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of cyclobenzaprine and an alkalizing agent.

[0142] In some embodiments, the compositions of the present disclosure comprise 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5.6 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 2.8 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises about 5.6 mg of cyclobenzaprine-HCl. In some embodiments, the composition comprises about 2.8 mg of cyclobenzaprine-HCl.

[0143] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalation, intranasal, 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 mucosal 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.

[0144] In some embodiments, the dosage form of the composition of the present disclosure is a tablet, a film, a thin film, a liquid, a powder or a 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, a sublingual thin film, a sublingual liquid, a sublingual powder or a sublingual spray solution. In some embodiments, the dosage form is a sublingual tablet. In some embodiments, the dosage form is a sublingual thin 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

[0145] Example 1

[0146] Effects of a low-dose sublingual cyclobenzaprine formulation on female sexual function after 12 weeks of treatment in subjects with military-related PTSD

[0147] In this 12-week, multicenter, adaptive design, randomized controlled, fixed-dose trial, 5.6 mg cyclobenzaprine-HCl (2 x 2.8 mg sublingual tablets containing 75% ± 2% cyclobenzaprine-HCl and 25% ± 2% mannitol eutectic mixture and potassium phosphate dibasic anhydrate alkalizer) taken daily at bedtime was compared to placebo for the treatment of PTSD at 45 U.S. sites. Eligible participants (males and females) were aged 18-75 years, had experienced a trauma meeting DSM-5 PTSD Criterion A during military service since 2001, met the DSM-5 definition of PTSD according to the Clinician Administered PTSD Scale (CAPS-5), had a baseline CAPS-5 severity score ≥ 33, were not taking antidepressants, and were not taking or were clean from other psychotropic medications. A preplanned interim analysis was conducted when approximately half of the originally planned sample of 550 participants had outcome data.

[0148] After the interim analysis showed that the probability of achieving significant separation between treatment groups on the CAPS-5 primary endpoint was low, the study was stopped early. Therefore, all analyses were performed on the interim analysis sample of 274 participants. The modified treatment intention (mITT) population (which includes all randomized subjects with at least one baseline post-CAPS-5) included 125 participants treated with the above-mentioned cyclobenzaprine-HCl sublingual formulation at a dose of 5.6 mg per day, and 127 placebo participants were studied. The female subgroup of the study (which includes 10 participants treated with the above-mentioned cyclobenzaprine-HCl sublingual formulation at a dose of 5.6 mg per day and 17 participants with placebo) demonstrated the observed average large improvement relative to placebo CAPS-5 (improvement of -9.1 units after 12 weeks of treatment).

[0149] Sexual function was measured by the Sexual Function Change Questionnaire-14 (CSFQ-14), a validated 14-item measure (Keller, McGarvey, Clayton, 2006). Parallel gender-specific forms were administered to men (CSFQ-14-M) and women (CSFQ-14-F), and each gender was analyzed separately. In addition to the overall sexual function score, there are five subscales: desire / frequency, desire / interest, arousal / excitement, orgasm / complete, and pleasure. The scale ranges from (never) to (every day), and higher scores reflect higher levels of sexual function.

[0150] Moderate effect sizes were found between women treated with the 5.6 mg dose (N=8) and placebo (N=16) based on the CSFQ-14-F total score and 4 of the 5 subscales. Due to the difference in sample size between the active-treated and placebo groups of women, the results were better characterized using Hedge's g effect size. Specifically, there were moderate effects on the total score g=0.49 (95% CI-1.34, 0.37), the desire / interest subscale g=0.63 (95% CI-1.49, 0.25), the pleasure subscale g=0.54 (95% CI-1.40, 0.33), the desire / frequency subscale g=0.54 (95% CI-1.31, 0.40), and the arousal / excitement subscale g=0.55 (95% CI-1.41, 0.32). No effects were found on the orgasm / completion scale. Overall, adverse events (AEs) in this study were comparable to previous studies using a similar 5.6 mg cyclobenzaprine-HCl dose. The most common AE was oral hypoesthesia (tongue / mouth numbness) related to the application site, which was generally transient (<60 min after application) and was never rated as severe. The most common systemic AE was somnolence, which was also never rated as severe. Two placebo participants and eight participants receiving the 5.6 mg cyclobenzaprine-HCl dose had at least one AE that led to study discontinuation.

[0151] The results in the female group showed that a 5.6 mg daily dose of the cyclobenzaprine-HCl composition had a clinically meaningful effect on improvements in overall sexual function, frequency of sexual activity, interest in sexual experiences, ease of arousal, and current sexual enjoyment in women with military-related PTSD compared to placebo. This effect was robust for arousal / arousal, a major form of female sexual dysfunction for which limited effective and safe treatment options are available (Goldstein, 2000).

[0152] Example 2

[0153] Effects of sublingual cyclobenzaprine-HCl on female sexual function in a military and civilian phase 3 PTSD trial: preliminary evidence of female-specific sexual function improvements after 12 weeks

[0154] Three randomized, placebo-controlled, double-blind clinical trials of the above 5.6 mg cyclobenzaprine-HCl sublingual formulation (2 x 2.8 mg tablets) were conducted, one Phase 2 study and one Phase 3 study in military-related PTSD, and one Phase 3 study in primarily civilian PTSD. All three trials showed encouraging activity on clinician- and patient-rated global PTSD symptoms (Clinician Global Impression [CGI] and Patient Global Impression of Change [PGIC]) using the 5.6 mg cyclobenzaprine-HCl dose. Given the very low incidence of adverse events related to sexual function in both the drug and placebo groups in the Phase 2 studies, a systematic study was conducted to evaluate the effect of treatment on female sexual function in a subsequent Phase 3 study. This retrospective analysis examined the activity of the cyclobenzaprine-HCl sublingual formulation on the Sexual Function Change Questionnaire-14 (CSFQ-14) in two Phase 3 studies.

[0155] In the Phase 3 study of military-related PTSD, eligible participants (males and females) were aged 18-75 years, had experienced trauma meeting DSM-5 PTSD Criterion A during military service since 2001, met the DSM-5 definition of PTSD according to CAPS-5, had a baseline CAPS-5 severity score ≥33, were not taking antidepressants, and were not taking or clean of other psychotropic medications. In the Phase 3 study of primarily civilian PTSD, inclusion criteria were expanded to include civilian participants with current PTSD as determined by CAPS-5. Therefore, this study included 94% of civilian trauma with a minimum baseline severity score ≥33 on CAPS-5. Two studies were stopped early after interim analyses showed a low probability of achieving significant separation between treatment groups on the CAPS-5 primary endpoint. Therefore, an interim analysis sample of 252 participants in the military Phase 3 study (89% males [n = 225M; n = 27F]; 100% military PTSD) and 143 subjects in the civilian Phase 3 study (79% females [n = 129F; n = 34M]; 94% civilian PTSD) were analyzed.

[0156] The CSFQ-14 is a validated 14-item measure (Keller, McGarvey, Clayton, 2006) with separate male and female versions. In addition to the overall sexual function score, there are five subscales: desire / frequency, desire / interest, arousal / excitement, orgasm / complete, and pleasure. Items vary from (never) to (every day) on a 5-point Likert scale. Higher scores reflect higher levels of sexual function.

[0157] In a Phase 3 study of predominantly males and all military-related PTSD, the sample size of female completers (n=24) was small, and the study was not powered to detect differences in subgroups. Therefore, Hedges' g-characterized effect sizes were reported for women treated with the 5.6 cyclobenzaprine-HCl dose (N=8) relative to placebo (N=16) on the CSFQ-14 total score and 4 of the 5 subscales: total score 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 effects were found on the climax / completion scale.

[0158] In a Phase 3 study of primarily civilian PTSD subjects, female completers in the 5.6 mg cyclobenzaprine-HCl dose group (N=58) showed a trend toward improvement in CSFQ-14-F total scores compared to the placebo group (N=55), with a medium effect size (p=0.07, Hedges' g=0.37 [95% CI 0.00, 0.74]). Although the study was not powered to detect differences in subgroups, small to moderate effect sizes were observed for each subscale, 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 / arousal g = 0.33 (95% CI -0.04, 0.70), and orgasm / completion g = 0.29 (95% CI -0.08, 0.66).

[0159] Adverse events (AEs) in both Phase 3 studies were comparable to previous studies using the 5.6 mg cyclobenzaprine-HCl dose. The most common AE was oral hypoesthesia (tongue / mouth numbness) related to the application site, which was generally transient (<60 minutes after application) and was never rated as severe. The most common systemic AE was somnolence, which was also never rated as severe.

[0160] Results in the female groups of the two Phase 3 studies suggest a clinically meaningful trend toward improvement in overall sexual function in women with PTSD. Results from both studies demonstrate a strong effect on female arousal / arousal, which is a major form of female sexual dysfunction with limited available treatment options. Although the effect size was larger in the military Phase 3 study, there were relatively few women in that study. In the civilian Phase 3 study, the female sample was larger, and proportionally more female participants in that study reported index trauma related to sexual trauma.

[0161] These examples above demonstrate that a 5.6 mg dose of cyclobenzaprine-HCl of the disclosed composition is active against female SD in both military-related PTSD and civilian PTSD.

Claims

1. Use of a therapeutically effective amount of cyclobenzaprine and a pharmaceutically acceptable carrier in the preparation of a medicament for treating or preventing sexual dysfunction in a female subject who is in need of or at risk of such dysfunction.

2. The use according to claim 1, wherein cyclobenzaprine is a free base or a pharmaceutically acceptable salt thereof.

3. The use according to claim 2, wherein the pharmaceutically acceptable salt of cyclobenzaprine is cyclobenzaprine salt.

4. The use according to claim 3, wherein the cyclobenzaprine salt is cyclobenzaprine-HCl.

5. The use according to claim 4, wherein cyclobenzaprine-HCl is in the form of a mannitol eutectic mixture.

6. The use according to claim 5, wherein the mannitol eutectic is selected from a 75% ± 2% by weight cyclobenzaprine-HCl and 25% ± 2% β-mannitol eutectic, a 65% ± 2% by weight cyclobenzaprine-HCl and 35% ± 2% δ-mannitol eutectic, a mixture of a 75% ± 2% by weight cyclobenzaprine-HCl and 25% ± 2% β-mannitol eutectic and a 65% ± 2% by weight cyclobenzaprine-HCl and 35% ± 2% δ-mannitol eutectic, and particles 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.

7. The use of claim 4, wherein the preparation of the medicament further comprises using an alkalizing agent.

8. The method of claim 7, wherein the alkalizing agent is selected from the group consisting of monopotassium phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, monosodium phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate.

9. The method according to claim 8, wherein the alkalizing agent is dipotassium hydrogen phosphate.

10. The use of claim 1, wherein the medicament comprises 0.1 mg to 30 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

11. The use of claim 10, wherein the medicament comprises 1 mg to 20 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

12. The use of claim 11, wherein the medicament comprises less than 10 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

13. The use of claim 12, wherein the medicament comprises less than 5 mg of cyclobenzaprine or a pharmaceutically acceptable salt thereof.

14. The use of claim 4, wherein the medicament comprises 5.6 mg of cyclobenzaprine-HCl.

15. The use of claim 4, wherein the medicament comprises 2.8 mg of cyclobenzaprine-HCl.

16. The use of claim 14, wherein the medicament is formulated in two dosage units for simultaneous or sequential administration, and wherein the combined amount in the two dosage units is 5.6 mg of cyclobenzaprine-HCl.

17. The use of claim 14, wherein the medicament is formulated for simultaneous administration in two dosage units, and wherein each dosage unit comprises 2.8 mg of cyclobenzaprine-HCl.

18. The use of claim 1, wherein the medicament is formulated for daily administration.

19. The use according to claim 18, wherein the medicament is formulated for once-daily administration.

20. The use of claim 19, wherein the drug is formulated into a dosage form selected from tablets, films, liquids, powders or suppositories.

21. The use according to claim 20, wherein the tablet is a sublingual tablet.

22. The use of claim 20, wherein the medicament is formulated for administration sublingually, buccally, orally, intravenously, intramuscularly, subcutaneously, by inhalation, transdermally, rectally or vaginally.

23. The use of claim 22, wherein the medicament is formulated for sublingual administration.

24. The use of claim 1, wherein the medicament is formulated for sequential or simultaneous administration with one or more therapeutic agents selected from the group consisting of flibanserin, estrogen receptor modulators, synthetic or gonadal steroid agents, phosphodiesterase inhibitors, melanocortin receptor agonists, alpha 1 -adrenergic receptor antagonists, beta-adrenergic receptor antagonists, anticonvulsants, antidepressants, antianxiety agents, antihistamines, antihypertensives, antilipids, hormonal agents, gonadotropin-releasing hormone agonists, contraceptives, anticholinergics, dopamine receptor agonists, anorectics and anesthetics.

25. The use of claim 24, wherein the estrogen receptor modulator is ospemifene.

26. The use according to claim 24, wherein the dopaminergic receptor agonist is apomorphine.

27. The use of claim 24, wherein the steroid agent is tibolone, estrogen or testosterone.

28. The use of claim 24, wherein the phosphodiesterase inhibitor is sildenafil or tadalafil.

29. The use of claim 24, wherein the melanocortin receptor agonist is bumelatide.

30. The use of claim 24, wherein the alpha 1 -adrenergic receptor antagonist is prazosin, terazosin, doxazosin, silodosin, alfuzosin or tamsulosin.

31. The method of claim 24, wherein the beta-adrenergic receptor antagonist is propranolol, bucinolol, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, pindolol, sotalol, timolol, acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol, esmolol, butaxamine, ICI-118551, SR 59230A or nebivolol.

32. The use of claim 24, wherein the anticonvulsant is carbamazepine, divalproex sodium, dextromethorphan, gabapentin, lamotrigine, oxcarbazepine, pregabalin, tiagabine, topiramate or valproate.

33. The use of claim 24, wherein the antidepressant is a serotonin 1A receptor agonist, a serotonin 2A receptor antagonist, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor or an amphetamine.

34. The use of claim 24, wherein the antidepressant is trazodone, bupropion, amitriptyline, mirtazapine or nortriptyline.

35. The use of claim 33, wherein the selective serotonin reuptake inhibitor is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline.

36. The use of claim 33, wherein the serotonin-norepinephrine reuptake inhibitor is atomoxetine, duloxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, tramadol or venlafaxine.

37. The use of claim 24, wherein the antianxiety agent is a benzodiazepine, a barbiturate, a lithium salt, or buspirone.

38. The method of claim 37, wherein the benzodiazepine is quazepam, chlordiazepoxide, flurazepam, alprazolam, chlordiazepoxide, diazepam, estazolam, clonazepam, oxazepam, triazolam, lorazepam, temazepam, clobazam or midazolam.

39. The use of claim 1, wherein the medicament is formulated for sequential or simultaneous administration with an antipsychotic drug.

40. The use of claim 39, wherein the antipsychotic drug is quetiapine, trazodone, promazine, aripiprazole, ziprasidone, olanzapine or risperidone.

41. The method of claim 24, wherein the antihistamine is acrivastine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindane, diphenhydramine, doxylamine, ebastine, enbramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, azine, olopatadine, orphenadrine, phenindrine, pheniramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripeliramine, triprolidine, levocetirizine, desloratadine, pyrilamine, cimetidine, famotidine, lafutidine, nizatidine, ranitidine, roxatidine, thiotidine, clofenac, ABT-239, ciprofloxacin, kenesin, A-349821, thioperamide, thioperamide, JNJ7777120, or VUF-6002.

42. The use of claim 24, wherein the hormone drug is oxytocin, estrogen or testosterone.

43. The use of claim 1, wherein the female subject has female reproductive organs by birth, plastic surgery, or sex reassignment surgery.

44. The use of claim 43, wherein the female subject is a premenopausal, perimenopausal or postmenopausal female.

45. The use of claim 1, wherein the sexual dysfunction is associated with the use of one or more agents selected from the group consisting of antidepressants, antianxiety agents, antihypertensive agents, chemotherapeutic agents, hormonal agents, corticosteroids, antihistamines, antihypertensive agents, antilipid agents, gonadotropin-releasing hormone agonists, contraceptives, anticholinergics, anorectics, and anesthetics.

46. ​​The use of claim 1, wherein the sexual dysfunction is associated with a medical condition.

47. The use of claim 1, wherein the sexual dysfunction is sexual desire disorder, sexual arousal disorder, orgasmic disorder or dyspareunia disorder.

48. The use of claim 47, wherein the sexual dysfunction has one or more of the following symptoms: sexual aversion, low sexual desire or interest, sexual fear, inability to become aroused or maintain arousal during sexual activity, difficulty achieving sustained or recurring orgasm after adequate sexual arousal and sustained stimulation, and pain associated with sexual stimulation or vaginal contact.

49. The use of claim 47, wherein the sexual dysfunction comprises difficulty in sexual arousal.

50. The use of claim 46, wherein the medical condition is selected from cardiovascular disease, obesity, cancer, lung disorders, kidney disorders, bladder disorders, intestinal disorders, liver disorders, gynecological disorders, autoimmune diseases, hormonal disorders, viral infections, bacterial infections, and parasitic infections.

51. The use of claim 50, wherein the cardiovascular disease is selected from the group consisting of heart disease, hypertension and peripheral vascular disease.

52. The method of claim 50, 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, head and neck cancer, lung cancer, thyroid cancer, bladder cancer, esophageal cancer, mesothelioma, glioblastoma, thymic cancer, blood cancer, and colon cancer.

53. The use of claim 50, wherein the cancer is selected from the group consisting of lymphoma, leukemia and myeloma.

54. The use of claim 50, wherein the pulmonary disorder is selected from pneumonia, tuberculosis, emphysema, pulmonary edema, acute respiratory distress syndrome, pneumoconiosis, pulmonary embolism, pulmonary hypertension, pleural effusion, pneumothorax and mesothelioma.

55. The use of claim 50, wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, type I diabetes, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Addison's disease, Graves' disease, Sjögren's syndrome, myasthenia gravis, pernicious anemia, and celiac disease.

56. The use of claim 50, wherein the liver disorder is selected from the group consisting of hepatitis, fatty liver disease, liver cancer, hemochromatosis, and Wilson's disease.

57. The use of claim 50, wherein the gynecological condition is selected from the group consisting of menopause, peritonitis, uterine degeneration, fibroids, endometritis, uterine cysts, cystocele, rectocele, and uterine prolapse.

58. The use of claim 50, wherein the bladder disorder is selected from urethritis and interstitial cystitis.

59. The use of claim 50, wherein the bladder disorder is a urinary tract infection.

60. The use of claim 50, wherein the renal disorder is selected from the group consisting of chronic kidney disease, diabetes, anorexia nervosa, hypertension, high cholesterol, lupus, multiple myeloma, and hemolytic uremic syndrome.

61. The use of claim 50, wherein the hormonal disorder is associated with menopause, perimenopause, pregnancy or childbirth.

62. The use of claim 50, wherein the viral infection is caused by human papillomavirus, hepatitis C virus or herpes simplex virus.

63. The use of claim 50, wherein the bacterial infection is caused by Gardnerella vaginalis.

64. The use of claim 1, wherein the sexual dysfunction is associated with a mental health condition.

65. The use of claim 64, wherein the mental health condition is sexual, emotional or physical trauma or abuse.

66. The use of claim 64, wherein the mental health condition is depression, bipolar disorder, or a substance-induced disorder.

67. The use of claim 64, wherein the mental health condition is post-traumatic stress disorder, acute stress disorder, adjustment disorder, or reactive attachment disorder.

68. The use of claim 64, wherein the mental health condition is mild cognitive impairment, Parkinson's disease, Huntington's disease, Alzheimer's disease, or amyotrophic lateral sclerosis.

69. The use of claim 64, wherein the mental health condition is panic, generalized anxiety disorder, specific phobia, or social phobia.