Use of oxaprotiline for the treatment of nervous system disorders

Abstract

Described herein are methods of treating fibromyalgia comprising administering oxaprotiline to a human in need thereof. Oxaprotiline can also be used in the manufacture of a medicament for the treatment of fibromyalgia.

Description

[0001] Inventor: Herriot Tabuteau

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 623,678, filed January 22, 2024, which is incorporated herein by reference in its entirety. Background Technology

[0004] Fibromyalgia is a severe and debilitating chronic condition that causes widespread musculoskeletal pain, accompanied by fatigue, sleep, memory, and mood problems. It is estimated that fibromyalgia affects an estimated 4 million people in the United States. Fibromyalgia can cause pain, fatigue, muscle aches or tenderness, tiredness, facial and jaw pain, headaches and migraines, digestive problems (including diarrhea and constipation), bladder control problems, memory problems, anxiety, depression, insomnia, and other sleep disorders. Unfortunately, there are currently few approved treatments for this poorly understood condition, and they are limited by differences in efficacy among patients, tolerability issues, and the need for DEA (Department of Drug Enforcement) dispatch. Summary of the Invention

[0005] Some implementation methods include a method for treating fibromyalgia, the method comprising administering approximately 4 mg to approximately 10 mg of oxprexetine daily to a person with fibromyalgia who has a visual analog scale score of at least approximately 40 nm on a 100 nm scale.

[0006] Some implementations include a method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 1 mg to about 2 mg for at least six weeks, wherein the person experiences a reduction in fibromyalgia pain during the treatment process that is greater than the pain reduction that the person would experience with placebo, as measured by a visual analog scale (VAS) score.

[0007] Some implementations include a method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 2 mg to about 4 mg for at least six weeks, wherein the person experiences pain relief during the treatment process that is greater than the pain relief that the person would experience with placebo, as measured by a visual analog scale (VAS) score.

[0008] Some implementations include a method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 0.5 mg to about 1 mg for at least six weeks, wherein the person experiences pain relief during the treatment process that is greater than the pain relief that the person would experience with placebo, as measured by a visual analog scale (VAS) score. Detailed Implementation

[0009] Antidepressants, such as reboxetine or S,S-reboxetine, can be used to treat conditions such as neurological disorders, including addiction disorders (including those caused by alcohol, nicotine, and other psychoactive substances), withdrawal syndromes, adjustment disorders (including depressive mood, anxiety, mixed anxiety and depressive mood, conduct disorder, and mixed conduct and mood disorders), depression (including major depressive disorder, alone or in combination with other antidepressants), age-related learning or mental disorders (including Alzheimer's disease), anorexia nervosa, apathy, attention deficit (or another cognitive) disorder due to general medical conditions, attention deficit hyperactivity disorder (ADHD), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, chronic or acute stress, chronic pain, conduct disorder, cyclical mood disorders, depression (including adolescent depression and mild depression), dysphoric disorder, fibromyalgia, and other somatic symptom disorders (including somatization disorder, conversion disorder, etc.). Disorders, pain disorders, hypochondriasis, somatic dysmorphic disorders, undifferentiated somatic symptom disorder and somatic symptom NOS), generalized anxiety disorder (GAD), incontinence (i.e., stress incontinence, true stress incontinence, and mixed incontinence), stress urinary incontinence, aspiration disorders, toxic disorders (alcohol addiction), mania, migraine, obesity (e.g., weight loss in obese or overweight patients), obsessive-compulsive disorder or related spectrum disorders, oppositional defiant disorder, panic disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual anxiety disorder (i.e., premenstrual syndrome and late luteal phase anxiety), psychotic disorders (including schizophrenia, negative symptoms of schizophrenia, schizoaffective disorder, or schizophrenia-like disorders, alone or as adjunctive therapy), seasonal affective disorder, sleep disorders (such as narcolepsy or enuresis), social phobia (including social anxiety disorder), specific developmental disorders, selective serotonin reuptake inhibition (SSRI) "failure" (poop "Out of Response" syndrome (i.e., where a patient fails to maintain a satisfactory response after an initial satisfactory phase of SSRI therapy), TIC disorders (e.g., Tourette's disease), postherpetic neuralgia, painful diabetic peripheral neuropathy, postherpetic neuralgia, syncope, and / or vasovagal syncope, etc. In some embodiments, S,S-reboxetine is used to treat fibromyalgia. In some embodiments, reboxetine is used to treat fibromyalgia.

[0010] Treatment with S,S-reboxetine can lead to improvement in disease symptoms. For example, in pain conditions such as fibromyalgia, patients may experience pain reduction as measured on a visual analog scale (VAS) (e.g., 0-100 mm), which is greater than the pain reduction experienced with placebo. In some implementations, the improvement in VAS score is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1%-5%, about 1%-10%, about 10%-20%, about 20%-30%, about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%-100%, about 1%-25%, about 25%-50%, about 50%-75%, or about 75%-100%, for example, at least about 50 mm, at least about 40 mm, at least about 30 mm, at least about 20 mm, at least about 10 mm, about 0-10 mm, about 10-20 mm, about 20-30 mm, about 30-40 mm. mm, approximately 40-50 mm, approximately 0-25 mm, or approximately 25-50 mm. In some implementations, the improvement in VAS score compared to baseline (e.g., immediately before treatment begins) is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1%-5%, about 1%-10%, about 10%-20%, about 20%-30%, about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%-100%, about 1%-25%, about 25%-50%, about 50%-75%, or about 75%-100%, for example, at least about 50 mm, at least about 40 mm, at least about 30 mm, at least about 20 mm, at least about 10 mm, about 0-10 mm, about 10-20 mm, about 20-30 mm. mm, approximately 30-40 mm, approximately 40-50 mm, approximately 0-25 mm, or approximately 25-50 mm.

[0011] Antidepressants (such as bupropion, hydroxybupropion, erythrobupropion, threobupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimethoprim, nortriptyline, maprotiline, phenelzine, isocarboxazid, transphenylcyclopropionamide, paroxetine, trazodone, citalopram, sertraline, aryloxyindamine, benatizine, escitalopram, fluvoxamine, venlafaxine, nortriptyline) Venlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, mirnacilin, tersofencin, butofencin, moclobemide, rasagiline, nipramine, isoniazid, isopronil, toloxacin, butiline, duthiramine, dibenzepine, iproindole, lofepramine, opipipexole, norfluoxetine, dapoxetine, ketamine, etc., including norepinephrine reuptake inhibitors (such as atormoxetine, edoxetine, or S,S-reboxetine) can be used to treat fibromyalgia.

[0012] In some implementations, prior to receiving the antidepressant (including norepinephrine inhibitors such as S,S-reboxetine) used for treatment, the patient had fibromyalgia for approximately 1–365 days, 1–5 years, 5–10 years, 10–15 years, 15–20 years, 20–25 years, 25–30 years, 30–35 years, 35–40 years, 40–45 years, 45–50 years, 50–55 years, 55–60 years, 60–65 years, 65–70 years, 70–75 years, or more than 75 years, and / or may be selected based on the duration of the fibromyalgia.

[0013] In some implementations, prior to receiving the antidepressant (including norepinephrine inhibitors such as S,S-reboxetine) for treatment, the patient is approximately 0–18 years old, approximately 18–100 years old, approximately 0–5 years old, approximately 5–10 years old, approximately 10–15 years old, approximately 15–18 years old, approximately 18–20 years old, approximately 15–20 years old, approximately 18–25 years old, approximately 20–25 years old, approximately 25–30 years old, approximately 30–35 years old, approximately 35–40 years old, approximately 40–45 years old, approximately 45–50 years old, approximately 50–55 years old, approximately 55–60 years old, approximately 60–65 years old, approximately 65–70 years old, approximately 70–75 years old, or over 75 years old, and / or may be selected based on having that age.

[0014] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may be women, and / or may be selected because they are women. In some implementations, patients may be selected because they are not breastfeeding or pregnant.

[0015] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may be male, and / or may be selected because they are male.

[0016] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take sodium oxybutyrate concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take stimulants concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take anticonvulsants concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take clonidine concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take selective serotonin reuptake inhibitors (SSRIs). Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take serotonin and norepinephrine reuptake inhibitors (SNRIs) concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take monoamine oxidase inhibitors (MAOIs) concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take tricyclic antidepressants (TCAs) concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take hypnotics concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take anti-anxiety medications concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take sedative-type antihistamines concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take antipsychotics concurrently. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not take any other medications used to treat fibromyalgia concurrently.

[0017] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a neurodegenerative disease, and / or may be selected because they do not have a neurodegenerative disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have an epileptic disorder, and / or may be selected because they do not have an epileptic disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a seizure disorder, and / or may be selected because they do not have a seizure disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have been diagnosed with cancer in the past 5 years (except possibly basal cell carcinoma), and / or may be selected because they have not been diagnosed with cancer in the past 5 years.

[0018] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bilirubin levels greater than twice the upper limit of normal, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have alanine aminotransferase (ALT) levels greater than twice the upper limit of normal, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have aspartate aminotransferase (AST) levels greater than twice the upper limit of normal, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have alkaline phosphatase levels greater than twice the upper limit of normal, and / or may be selected for treatment because they do not have alkaline phosphatase levels greater than twice the upper limit of normal.

[0019] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have clinically significant hypertension, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have uncontrolled hypertension, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a history of cardiovascular disease, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had a myocardial infarction, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have angina, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have arrhythmias, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have heart failure, and / or may be selected for this reason.

[0020] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a history of narrow-angle glaucoma, and / or may be selected because they do not have a history of narrow-angle glaucoma. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have undergone gastric bypass surgery, and / or may be selected because they have not undergone gastric bypass surgery. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have any conditions expected to affect drug absorption, and / or may be selected because they do not have any conditions expected to affect drug absorption.

[0021] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have headaches, and / or may be selected because they do not have headaches. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have depression, and / or may be selected because they do not have depression. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have major depressive disorder, and / or may be selected because they do not have major depressive disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have treatment-resistant depression, and / or may be selected because they do not have treatment-resistant depression.

[0022] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have treatment-resistant bipolar disorder, and / or may be selected because they do not have treatment-resistant bipolar disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bipolar disorder, and / or may be selected because they do not have bipolar disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cyclothymia, and / or may be selected because they do not have cyclothymia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have seasonal affective disorder, and / or may be selected because they do not have seasonal affective disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a mood disorder, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have chronic depression (e.g., dysphoric mood), and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have psychotic depression, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a history of psychotic episodes, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a significant risk of self-harm, suicide, or aggression against others, and / or may be selected for this reason.

[0023] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have postpartum depression, and / or may be selected because they do not have postpartum depression. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have premenstrual anxiety disorder (PMDD), and / or may be selected because they do not have PMDD. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have situational depression, and / or may be selected because they do not have situational depression. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have atypical depression, and / or may be selected because they do not have atypical depression. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have mania, and / or may be selected because they do not have mania. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have anxiety disorders, and / or may be selected because they do not have anxiety disorders. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have attention deficit disorder (ADD), and / or may be selected because they do not have attention deficit disorder (ADD).

[0024] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have attention deficit hyperactivity disorder (ADDH), and / or may be selected because they do not have ADDH. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have attention deficit / hyperactivity disorder (AD / HD), and / or may be selected because they do not have AD / HD. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a manic state, and / or may be selected because they do not have a manic state. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have obsessive-compulsive disorder (OCD), and / or may be selected because they do not have OCD. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bulimia nervosa, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have obesity or weight gain, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have chronic fatigue syndrome, and / or may be selected for this reason.

[0025] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have premenstrual syndrome (PMS), and / or may be selected because they do not have PMS. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have substance addiction or abuse, and / or may be selected because they do not have substance addiction or abuse. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have nicotine addiction, and / or may be selected because they do not have nicotine addiction. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have psychogenic sexual dysfunction, and / or may be selected because they do not have psychogenic sexual dysfunction. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have pseudobulbar mood disorders, and / or may be selected for this reason.

[0026] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have anxiety disorders, and / or may be selected because they do not have anxiety disorders. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have phobias, and / or may be selected because they do not have phobias. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have generalized anxiety disorder, and / or may be selected because they do not have generalized anxiety disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have social anxiety disorder, and / or may be selected because they do not have social anxiety disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have panic disorder, and / or may be selected because they do not have panic disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have agoraphobia, and / or may be selected because they do not have agoraphobia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have obsessive-compulsive disorder, and / or may be selected because they do not have obsessive-compulsive disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have post-traumatic stress disorder (PTSD), and / or may be selected because they do not have PTSD. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have mania, and / or may be selected because they do not have mania.

[0027] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bipolar disorder, and / or may be selected because they do not have bipolar disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have hypomania, and / or may be selected because they do not have hypomania. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have unipolar depression, and / or may be selected because they do not have unipolar depression. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have stress disorders, and / or may be selected because they do not have stress disorders. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have somatic symptom disorder, and / or may be selected for not having somatic symptom disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have personality disorder, and / or may be selected for not having personality disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have psychosis, and / or may be selected for not having psychosis.

[0028] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have schizophrenia, and / or may be selected because they do not have schizophrenia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have delusional disorders, and / or may be selected because they do not have delusional disorders. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have schizoaffective disorder, and / or may be selected because they do not have schizoaffective disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have schizotypal traits, and / or may be selected because they do not have schizotypal traits. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not be aggressive, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not exhibit aggressive behavior typical of Alzheimer's disease, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not exhibit agitation, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not exhibit agitation typical of Alzheimer's disease, and / or may be selected for this reason.

[0029] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have drug dependence, and / or may be selected because they do not have drug dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cocaine addiction, and / or may be selected because they do not have cocaine addiction. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have stimulant addiction or dependence, and / or may be selected because they do not have stimulant addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have climacteric addiction or dependence, and / or may be selected because they do not have climacteric addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cocaine addiction or dependence, and / or may be selected because they do not have cocaine addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have speed pill addiction or dependence, and / or may be selected because they do not have speed pill addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have methamphetamine addiction or dependence, and / or may be selected because they do not have methamphetamine addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have nicotine addiction or dependence, and / or may be selected because they do not have nicotine addiction or dependence.

[0030] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have alcohol addiction or dependence, and / or may be selected because they do not have alcohol addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have opioid addiction or dependence, and / or may be selected because they do not have opioid addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have anxiolytic and / or hypnotic drug addiction or dependence, and / or may be selected because they do not have anxiolytic and / or hypnotic drug addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a cannabis (cannabis or marijuana) addiction or dependence, and / or may be selected because they do not have a cannabis addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have amphetamine addiction or dependence, and / or may be selected because they do not have amphetamine addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have hallucinogen addiction or dependence, and / or may be selected because they do not have hallucinogen addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have phencyclidine addiction or dependence, and / or may be selected because they do not have phencyclidine addiction or dependence.

[0031] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have volatile solvent addiction or dependence, and / or may be selected because they do not have volatile solvent addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have volatile nitrite addiction or dependence, and / or may be selected because they do not have volatile nitrite addiction or dependence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Alzheimer's disease, and / or may be selected because they do not have Alzheimer's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Alzheimer's disease, and / or may be selected because they do not have Alzheimer's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have memory loss, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have amnesia / amnesia syndrome, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have epilepsy, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have altered consciousness, and / or may be selected for this reason.

[0032] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a coma, and / or may be selected because they do not have a coma. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have decreased attention, and / or may be selected because they do not have decreased attention. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a speech disorder, and / or may be selected because they do not have a speech disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have voice spasm, and / or may be selected because they do not have voice spasm. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Parkinson's disease, and / or may be selected because they do not have Parkinson's disease.

[0033] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have autism, and / or may be selected because they do not have autism. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have hyperkinesis syndrome, and / or may be selected because they do not have hyperkinesis syndrome. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have schizophrenia, and / or may be selected because they do not have schizophrenia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had a stroke, and / or may be selected because they have not had a stroke. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had a stroke, and / or may be selected because they do not have a stroke. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had a cerebral hemorrhage, and / or may be selected because they do not have a cerebral hemorrhage. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cerebral arteriosclerosis, and / or may be selected because they do not have cerebral arteriosclerosis. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had cerebral venous thrombosis, and / or may be selected because they do not have cerebral venous thrombosis. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have had a head injury, and / or may be selected because they do not have a head injury.

[0034] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have akinesia, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have choreoathetosis, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have ataxia, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have throwing disorder, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have unilateral throwing disorder, and / or may be selected because they do not have unilateral throwing disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bradykinesia, and / or may be selected because they do not have bradykinesia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cerebral palsy, and / or may be selected because they do not have cerebral palsy.

[0035] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have chorea, and / or may be selected because they do not have chorea. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Huntington's disease, and / or may be selected because they do not have Huntington's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have rheumatic chorea, and / or may be selected because they do not have rheumatic chorea. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Sydenham's chorea, and / or may be selected because they do not have Sydenham's chorea. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have movement disorders, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have tardive dyskinesia, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have dystonia, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have blepharospasm, and / or may be selected for this reason.

[0036] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spasmodic torticollis, and / or may be selected because they do not have spasmodic torticollis. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have dopamine-responsive dystonia, and / or may be selected because they do not have dopamine-responsive dystonia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have restless legs syndrome (RLS), and / or may be selected because they do not have restless legs syndrome (RLS). Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have tremor, and / or may be selected because they do not have tremor. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have essential tremor, and / or may be selected because they do not have essential tremor. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Tourette syndrome, and / or may be selected because they do not have Tourette syndrome. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Wilson's disease, and / or may be selected because they do not have Wilson's disease.

[0037] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have vascular dementia, and / or may be selected because they do not have vascular dementia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Lewy body dementia, and / or may be selected because they do not have Lewy body dementia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have mixed dementia, and / or may be selected because they do not have mixed dementia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have frontotemporal dementia, and / or may be selected because they do not have frontotemporal dementia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Kreutzfeldt-Jacob disease, and / or may be selected because they do not have Kreutzfeldt-Jacob disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have normal pressure hydrocephalus, and / or may be selected because they do not have normal pressure hydrocephalus. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Wernicke-Korsakov syndrome, and / or may be selected because they do not have Wernicke-Korsakov syndrome.

[0038] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Pick's disease, and / or may be selected because they do not have Pick's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have progressive bulbar palsy, and / or may be selected because they do not have progressive bulbar palsy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have primary lateral sclerosis (PLS), and / or may be selected because they do not have primary lateral sclerosis (PLS). Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have progressive muscular atrophy, and / or may be selected because they do not have progressive muscular atrophy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have sequelae of poliomyelitis (PPS), and / or may be selected because they do not have PPS. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spinal muscular atrophy (SMA), and / or may be selected because they do not have SMA.

[0039] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spinal motor atrophy, and / or may be selected because they do not have spinal motor atrophy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Ty-Sachs disease, and / or may be selected because they do not have Ty-Sachs disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Sandhof's disease, and / or may be selected because they do not have Sandhof's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have hereditary spastic paraplegia, and / or may be selected because they do not have hereditary spastic paraplegia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Alzheimer's disease, and / or may be selected because they do not have Alzheimer's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have prion-related diseases, and / or may be selected because they do not have prion-related diseases. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have cerebellar ataxia, and / or may be selected because they do not have cerebellar ataxia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spinocerebellar ataxia (SCA), and / or may be selected because they do not have SCA.

[0040] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spinal muscular atrophy (SMA), and / or may be selected because they do not have SMA. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have bulbar muscular atrophy, and / or may be selected because they do not have bulbar muscular atrophy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Friedrich's ataxia, and / or may be selected because they do not have Friedrich's ataxia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Lewy body disease, and / or may be selected because they do not have Lewy body disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have amyotrophic lateral sclerosis (ALS or Luglick's disease), and / or may be selected because they do not have ALS. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have multiple sclerosis (MS), and / or may be selected because they do not have MS. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have multiple system atrophy, and / or may be selected because they do not have multiple system atrophy.

[0041] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Chard syndrome, and / or may be selected because they do not have Chard syndrome. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have corticobasal degeneration, and / or may be selected because they do not have corticobasal degeneration. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have progressive supranuclear palsy, and / or may be selected because they do not have progressive supranuclear palsy.

[0042] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Wilson's disease, and / or may be selected because they do not have Wilson's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Menx's disease, and / or may be selected because they do not have Menx's disease. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have adrenoleukodystrophy, and / or may be selected because they do not have adrenoleukodystrophy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy (CADASIL), and / or may be selected because they do not have CADASIL.

[0043] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Charcoal-Marie-Tooth disease (CMT), and / or may be selected because they do not have CMT. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have familial spastic paraplegia, and / or may be selected because they do not have familial spastic paraplegia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have neurofibromatosis, and / or may be selected because they do not have neurofibromatosis. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have olivary pontocerebellar atrophy or degeneration, and / or may be selected because they do not have olivary pontocerebellar atrophy or degeneration. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have striatal nigra degeneration, and / or may be selected because they do not have striatal nigra degeneration. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Guillain-Barré syndrome, and / or may be selected because they do not have Guillain-Barré syndrome. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have spastic paraplegia, and / or may be selected because they do not have spastic paraplegia. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have seizures, and / or may be selected because they do not have seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have non-epileptic seizures, and / or may be selected because they do not have non-epileptic seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have epilepsy, and / or may be selected because they do not have epilepsy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have febrile seizures, and / or may be selected because they do not have febrile seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have partial seizures, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have simple partial seizures, and / or may be selected for this reason.Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have Jacksonian epilepsy, and / or may be selected because they do not have Jacksonian epilepsy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have complex partial seizures, and / or may be selected because they do not have complex partial seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have persistent partial seizures, and / or may be selected because they do not have persistent partial seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as s,S-reboxetine) may not have generalized seizures, and / or may be selected because they do not have generalized seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have generalized tonic-clonic seizures, and / or may be selected for this reason. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have absence seizures, and / or may be selected for this reason.

[0044] Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have atonic seizures, and / or may be selected because they do not have atonic seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have myoclonic seizures, and / or may be selected because they do not have myoclonic seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have juvenile myoclonic seizures, and / or may be selected because they do not have juvenile myoclonic seizures. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have infantile spasms, and / or may be selected because they do not have infantile spasms. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have status epilepticus, and / or may be selected because they do not have status epilepticus. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have Rett syndrome, and / or may be selected because they do not have Rett syndrome. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have tinnitus, and / or may be selected because they do not have tinnitus. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have a disorder of consciousness, and / or may be selected because they do not have a disorder of consciousness. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have sexual dysfunction, and / or may be selected because they do not have sexual dysfunction. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have voice disorders caused by uncontrolled laryngeal spasm, and / or may be selected because they do not have voice disorders caused by uncontrolled laryngeal spasm. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have abducens spasmodic voice disorder, and / or may be selected because they do not have abducens spasmodic voice disorder. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have adductor spasmodic voice disorder, and / or may be selected because they do not have adductor spasmodic voice disorder.Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have vocal tremor, and / or may be selected because they do not have vocal tremor. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have diabetic neuropathy, and / or may be selected because they do not have diabetic neuropathy. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have chemotherapy-induced neurotoxicity, and / or may be selected because they do not have chemotherapy-induced neurotoxicity. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have methotrexate neurotoxicity, and / or may be selected because they do not have methotrexate neurotoxicity. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have stress urinary incontinence, and / or may be selected because they do not have stress urinary incontinence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have urge urinary incontinence, and / or may be selected because they do not have urge urinary incontinence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have fecal incontinence, and / or may be selected because they do not have fecal incontinence. Some patients treated with antidepressants for fibromyalgia (including norepinephrine inhibitors such as S,S-reboxetine) may not have erectile dysfunction, and / or may be selected because they do not have erectile dysfunction.

[0045] In some implementations, administering antidepressants (including norepinephrine inhibitors such as S,S-reboxetine) can improve sleep quality. For example, patients may report improved sleep quality. In some implementation schemes, such as compared to baseline, placebo, or some other appropriate controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs), the number of patients reporting improved sleep quality may be at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 20%-30%, about 30%-40%, about 40%-50%, about 50%-60%, about 60%-70%, about 70%-80%, about 80%-90%, about 90%-100%, about 1%-25%, about 25%-50%, about 50%-75%, or about 75%-100%, about 40%-60%, about 42%-47%. In some implementation schemes, such as compared to baseline, placebo, or some other appropriate controls (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs), patients may have the following improvements in sleep quality: at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 80%, at least approximately 90%, at least approximately... 95%, approximately 10%-20%, approximately 20%-30%, approximately 30%-40%, approximately 40%-50%, approximately 40%-45%, approximately 45%-40%, approximately 50%-60%, approximately 60%-70%, approximately 70%-80%, approximately 80%-90%, approximately 90%-100%, approximately 1%-25%, approximately 25%-50%, approximately 50%-75%, or approximately 75%-100%, approximately 40%-60%, approximately 42%-47%, or approximately 45%. This improvement can be observed at times such as 1 week, 2 weeks, at overall evaluation, or at any other relevant time (e.g., 1 month, 6 months, 1 year, 2 years, etc.) with reboxetine treatment. This improvement in reboxetine treatment compared to placebo can be statistically significant (p ≤ 0.05), for example, p = 0.01-0.05, < 0.01, 0.001-0.01, 0.001-0.005, 0.005-0.01, or 0.007.

[0046] S,S-reboxetine (e.g., having the structure shown below) is a highly selective and potent norepinephrine reuptake inhibitor with the potential to treat fibromyalgia.

[0047] (S,S-reboxetine, as a mesylate)

[0048] Unless otherwise indicated, any reference to the compounds described herein (such as reboxetine) by structure, name or any other means includes pharmaceutically acceptable salts; free acids or bases; alternative solid forms such as polymorphs, solvates, hydrates, etc.; tautomers; enantiomers; deuterium-modified compounds such as deuterium-modified reboxetine; or any chemical substance that can be rapidly converted into the compounds described herein under the conditions under which the compounds are used.

[0049] In some embodiments, reboxetine is in salt form, free base form, or may contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (+)-reboxetine (also known as S,S-reboxetine or oxoxetine); or an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (−)-reboxetine.

[0050] For the treatment of narcolepsy, S,S-reboxetine can be administered in a manner that results in 1) a first local maximum plasma concentration of S,S-reboxetine and 2) a second local maximum plasma concentration of S,S-reboxetine.

[0051] For the treatment of fibromyalgia, S,S-reboxetine can be administered in a manner that results in 1) a first local maximum plasma concentration of S,S-reboxetine and 2) a second local maximum plasma concentration of S,S-reboxetine.

[0052] In some implementations, the daily dose of S,S-reboxetine can be approximately 0.5-1 mg, approximately 1-1.5 mg, approximately 1.5-2 mg, approximately 1-2 mg, approximately 2-3 mg, approximately 3-4 mg, approximately 4-5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 10-11 mg, approximately 11-12 mg, approximately 12-13 mg, approximately 13-14 mg, approximately 14-15 mg, approximately 15-16 mg, approximately 16-17 mg, approximately 2-5 mg, approximately 5-8 mg, approximately 8-11 mg, approximately 11-14 mg, approximately 14-17 mg, approximately 17-20 mg, approximately 8-10 mg, approximately 8-12 mg, approximately 0.0015-0.003 mmol, or approximately 0.003-0.0045 mmol. mmol, approximately 0.0045-0.006 mmol, approximately 0.003-0.006 mmol, approximately 0.006-0.009 mmol, approximately 0.009-0.012 mmol, approximately 0.012-0.015 mmol, approximately 0.015-0.018 mmol, approximately 0.018-0.021 mmol, approximately 0.021-0.024 mmol, approximately 0.024-0.027 mmol, approximately 0.027-0.03 mmol, approximately 0.03-0.033 mmol, approximately 0.033-0.036 mmol, approximately 0.036-0.039 mmol, approximately 0.039-0.042 mmol, approximately 0.042-0.045 mmol, approximately 0.045-0.048 The daily dose is the total amount of reboxetine administered within a single day. (The dosage ranges from approximately 0.048-0.051 mmol, 0.051-0.054 mmol, 0.054-0.057 mmol, 0.057-0.06 mmol, 0.06-0.063 mmol, 0.063-0.066 mmol, 0.066-0.069 mmol, 0.006-0.01 mmol, 0.01-0.02 mmol, 0.02-0.03 mmol, 0.03-0.04 mmol, 0.04-0.05 mmol, 0.05-0.06 mmol, 0.06-0.07 mmol, or approximately 0.07-0.08 mmol.)The daily dose can be administered for at least approximately 1 week, at least approximately 2 weeks, at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, at least approximately 6 weeks, at least approximately 7 weeks, at least approximately 8 weeks, at least approximately 9 weeks, at least approximately 10 weeks, at least approximately 11 weeks, at least approximately 12 weeks, at least 4 months, at least 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, at least 1.5 years, at least 2 years, at least approximately 3 years, at least approximately 4 years, at least approximately 5 years, at least approximately 10 years, at least approximately 20 years, or longer. In some embodiments, the daily dose can be administered for up to approximately 6 months, up to approximately 1 year, up to approximately 2 years, up to approximately 5 years, up to approximately 10 years, up to approximately 20 years, up to approximately 40 years, up to approximately 60 years, or up to approximately 90 years.

[0053] The dose of S,S-reboxetine can be gradually increased over time (e.g., over 1, 2, 3, 4, 5, 6, or 7 days) to a maintenance dose, which is the total daily dose (e.g., a 10 mg maintenance dose could be a 10 mg dose once daily, a 6 mg morning dose and a 4 mg afternoon dose, or a 5 mg dose twice daily for a total of 10 mg daily). In some implementations, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, about 14-17 mg, about 17-20 mg, about 8-10 mg, about 8-12 mg, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, or about 0.018-0.021 mmol. mmol, approximately 0.021-0.024 mmol, approximately 0.024-0.027 mmol, approximately 0.027-0.03 mmol, approximately 0.03-0.033 mmol, approximately 0.033-0.036 mmol, approximately 0.036-0.039 mmol, approximately 0.039-0.042 mmol, approximately 0.042-0.045 mmol, approximately 0.045-0.048 mmol, approximately 0.048-0.051 mmol, approximately 0.051-0.054 mmol, approximately 0.054-0.057 mmol, approximately 0.057-0.06 mmol, approximately 0.06-0.063 mmol, approximately 0.063-0.066 mmol, approximately 0.066-0.069 mmol, approximately 0.006-0.01 mmol, approximately 0.01-0.02 mmol, approximately 0.02-0.03 mmol, approximately 0.03-0.04 mmol, approximately 0.04-0.05 mmol, approximately 0.05-0.06 mmol, approximately 0.06-0.07 mmol, or approximately 0.07-0.08 mmol. In some embodiments, the first dose (e.g., administered in the morning) may contain more S,S-reboxetine than the second dose administered during the day (e.g., administered in the afternoon). For example, the first dose of the day (e.g., administered in the morning) may have 10%-20%, approximately 20%-30%, or approximately 30%-40% more S,S-reboxetine than the second dose of the day (e.g., administered in the afternoon).The maintenance dose may be administered for at least approximately 1 week, at least approximately 2 weeks, at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, at least approximately 6 weeks, at least approximately 7 weeks, at least approximately 8 weeks, at least approximately 9 weeks, at least approximately 10 weeks, at least approximately 11 weeks, at least approximately 12 weeks, at least 4 months, at least 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, at least 1.5 years, at least 2 years, at least approximately 3 years, at least approximately 4 years, at least approximately 5 years, at least approximately 10 years, at least approximately 20 years, or longer. In some embodiments, the maintenance dose may be administered for up to approximately 6 months, up to approximately 1 year, up to approximately 2 years, up to approximately 5 years, up to approximately 10 years, up to approximately 20 years, up to approximately 40 years, up to approximately 60 years, or up to approximately 90 years.

[0054] In some implementations, patients receive approximately 110-130 mg of S,S-reboxetine over a two-week period.

[0055] In some embodiments, the first releasing component provides immediate release of S,S-reboxine. In some embodiments, the first releasing component provides delayed release of S,S-reboxine. In some embodiments, the first releasing component provides sustained release of S,S-reboxine.

[0056] In some embodiments, the second releasing component provides immediate release of S,S-reboxine. In some embodiments, the second releasing component provides delayed release of S,S-reboxine. In some embodiments, the second releasing component provides sustained release of S,S-reboxine.

[0057] In some embodiments, the first releasing component provides immediate release of S,S-reboxine, and the second releasing component provides delayed release of S,S-reboxine. In some embodiments, the first releasing component provides immediate release of S,S-reboxine, and the second releasing component provides sustained release of S,S-reboxine.

[0058] Regarding the methods of administering S,S-reboxetine in both the first and second dosage forms containing S,S-reboxetine, any suitable amount of S,S-reboxetine may be present in the first dosage form, such as about 1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mg. mmol, approximately 0.006–0.009 mmol, approximately 0.009–0.012 mmol, approximately 0.012–0.015 mmol, approximately 0.015–0.018 mmol, approximately 0.018–0.021 mmol, approximately 0.021–0.024 mmol, approximately 0.024–0.027 mmol, approximately 0.027–0.03 mmol, approximately 0.03–0.033 mmol, or any amount within a range bounded by any of these values.

[0059] Regarding the methods of administering S,S-reboxetin in both a first dosage form and a second dosage form, any suitable amount of S,S-reboxetin may be present in the second dosage form, such as about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mg. mmol, approximately 0.006–0.009 mmol, approximately 0.009–0.012 mmol, approximately 0.012–0.015 mmol, approximately 0.015–0.018 mmol, approximately 0.018–0.021 mmol, approximately 0.021–0.024 mmol, approximately 0.024–0.027 mmol, approximately 0.027–0.03 mmol, approximately 0.03–0.033 mmol, or any amount within a range bounded by any of these values.

[0060] In some implementations, the first dosage form may contain more S,S-reboxetine than the second dosage form, such as about 10%-20%, about 20%-30%, or about 30%-40% more S,S-reboxetine than the second dosage form.

[0061] In some embodiments, the first dosage form provides immediate release of S,S-reboxine. In some embodiments, the first dosage form provides delayed release of S,S-reboxine. In some embodiments, the first dosage form provides sustained release of S,S-reboxine.

[0062] In some embodiments, the second dosage form provides immediate release of S,S-reboxetine. In some embodiments, the second dosage form provides delayed release of S,S-reboxetine. In some embodiments, the second dosage form provides sustained release of S,S-reboxetine.

[0063] Regarding a single dosage form containing both a first releasing component and a second releasing component, in some embodiments, a single dose is administered within two hours of waking from overnight sleep.

[0064] For some implementation schemes that administer more than one dosage form, the first dosage form may be administered within two hours of waking from overnight sleep.

[0065] Many factors can affect the total time required for a drug substance (such as S,S-reboxetine) to be completely absorbed and / or reach its maximum plasma concentration in a human body. Some of these factors include the human patient's age, weight, sex, stress level, gastric contents, gastric pH level, and the presence of other medications. The time required to reach the maximum plasma concentration of a drug (such as S,S-reboxetine) can also be affected by the time of day when the drug (such as S,S-reboxetine) is taken and the human patient's level of physical activity. Another factor that may affect the time required to reach the maximum plasma concentration of a drug (such as S,S-reboxetine) is the presence or absence of a controlled-release coating on the drug (such as S,S-reboxetine).

[0066] Controlled release includes: the immediate release of a drug substance (such as S,S-reboxetine) at a certain time or in a certain area of ​​the body; the delayed release of a drug substance; the sustained release of a drug substance at a certain time or in a certain place in the body; or the prolonged release of a drug substance (such as S,S-reboxetine).

[0067] S,S-reboxetine is typically rapidly absorbed in human patients, reaching peak plasma concentrations in approximately 2–4 hours. To delay the time required to reach peak plasma concentrations, controlled-release coatings or mixtures can be used.

[0068] Delayed release is a general term for drug delivery, describing an orally administered form of medicine in which the active pharmaceutical ingredient is not immediately expelled from the patient's mouth or stomach. While there are many ways to achieve delayed release, it can be achieved by completely or partially enveloping S,S-reboxetine (e.g., in a second release component) with a coating or layer that does not immediately dissolve upon swallowing (e.g., an internal controlled-release coating). For example, the material of the coating or layer may slowly dissolve in the stomach and / or slowly disintegrate in the stomach through a chemical reaction (e.g., by hydrolysis) until the layer is no longer able to prevent S,S-reboxetine from contacting gastric juices.

[0069] In some embodiments, the delayed-release coating ensures delivery to the intestines via the stomach. Once in the duodenum, the coating can begin to break down and release S,S-reboxetine. In some cases, S,S-reboxetine may be completely released in the duodenum. In some embodiments, S,S-reboxetine may be partially released in the duodenum and also partially released in the jejunum. In some cases, S,S-reboxetine may be completely released in the jejunum. In some cases, S,S-reboxetine may be partially released in the jejunum and also partially released in the ileum. In some cases, S,S-reboxetine may be completely released in the ileum. In some cases, S,S-reboxetine may be partially released in the duodenum, jejunum, and ileum. In some embodiments, S,S-reboxetine may be partially released in the ileum and also partially released in the colon. In some cases, S,S-reboxetine may be completely released in the colon.

[0070] The time of delayed release (e.g., between the release of the first S,S-reboxetine component and the second S,S-reboxetine component) can be adjusted by using materials that dissolve or disintegrate more slowly or faster in the digestive system, adjusting the thickness of the coating layer or coating material (e.g., a thicker layer will provide a longer release time), and / or by using materials with pH-sensitive properties. For example, materials that are less stable at acidic pH or more soluble at acidic pH can dissolve or disintegrate more quickly in the stomach because the stomach pH is lower than the intestinal pH. Conversely, materials that are stable at low pH but less stable at higher pH can dissolve or disintegrate more slowly because the dosage form requires time to pass through the gastrointestinal tract.

[0071] Controlled-release formulations containing S,S-reboxetine can be coated with one or more functional or non-functional coatings. Examples of functional coatings include controlled-release polymer coatings (i.e., controlled-release coatings), moisture-proof coatings, enteric polymer coatings, etc.

[0072] Depending on the formulation's structure, controlled-release polymers can be used for both sustained and delayed release. For example, dispersing S,S-reboxetine throughout a controlled-release polymer can provide sustained release because the drug is released as long as the polymer is present in the gastrointestinal tract. Delayed release can be achieved by creating a barrier (such as a coating) designed to last for a short time (e.g., less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) so that S,S-reboxetine is freely released when the barrier is breached. The delay time can be controlled using the barrier thickness.

[0073] Any suitable controlled-release polymer can be used, such as acrylic acid and methacrylic acid copolymers and their various esters, such as methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer.

[0074] Other suitable controlled-release polymers include polymerizable quaternary ammonium compounds, such as quaternized aminoalkyl esters and aminoalkylamides of acrylic acid and methacrylic acid, such as β-methacryloyloxyethyltrimethylmethylammonium sulfate, β-acryloyloxypropyltrimethylammonium chloride, and trimethylaminomethylmethacrylamide methyl sulfate. The quaternary ammonium atom can also be part of a heterocycle, such as in methacryloyloxyethylmethylmorpholinium chloride or the corresponding piperidinium salt, or it can be bonded to an acrylic acid group or a methacrylic acid group via a heteroatom-containing group (such as a polyglycol ether group). Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles, such as methyl-vinylpyridinium salts, quaternized vinyl esters of aminocarboxylic acids, styryltrialkylammonium salts, etc. Other polymerizable quaternary ammonium compounds include benzyl dimethylammonium ethyl methacrylate chloride, diethylmethylammonium ethyl methacrylate methyl sulfate and diethylmethylammonium ethyl methacrylate methyl sulfate, N-trimethylammonium propyl methacrylamide chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

[0075] Delayed release can also be achieved by using controlled-release polymers that target a specific pH, and it should be understood that, under appropriate fasting or eating conditions, the specific pH may correspond to a specific time after administration.

[0076] For some controlled-release polymers, acrylic or methacrylic acid polymers contain one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers (such as those from Evonik under the trademark EUDRAGIT) ®Those sold by RS and RL are fully polymerized copolymers of acrylates and methacrylates with low quaternary ammonium group content. Ammonium groups are attached to the ester portion of the methacrylate (e.g., 2-trimethylammonium-ethyl methacrylate). The charged ammonium groups in these polymers make them insoluble and highly permeable, exhibiting pH-independent swelling. These properties make these polymers suitable for customized timed release of coated drugs. To obtain a desired dissolution profile for a given therapeutic agent (e.g., S,S-reboxetine), two or more ammonium methacrylate copolymers with different physical properties can be incorporated. For example, it is known that the permeability characteristics of the resulting coating can be altered by changing the molar ratio of a prepolymer containing quaternary ammonium groups to a prepolymer containing uncharged neutral methacrylates or acrylates.

[0077] In other embodiments, the controlled-release coating further comprises a polymer with pH-dependent permeability, such as an anionic polymer synthesized from methacrylic acid and methyl methacrylate. Such polymers may be traded under the name EUDRAGIT. ® L and EUDRAGIT ® Purchased from S, for example, from Evonik. The ratio of free carboxyl groups to esters is known in EUDRAGIT. ® In L, the ratio is 1:1, and in EUDRAGIT ® The ratio in S is 1:2. EUDRAGIT ® L is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0. This makes EUDRAGIT... ® L is suitable for the targeted release of coated drug substances (such as coated S,S-reboxetine) in the duodenum and jejunum of the small intestine. Therefore, compared to uncoated or immediately released drug substances (e.g., S,S-reboxetine in the first-release component), EUDRAGIT ® L-coated drug substances can achieve a maximum plasma concentration delay of approximately 30 min to approximately 1 hour, approximately 1–1.5 hours, approximately 1.5–2 hours, approximately 2–2.5 hours, approximately 2.5–3 hours, or approximately 3.5–4 hours.

[0078] EUDRAGIT ® S and EUDRAGIT ® L is similar, but it becomes increasingly permeable above pH 7. This makes EUDRAGIT ® S is suitable for the targeted release of coated drug substances (such as coated S,S-reboxetine) in the ileum of the small intestine and the colon. Therefore, compared to uncoated or immediately released drug substances (e.g., S,S-reboxetine in the first-release component), EUDRAGIT ®S-coated drug substances can achieve a maximum plasma concentration delay of approximately 1-2 hours, approximately 2-3 hours, approximately 3-4 hours, approximately 4-5 hours, approximately 5-6 hours, approximately 6-7 hours, approximately 7-8 hours, approximately 8-9 hours, or approximately 9-10 hours.

[0079] Hydrophobic acrylic polymer coatings can also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylates (such as EUDRAGIT). ® E, available commercially from Evonik). EUDRAGIT ® E is insoluble in saliva (making it useful for masking tastes and odors), but soluble in gastric juices at pH 5 or lower, thus providing immediate release of the drug in the stomach. Following oral administration of the dosage form, administer EUDRAGIT at approximately 0–30 minutes, 30–60 minutes, 60–90 minutes, or 90–120 minutes, or at any time within the range bounded by any of these values. ® S,S-reboxetine encapsulated in E coating can release S,S-reboxetine, can begin releasing S,S-reboxetine, or can reach the first local maximum plasma concentration of S,S-reboxetine.

[0080] Hydrophobic acrylic polymer coatings can include neutral copolymers based on polymethacrylates, such as EUDRAGIT. ® NE (NE = neutral ester), commercially available from Evonik. EUDRAGIT ® The NE 30D lacquer film is insoluble in water and digestive fluids, but is permeable and swellable, thus providing another option for timed release. EUDRAGIT ® NE has a pH-independent sustained release effect, which can release drug substances (such as S,S-reboxetine) over a period of time or delay the release for a period of time, with the release or delay time being approximately 1-24 hours, approximately 1-18 hours, approximately 1-12 hours, approximately 1-8 hours, or approximately 1-6 hours.

[0081] In some embodiments, the controlled-release coating comprises a polymer containing ethyl acrylate and methyl methacrylate in a 2:1 ratio (KOLLICOAT). ® EMM 30 D, BASF). KOLLICOAT ® EMM 30 D has a pH-independent sustained-release effect, which can release drug substances (such as S,S-reboxetine) over a period of time or delay the release for a period of time, with the release or delay time being approximately 1-24 hours, approximately 1-18 hours, approximately 1-12 hours, approximately 1-8 hours, or approximately 1-6 hours.

[0082] In some implementations, the controlled-release coating comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate, such as KOLLICOAT. ® SR30D (BASF). The dissolution profile can be altered by changing the relative amounts of different acrylic resins contained in the coating. Furthermore, the permeability characteristics of the resulting coating (which affects the dissolution profile) can be changed by altering the molar ratio of a polymerizable permeability enhancer (e.g., a quaternary ammonium compound) to a neutral methacrylate. KOLLICOAT ® SR30D is another coating that has a pH-independent sustained release effect. It can release drug substances (such as S,S-reboxetine) over a period of time or delay the release for a period of time, with the release or delay time being approximately 1-24 hours, approximately 1-18 hours, approximately 1-12 hours, approximately 1-8 hours, approximately 1-6 hours, approximately 1-4 hours, or approximately 1-2 hours.

[0083] In some implementations, the controlled-release coating comprises ethyl cellulose, which can be used as a dry polymer dissolved in an organic solvent prior to use (e.g., ETHOCEL™, Dow Chemical Company) or as an aqueous dispersion. A suitable commercially available aqueous dispersion of ethyl cellulose is Aquacoat. ® (Danisco). Aquacoat ® ECD (Ethylcellulose Aqueous Dispersion), Aquacoat ® ARC (alcohol-resistant aqueous dispersion of ethyl cellulose) and Aquacoat ® CPD (cellulose acetate phthalate aqueous dispersion) are all commercially available controlled-release coatings. Another suitable aqueous dispersion of ethyl cellulose can be used as a sulfonate. ® Available commercially from Colorcon, Inc. This product can be prepared by incorporating a plasticizer into the dispersion during manufacturing. A hot melt mixture of a polymer, plasticizer (e.g., dibutyl sebacate), and stabilizer (e.g., oleic acid) can be prepared into a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion that can be applied directly to a substrate. These coatings have a pH-independent sustained-release effect, which can release a drug substance (such as S,S-reboxetine) over a period of time, or can delay release over a period of time, wherein the release or delay time is about 1–24 hours, about 1–18 hours, about 1–12 hours, about 1–8 hours, about 1–6 hours, about 1–4 hours, or about 1–2 hours.

[0084] Other examples of polymers that can be used in controlled-release coatings include cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based crosslinked polymers (where the degree of crosslinking is low to promote water adsorption and swelling of the polymer matrix), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, short-stalked polysaccharide, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose (a swellable hydrophilic polymer), poly(hydroxyalkyl methacrylate) (molecular weight from 5 kJ to 5000 kJ), polyvinylpyrrolidone (molecular weight from 10 kJ to 360 kJ). k), anionic and cationic hydrogels, zein, polyamides, polyvinyl alcohol with low acetic acid residue, swellable mixtures of agar and carboxymethyl cellulose, copolymers of maleic anhydride with styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, gum arabic, ark tar, astragalus gum, alginate and guar gum, polyacrylamide, POLYOX ® Polyethylene oxide (molecular weight from 100 k to 5000 k, Dow), AQUA KEEP ® Acrylic polymers (mainly composed of acrylic polymers and sodium salts), diesters of polydextrose, crosslinked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, methylethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pachymannan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithin, pectin, alginate, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar and gums (such as gum arabic, ebony gum, locust bean gum, astragalus gum, carrageenan, guar gum, xanthan gum, stearin) and mixtures and blends thereof.

[0085] In some embodiments, the dosage form of S,S-reboxetine is coated with a polymer to promote mucosal adhesion in the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucosal adhesion include carboxymethyl cellulose, polyacrylic acid, Carbopol™ (Lubrizol), polycarboxylic acid, gelatin, and other natural or synthetic polymers.

[0086] The polymer coating of this disclosure may be any one of the coatings, or a combination of two or more of the coatings, to achieve the desired release profile of S,S-reboxetine.

[0087] In addition to the modified-release dosage forms described herein, other modified-release technologies known to those skilled in the art can be used to realize the modified-release formulations of this disclosure, i.e., providing the average Ta of the drug described herein when administered to human patients (e.g., orally or via other routes of administration). max And / or other pharmacokinetic parameters of the formulation. Such formulations can be manufactured as modified-release oral formulations in the form of suitable tablets or multiparticle formulations known to those skilled in the art. In either case, the modified-release dosage form may optionally include a controlled-release carrier incorporated into the matrix together with the drug or used as a controlled-release coating.

[0088] Any dosage form containing an effective amount of S,S-reboxetine may further contain binders, lubricants, and other conventional inert excipients.

[0089] Binders (sometimes also called adhesives) can be added to drug-filler mixtures to increase the mechanical strength of granules and tablets during formation. Binders can be added to formulations in different ways: (1) as a dry powder, which is mixed with other ingredients prior to wet agglomeration; (2) as a solution, which is used as an agglomeration liquid during wet agglomeration and is called a solution binder; and (3) as a dry powder, which is mixed with other ingredients prior to compaction. Binders in this form are called dry binders. Solution binders are a common way to incorporate binders into granules. In some embodiments, the binder used in tablets is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin wax, higher fatty alcohols, higher fatty acids, long-chain fatty acids, fatty acid esters, waxy materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, common waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having a hydrocarbon backbone, and mixtures thereof. Specific examples of water-soluble polymeric binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol, and mixtures thereof. Any suitable amount of binder may be present, such as about 0.5%-5%, about 5%-10%, about 10%-15%, about 15%-20%, about 20%-25%, about 0.5%-25%, about 0.5%-15%, about 1%-6%, or about 3% based on the dry weight of the tablets. In some embodiments, the binder is polyvinyl alcohol.

[0090] Lubricants can be added to pharmaceutical formulations to reduce any friction that occurs between the solid and the mold wall during tablet manufacturing. High friction during tableting can lead to a range of problems, including substandard tablet quality (tablets cracking or even breaking during ejection, and vertical scratches on tablet edges), and may even halt production. Therefore, lubricants can be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, and hydrogenated vegetable oils (such as hydrogenated cottonseed oil). ® ), hydrogenated soybean oil (STEROTEX) ® HM) and hydrogenated soybean oil and castor wax (STEROTEX) ® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymers (e.g., can be trademarked CARBOWAX) ® (Originally from Union Carbide, Inc., Danbury, Connecticut), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearoyl fumarate, DL-leucine, colloidal silica, mixtures thereof, and other lubricants known in the art. In some embodiments, the lubricant is glyceryl behenate (e.g., COMPRITOL). ® 888). Any suitable amount of binder may be present, such as about 0.5%-5%, about 5%-10%, about 10%-15%, about 15%-20%, about 20%-25%, about 0.5%-25%, about 0.5%-15%, about 1%-6% or about 3% based on the dry weight of the tablets.

[0091] In some implementations, S,S-reboxetine is administered once or twice daily for at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, at least approximately 6 weeks, at least approximately 7 weeks, at least approximately 8 weeks, at least approximately 9 weeks, at least approximately 10 weeks, at least approximately 11 weeks, at least approximately 12 weeks, at least approximately 4 months, at least approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, at least 1.5 years, at least 2 years, at least approximately 3 years, at least approximately 4 years, at least approximately 5 years, approximately 0.1-5 years, approximately 5-10 years, at least approximately 10 years, approximately 10-15 years, at least approximately 15 years, approximately 15-20 years, at least approximately 20 years, or longer. In some implementations, S,S-reboxetine is administered for up to approximately 6 months, up to approximately 1 year, up to approximately 2 years, up to approximately 5 years, up to approximately 10 years, up to approximately 20 years, up to approximately 40 years, up to approximately 60 years, or up to approximately 90 years.

[0092] Without attempting to limit the scope of this disclosure, examples of useful compositions containing dosage forms of approximately 4-10 mg of S,S-reboxetine are shown in Table 1 below:

[0093] Table 1. Examples of Reboxetine Dosage Forms

[0094]

[0095] Treatment of fibromyalgia with S,S-reboxetine in the formulations described herein can be performed without the severe side effects associated with existing treatment options. Treatment of fibromyalgia with S,S-reboxetine in the formulations described herein is well tolerated in mammals, such as humans.

[0096] Some embodiments include a kit containing a pharmaceutical composition and instructions for using the pharmaceutical composition to treat fibromyalgia in humans, the pharmaceutical composition comprising one or more units of a dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units), one unit of which contains about 0.1-5 mg of S,S-reboxetine.

[0097] Some embodiments include a kit containing a pharmaceutical composition and instructions for using the pharmaceutical composition to treat fibromyalgia in humans, the pharmaceutical composition comprising one or more units of a dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units), one unit of which contains about 5-10 mg of S,S-reboxetine.

[0098] Some embodiments include a kit containing a pharmaceutical composition and instructions for using the pharmaceutical composition to treat fibromyalgia in humans, the pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units), one unit dosage form containing about 10-15 mg of S,S-reboxetine.

[0099] Some embodiments include a kit containing a pharmaceutical composition and instructions for using the pharmaceutical composition to treat fibromyalgia in humans, the pharmaceutical composition comprising one or more unit dosage forms (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units), one unit dosage form containing about 15-20 mg of S,S-reboxetine.

[0100] Some embodiments include a kit containing a pharmaceutical composition and instructions for using the pharmaceutical composition to treat fibromyalgia in humans, the pharmaceutical composition comprising one or more units of a dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units), one unit of which contains about 5-20 mg of S,S-reboxetine.

[0101] The following implementation plan was specifically considered.

[0102] Implementation Scheme 1. A method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 1 mg to about 10 mg for at least six weeks, wherein the person experiences a reduction in fibromyalgia pain during the treatment process that is greater than the reduction in pain that the person would experience with placebo, as measured by a visual analog scale (VAS) score.

[0103] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein about 4 mg to about 10 mg of oxprexetine is administered once daily.

[0104] Implementation Scheme 3. The method according to Implementation Scheme 1, wherein about 1 mg to about 2 mg of oxprexetine is administered once daily.

[0105] Implementation Scheme 4. The method according to Implementation Scheme 1, wherein about 0.5 mg to about 1 mg of oxprexetine is administered twice daily.

[0106] Implementation Scheme 5. The method according to Implementation Scheme 1, 2, 3, 4 or 5, wherein, after continuous daily administration of oxathine for six weeks, the VAS score of the person with fibromyalgia pain is reduced by at least 20% compared to the VAS score of the person with fibromyalgia pain prior to administration of the first dose of oxathine.

[0107] Implementation Scheme 6. The method according to Implementation Scheme 5, wherein, after continuous daily administration of oxoxetine for six weeks, the VAS score of the person's fibromyalgia pain is reduced by at least 50% compared to the VAS score of the person's fibromyalgia pain prior to the administration of the first dose of oxoxetine.

[0108] Implementation Scheme 7. A method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 2 mg to about 4 mg for at least six weeks, wherein the person experiences pain relief during the treatment process that is greater than the pain relief that the person would experience with placebo, as measured by a visual analog scale (VAS) score.

[0109] Implementation Scheme 8. The method according to Implementation Scheme 7, wherein about 1 mg to about 2 mg of oxprexetine is administered once daily.

[0110] Implementation Scheme 9. The method according to Implementation Scheme 7, wherein about 0.5 mg to about 1 mg of oxprexetine is administered twice daily.

[0111] Implementation Scheme 10. The method according to Implementation Scheme 7, 8 or 9, wherein, after six weeks of continuous daily administration of oxathine, the VAS score of the person with fibromyalgia pain is reduced by at least 20% compared to the VAS score of the person with fibromyalgia pain prior to the administration of the first dose of oxathine.

[0112] Implementation Scheme 11. The method according to Implementation Scheme 10, wherein, after continuous daily administration of oxathine for six weeks, the VAS score of the person's fibromyalgia pain is reduced by at least 50% compared to the VAS score of the person's fibromyalgia pain prior to the administration of the first dose of oxathine.

[0113] Implementation Scheme 12. A method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 0.5 mg to about 1 mg for at least six weeks, wherein the person experiences pain relief during the treatment process that is greater than the pain relief the person would experience with placebo, as measured by a visual analog scale (VAS) score.

[0114] Implementation Scheme 13. The method according to Implementation Scheme 12, wherein about 1 mg to about 2 mg of oxprexetine is administered once daily.

[0115] Implementation Scheme 14. The method according to Implementation Scheme 12, wherein about 0.5 mg to about 1 mg of oxprexetine is administered twice daily.

[0116] Implementation Scheme 15. The method according to Implementation Scheme 12, 13 or 14, wherein, after continuous daily administration of oxoxetine for six weeks, the VAS score of the person with fibromyalgia pain is reduced by at least 20% compared to the VAS score of the person with fibromyalgia pain prior to administration of the first dose of oxoxetine.

[0117] Implementation Scheme 16. The method according to Implementation Scheme 15, wherein, after continuous daily administration of oxoxetine for six weeks, the VAS score of the person's fibromyalgia pain is reduced by at least 50% compared to the VAS score of the person's fibromyalgia pain prior to the administration of the first dose of oxoxetine.

[0118] The U.S. Patent Application Publication No. 20210110809 (Serial No. 17 / 11,792, filed on November 20, 2021) of Tabeau, published on April 8, 2021, is incorporated herein by reference in its entirety.

[0119] Example 1

[0120] Currently, only three FDA-approved drugs are used to treat fibromyalgia. Real-world studies show that these drugs are frequently discontinued within 6 to 12 months of initiation, usually due to tolerability issues. This limits treatment options for patients with this debilitating condition. Oxyphenidyl is a novel, sustained-release, potent, and highly selective norepinephrine reuptake inhibitor in investigations for the treatment of fibromyalgia in adults. Here, we present the long-term safety profile of flexibly administered oxyphenidyl (4–10 mg) in patients with fibromyalgia enrolled in an open-label extension study following completion of a 14-week, phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial.

[0121] A total of 386 participants (93% female) were included in the safety cohort. The median treatment duration was 101 days (range 1–297), and 64 participants were treated for more than six months.

[0122] A total of 287 (74.4%) participants reported adverse events (AEs), and 47 (12.2%) discontinued the event due to AEs (all causes). The most common AEs (>10%) were dry mouth (15.0%), constipation (14.2%), nausea (12.2%), and insomnia (10.9%). Most AEs were mild to moderate in severity and consistent with the pharmacology of oxadiazine. Only 6 participants (1.6%) discontinued the event due to inadequate clinical response.

[0123] These data provide further support for the overall safety, tolerability, and continued clinical development of oxprexetine for the treatment of fibromyalgia (a patient population with significantly unmet medical needs).

[0124] Example 2

[0125] Several unmet needs exist in the treatment of fibromyalgia, including long-term efficacy. Oxyprexa is a sustained-release, potent, and highly selective norepinephrine reuptake inhibitor used in investigations for fibromyalgia. This open-label study evaluated the long-term treatment of flexibly administered oxyprexa (4–10 mg) in adult patients with fibromyalgia.

[0126] At baseline, all participants (N = 572; 91% female) scored ≥ 40 on the 100 mm Visual Analogue Scale (VAS) for Pain and met the 1990 American College of Rheumatology criteria for fibromyalgia. The median duration of treatment was 140 days; 265 participants received treatment for more than 6 months, and 77 received treatment for more than 1 year. Discontinuation due to adverse events (AEs) (all causes) occurred in 35.3% of participants, primarily in the early stages of treatment. The severity of AEs was mostly mild to moderate, and the most common (>10%) AEs were dry mouth, constipation, insomnia, headache, hyperhidrosis, nausea, and dizziness.

[0127] Pain improved at all time points. At week 2, the mean VAS score decreased to -10.2 (baseline score = 70.4). Further improvements were recorded with continued treatment: -15.8 (week 4; n = 447), -23.2 (week 8; n = 370), -28.6 (week 32; n = 242), and -31.2 (week 44; n = 143).

[0128] A similar trend of improvement was reported on the Fibromyalgia Impact Questionnaire (FIQ): the mean FIQ decreased to -18.27 at week 32.

[0129] These results demonstrate the efficacy and safety of oxoxetine in the treatment of fibromyalgia and support the continued development of oxoxetine as a promising treatment for fibromyalgia.

[0130] Unless otherwise indicated, all figures representing quantities, characteristics (such as amounts, percentages), etc., of the expressed components used in the specification and claims should in all cases be understood as indicating precise values ​​as shown and modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximate values ​​that may vary depending on the desired characteristic being sought. At least and without attempt to limit the application of the doctrine of equivalence to the claims, each numerical parameter should be interpreted at least based on the number of significant figures reported and by applying common rounding techniques.

[0131] Unless otherwise indicated herein or clearly contradicted by the context, the terms “a” and “an”, “described,” and similar pronouns used in the context of describing embodiments (especially in the context of the appended claims) should be interpreted as encompassing both the singular and plural. Unless otherwise indicated herein or clearly contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., “such”) provided herein is intended only to better illustrate the embodiments and does not constitute a limitation on the scope of any claim. No language in this specification should be construed as indicating that any unclaimed element is necessary for the practice of the claims.

[0132] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of the group or other elements found herein. For convenience and / or to expedite the application process, it is contemplated that one or more members of a group may be included in or removed from the group. When any such inclusion or removal occurs, this specification shall be deemed to include the modified group, thereby satisfying the written description of all Markush groups if used in the appended claims.

[0133] This document describes certain embodiments, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these embodiments will be apparent to those skilled in the art after reading the foregoing description. The inventors anticipate that those skilled in the art can employ such variations as needed, and that the claimed embodiments can be practiced in ways other than those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Furthermore, any combination of the foregoing elements in all possible variations is contemplated unless otherwise indicated herein or clearly contradicted by the context.

[0134] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative embodiments may be used in accordance with the teachings of this document, by way of example rather than limitation. Thus, the claims are not precisely limited to the embodiments shown and described.

Claims

1. A method for treating fibromyalgia, the method comprising administering approximately 4 mg to approximately 10 mg of oxprexetine daily to a person suffering from fibromyalgia who has a visual analogue pain scale score of at least about 40 nm on a 100 nm scale.

2. The method of claim 1, wherein the oxprexetine is administered daily for at least 6 months.

3. The method of claim 1, wherein the oxprexetine is administered daily for at least one year.

4. A method for treating fibromyalgia, the method comprising administering oxprexetine to a person in need, wherein the administration of oxprexetine at a daily dose of about 0.5 mg to about 4 mg for at least six weeks, wherein the person experiences pain relief during the treatment process that is greater than the pain relief the person would experience with placebo, as measured by a visual analog scale (VAS) score.

5. A pharmaceutical composition comprising oxadiazine according to claim 1, wherein the pharmaceutical composition comprises oxadiazine and a pharmaceutically acceptable excipient.

6. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein a pharmaceutically acceptable excipient comprises hydroxypropyl methylcellulose.

7. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein a pharmaceutically acceptable excipient comprises microcrystalline cellulose.

8. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein a pharmaceutically acceptable excipient comprises starch.

9. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein a pharmaceutically acceptable excipient comprises colloidal silica.

10. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein a pharmaceutically acceptable excipient comprises magnesium stearate.

11. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein pharmaceutically acceptable excipients include microcrystalline cellulose, starch, and hydroxypropyl methylcellulose.

12. A pharmaceutical composition comprising oxprexetine according to claim 1, wherein pharmaceutically acceptable excipients include magnesium stearate and colloidal silica.

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