Pharmaceutical composition containing leboxetine

Abstract

This invention provides a pharmaceutical composition for a method of treating narcolepsy accompanied by cataplexy. [Solution] A pharmaceutical composition is provided for a method of treating narcolepsy with cataplexy, comprising administering a pharmaceutical composition containing reboxetine and hydroxypropyl methylcellulose once daily to a person who requires treatment for narcolepsy with cataplexy.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 745,956, filed Oct. 15, 2018, and all of the content described in the provisional application is incorporated herein by reference.

Background Art

[0002] Narcolepsy is a severe and highly disabling neurological condition that causes a disruption in the regulation of the sleep - wake cycle, characterized clinically by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nighttime sleep. Narcolepsy is estimated to affect approximately 185,000 people in the United States. Cataplexy is seen in an estimated 70% of narcolepsy patients and typically causes a sudden decrease or loss of muscle tone while the patient is awake, usually triggered by strong emotions such as laughter, fear, anger, stress, or excitement. Type 1 narcolepsy includes cataplexy, while type 2 narcolepsy does not. Narcolepsy causes cognitive, psychological, and social dysfunction, increases the risk of accidents related to work and driving, and has a mortality rate 1.5 times higher. Depression symptoms are reported in approximately 57% of patients. Nearly 200,000 patients in the United States suffering from this disorder are debilitated by narcolepsy. Narcolepsy causes mental and social dysfunction, increases accidents related to work and driving, and has a mortality rate that is nearly twice as high. Unfortunately, due to under - diagnosis of rare diseases, there are few approved treatments, which are limited by variability in patient - to - patient effects, tolerability issues, and the need for DEA scheduling management.

Summary of the Invention

Means for Solving the Problems

[0003] This specification describes a method for treating narcolepsy with cataplexy, comprising administering reboxetine to a person in need of treatment for narcolepsy with cataplexy.

[0004] Some embodiments include the use of reboxetine in the manufacture of pharmaceuticals for the treatment of narcolepsy with cataplexy.

[0005] Some embodiments include a kit comprising a pharmaceutical composition containing reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0006] In some embodiments, reboxetine is administered at least once daily for at least three weeks. In some embodiments, within three weeks of the start of treatment, as a result of treatment, humans showed a reduction in the number of cataplexy attacks per week, a decrease in the Epworth sleepiness scale score, or a decrease in the sustained alertness test score. [Modes for carrying out the invention]

[0007] Reboxetine may improve the symptoms of narcolepsy and is not listed as a drug for scheduled management under the DEA (Dementia of Arbitration for Aid), which would be a significant benefit for patients with narcolepsy.

[0008] A person may have type 1 narcolepsy if they meet criteria A and B. A. I have been experiencing symptoms such as feeling uncontrollably sleepy every day or napping during the day for more than three months. B. Having one or both of the following symptoms: 1. The patient has cataplexy (as defined in Essential Features), a mean sleep latency of less than 8 minutes on a standardized multiple sleep latency test (MSLT), and at least two or more initial REM sleep periods (SOREMP). A SOREMP from a preceding laboratory-based polysomnography (PSG) within 15 minutes of falling asleep may substitute for one of the two or more SOREMPs on the MSLT. 2. The CSF hypocretin-1 concentration measured by immunoassay is less than 110 pg / mL, or less than one-third of the average value for healthy individuals using the same measurement method.

[0009] In infants with narcolepsy, nighttime sleep duration may become excessively long, or previously interrupted daytime naps may resume. Furthermore, if type 1 narcolepsy is strongly suspected clinically but criteria B2 are not met, repeated MSLT (Multiple Stress Test) may be considered as a possible strategy.

[0010] Patients receiving reboxetine treatment may experience daily, unbearable sleepiness and daytime napping for at least approximately 3 months, 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 approximately 13 months, at least approximately 14 months, at least approximately 15 months, at least approximately 16 months, at least approximately 17 months, at least approximately 18 months, at least approximately 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 15 years, at least approximately 20 years, at least approximately 25 years, at least approximately 30 years, at least approximately 40 years, or at least approximately 50 years. This may include patients whose condition lasts for at least approximately 60 years, approximately 3 to 9 months, approximately 9 to 18 months, approximately 18 months to 2 years, approximately 2 to 5 years, approximately 5 to 10 years, approximately 10 to 15 years, approximately 15 to 20 years, approximately 20 to 25 years, approximately 25 to 30 years, approximately 30 to 35 years, approximately 35 to 40 years, approximately 40 to 50 years, approximately 50 to 60 years, or longer, or patients selected for such conditions.

[0011] Patients receiving reboxetine treatment may include those with an average sleep latency of less than approximately 1 minute, less than 2 minutes, less than 3 minutes, less than 4 minutes, less than 5 minutes, less than 6 minutes, less than 7 minutes, less than 8 minutes, approximately 0.1 to 1 minute, approximately 1 to 2 minutes, approximately 2 to 3 minutes, approximately 3 to 4 minutes, approximately 4 to 5 minutes, approximately 5 to 6 minutes, approximately 6 to 7 minutes, approximately 7 to 8 minutes, approximately 1 minute, approximately 2 minutes, approximately 3 minutes, approximately 4 minutes, approximately 5 minutes, approximately 6 minutes, approximately 7 minutes, or approximately 8 minutes, or patients selected for such symptoms.

[0012] Patients receiving reboxetine treatment may include those who have at least two, at least three, or at least four SOREMPs in a standardized MSLT (Multiple Sleep Latency Test), or those selected based on such test results. A SOREMP occurring within 15 minutes of sleep onset in the preceding nocturnal PSG may be replaced by one of at least two SOREMPs in the MSLT.

[0013] Patients receiving reboxetine treatment may include those with CSF hypocretin-1 concentrations measured by immunoassay of approximately 40 pg / mL, 50 pg / mL, 60 pg / mL, 70 pg / mL, 80 pg / mL, 90 pg / mL, 100 pg / mL, or 110 pg / mL, or those selected for such conditions.

[0014] Patients receiving reboxetine treatment may include those whose CSF hypocretin-1 concentration, as measured by immune response, is less than approximately 1 / 10, 1 / 9, 1 / 8, 1 / 7, 1 / 6, 1 / 5, 1 / 4, or 1 / 3 of the average value for healthy individuals using the same measurement method, or patients selected for such symptoms.

[0015] Patients receiving reboxetine treatment may include infants with excessive nighttime sleep duration as a symptom, or patients selected for such symptoms.

[0016] Patients receiving reboxetine treatment may include infants whose naps, which were previously interrupted, have resumed, or patients selected for such symptoms.

[0017] Patients receiving reboxetine treatment may include patients whose cataplexy subscore on the Uranium Narcolepsy Scale (UNS) is at least 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, at least about 10, about 11, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 10-11, about 2-4, about 4-6, about 6-8, about 8-10, about 2-6, or about 6-10, or any number between 1 and 11, or patients selected for such symptoms.

[0018] Patients receiving reboxetine treatment should have an Epworth Sleepiness Scale (ESS) score of approximately 10 or higher, approximately 11 or higher, approximately 12 or higher, approximately 13 or higher, approximately 14 or higher, approximately 15 or higher, approximately 16 or higher, approximately 17 or higher, approximately 18 or higher, approximately 19 or higher, at least approximately 20, at least approximately 21, at least approximately 22, at least approximately 23, at least approximately 24, approximately 10-11, approximately 11-12, approximately 1 This may include patients with scores of 2-13, approximately 13-14, approximately 14-15, approximately 15-16, approximately 16-17, approximately 17-18, approximately 18-19, approximately 19-20, approximately 20-21, approximately 21-22, approximately 22-23, approximately 23-24, approximately 10-13, approximately 13-16, approximately 16-19, approximately 19-22, or approximately 22-24, or patients selected for such symptoms.

[0019] For patients receiving reboxetine treatment, the Maintenance of Awareness Test (MWT) score should be approximately less than 1 minute, less than 2 minutes, less than 3 minutes, less than 4 minutes, less than 5 minutes, less than 6 minutes, less than 7 minutes, less than 8 minutes, less than 9 minutes, less than 10 minutes, less than 11 minutes, less than 12 minutes, less than 13 minutes, less than 14 minutes, less than 15 minutes, less than 16 minutes, or less than 17 minutes. This may include patients whose duration is less than approximately 18 minutes, less than approximately 19 minutes, less than approximately 20 minutes, approximately 0-1 minute, approximately 1-2 minutes, approximately 2-3 minutes, approximately 3-4 minutes, approximately 4-5 minutes, approximately 5-6 minutes, approximately 6-7 minutes, approximately 7-8 minutes, approximately 8-9 minutes, approximately 9-10 minutes, approximately 10-11 minutes, approximately 11-12 minutes, approximately 12-13 minutes, approximately 13-14 minutes, approximately 14-15 minutes, approximately 15-16 minutes, approximately 16-17 minutes, approximately 17-18 minutes, approximately 18-19 minutes, approximately 19-20 minutes, approximately 0-4 minutes, approximately 4-8 minutes, approximately 8-12 minutes, approximately 12-16 minutes, approximately 16-20 minutes, or approximately 0-19 minutes, or patients selected for such symptoms.

[0020] In some embodiments, patients may include those who have had symptoms of narcolepsy for approximately 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 75 years or more prior to receiving reboxetine treatment, or patients selected for such symptoms.

[0021] In some embodiments, patients may include patients who are approximately 0–5 years old, approximately 5–10 years old, approximately 10–15 years old, approximately 15–20 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 75 years of age or older, or patients selected for such conditions, prior to receiving reboxetine treatment.

[0022] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include female patients or patients who have chosen to be female.

[0023] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include male patients or patients who have chosen to be male.

[0024] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with clinically significant symptoms that could be a potential cause of EDS, or patients who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with clinically significant mental disorders, or patients who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with any type of depression not caused by narcolepsy, or patients who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with drowsiness due to depression not caused by narcolepsy, or patients who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit affective disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit psychiatric disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit brain dysfunction, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit motor dysfunction, or who have been selected for not exhibiting such symptoms.Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present dementia, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present motor neuron disease, or patients selected for not presenting such symptoms.

[0025] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present neurodegenerative diseases, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present episodic diseases, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present headache, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present depression, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present major depression, or patients selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present treatment-resistant depression, or patients selected for not presenting such symptoms.

[0026] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present treatment-resistant bipolar depression, or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present bipolar disorder, or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present cyclothymia, or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present seasonal affective disorder, or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present mood disorder, or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present chronic depression (e.g., dysthymia), or who have been selected for not presenting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present psychotic depression, or who have been selected for not presenting such symptoms.

[0027] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit postpartum depression, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit premenstrual dysphoric disorder (PMDD), or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit situational depression, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit atypical depression, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit manic episodes, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit anxiety disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit attention deficit disorder (ADD), or who have been selected for not exhibiting such symptoms.

[0028] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit attention deficit hyperactivity disorder (ADHD), or patients selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit attention deficit hyperactivity disorder (ADHD), or patients selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit manic episodes, or patients selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit obsessive-compulsive disorder, or patients selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit bulimia or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit obesity or weight gain or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit chronic fatigue syndrome or who have been selected for not exhibiting such symptoms.

[0029] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit premenstrual syndrome (PMS) or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit drug dependence or abuse or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit nicotine dependence or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit psychosexual dysfunction or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit emotional dysregulation, or who have been selected for not exhibiting such symptoms.

[0030] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit anxiety disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit phobias, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit generalized anxiety disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit social anxiety disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit panic disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit agoraphobia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit obsessive-compulsive disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit post-traumatic stress disorder (PTSD), or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit manic episodes, or who have been selected for not exhibiting such symptoms.

[0031] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit manic-depressive illness, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit hypomanic episodes, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit unipolar depression, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit stress disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit somatoform disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit personality disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit psychosis, or who have been selected for not exhibiting such symptoms.

[0032] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit schizophrenia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit delusional disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit schizoaffective disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit schizophrenic tendencies, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit aggression, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit aggression due to Alzheimer's disease, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit restlessness, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit restlessness due to Alzheimer's disease, or who have been selected for not exhibiting such symptoms.

[0033] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit drug dependence, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit cocaine dependence, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to stimulants, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to crack, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to cocaine, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to speed, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit dependence to methamphetamine, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to nicotine, or who have been selected for not exhibiting such symptoms.

[0034] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to alcohol, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to opioids, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to anxiolytics and / or hypnotics, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to cannabis (marijuana), or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to amphetamines, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to hallucinogens, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit addiction or dependence to phencyclidine, or who have been selected for not exhibiting such symptoms.

[0035] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit toxicity or dependence to volatile solvents, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit toxicity or dependence to volatile nitrites, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit senile dementia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Alzheimer's disease, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit memory loss, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit amnesia / amnesic syndrome, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit epilepsy, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit impaired consciousness, or who have been selected for not exhibiting such symptoms.

[0036] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit comatose states, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit impaired attention, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit speech disorders, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit vocal spasms, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Parkinson's disease, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Lennox-Gastaut syndrome, or who have been selected for not having such symptoms.

[0037] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit autism, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit hyperactivity disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit schizophrenia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit stroke, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with cerebral infarction, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with cerebral hemorrhage, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with cerebral arteriosclerosis, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with cerebral venous thrombosis, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with head trauma, or who have been selected for not presenting with such symptoms.

[0038] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit akinesia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit amorphosophical disorder, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit ataxia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit ballism, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit unilateral ballism, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit bradykinetics, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit cerebral palsy, or who have been selected for not exhibiting such symptoms.

[0039] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have chorea, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Huntington's disease, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have rheumatic chorea, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit sydenham chorea, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit motor impairment, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit late-onset motor impairment, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit dystonia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit blepharospasm, or who have been selected for not exhibiting such symptoms.

[0040] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit spasmodic torticollis, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit dopamine-responsive myotonia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit restless legs syndrome (RLS), or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit tremor, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit essential tremor, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Tourette syndrome, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Wilson's disease, or who have been selected for not exhibiting such symptoms.

[0041] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with vascular dementia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with Lewy body dementia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with mixed dementia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with frontotemporal dementia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Creutzfeldt-Jakob disease, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have normal pressure hydrocephalus, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Wernicke-Korsakoff syndrome, or who have been selected for not having such symptoms.

[0042] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Pick's disease, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have progressive bulbar palsy, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have primary lateral sclerosis (PLS), or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have progressive muscular atrophy, or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with post-polio syndrome (PPS), or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with spinal muscular atrophy (SMA), or who have been selected for not presenting with such symptoms.

[0043] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit spinal motor atrophy, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Tay-Sack disease, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Sandoff disease, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit hereditary spastic paraplegia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with Alzheimer's disease, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with prion-related disease, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with cerebellar ataxia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with spinocerebellar ataxia (SCA), or who have been selected for not presenting with such symptoms.

[0044] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with spinal muscular atrophy (SMA), or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with medullary muscular atrophy, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with Friedrich's ataxia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with Lewy body dementia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have multiple sclerosis (MS), or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have multiple system atrophy, or who have been selected for not having such symptoms.

[0045] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Shy-Drager syndrome, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit corticobasal degeneration, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit progressive supranuclear palsy, or who have been selected for not exhibiting such symptoms.

[0046] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Wilson's disease or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Menkes' disease or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have adrenoleukodystrophy or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have autosomal dominant cerebral arteriovenous disease (CADASIL) with subcortical infarction and leukoencephalopathy or who have been selected for not having such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit muscular atrophy, or who have been selected for not exhibiting such symptoms.

[0047] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with Charcot-Marie-Tooth disease (CMT), or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with familial spastic paraplegia, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with neurofibromatosis, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with olivopontin cerebellar atrophy or degeneration, or who have been selected for not presenting with such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit striatonigral degeneration, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Guillain-Barré syndrome, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit spastic paraplegia, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit epileptic seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit non-epileptic seizures, or who have been selected for not exhibiting such symptoms.Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit epilepsy, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit febrile seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit partial seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit simple partial seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Jacksonian seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit complex partial seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit persistent partial epilepsy, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit generalized seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit generalized tonic-clonic seizures, or who have been selected for not exhibiting such symptoms.Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit absence seizures, or who have been selected for treatment for not exhibiting such symptoms.

[0048] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit atonic seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit myoclonic seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit juvenile myoclonic seizures, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit infantile spasms, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit status epilepticus, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Rett syndrome, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit tinnitus, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit disturbances of consciousness, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit sexual dysfunction, or who have been selected for not exhibiting such symptoms.Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit dysphonia due to uncontrolled spasms of the laryngeal muscles, or patients who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit abductor muscle spasmodic dysphonia, or patients who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit adductor muscle spasmodic dysphonia, or patients who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit myotonic dysphonia, or patients who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit vocal cord tremor, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit diabetic neuropathy, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit chemotherapy-induced neurotoxicity, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit methotrexate neurotoxicity, or who have been selected for not exhibiting such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit stress urinary incontinence, or who have been selected for treatment for not exhibiting such symptoms.Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not experience urge urinary incontinence, or who have been selected for not experiencing such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not experience fecal incontinence, or who have been selected for not experiencing such symptoms. Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not experience erectile dysfunction, or who have been selected for not experiencing such symptoms.

[0049] Cataplexy is a sudden decrease or loss of muscle tone while a person is awake, and can affect specific parts of the body or the whole, including eyelids, head drooping, facial sagging and / or spasms, speech disorders, jaw weakness, weakness of the arms, shoulders or hands, and / or knee flexion and extension. Cataplexy can be an etiology of narcolepsy. Cataplexy can be triggered by strong emotions such as laughter, euphoria, surprise, and anger. In about 75% of cases, cataplexy occurs partially or locally and is usually short-lived. There is considerable variation in the incidence of cataplexy. Narcolepsy with cataplexy can lead to social helplessness and isolation.

[0050] Patients receiving reboxetine treatment may include those with narcolepsy (type 1) with cataplexy, an autoimmune disorder resulting in a deficiency of hypocretin (orexin)-producing neurons in the CNS, or those selected for such conditions. Hypocretin (orexin) is a neuroexcitatory peptide specifically present in the hypothalamus. Patients receiving reboxetine treatment for narcolepsy with cataplexy may include those predisposed to certain genetic markers, including human leukocyte antigen (HLADQB1 / 06:02) and / or T-cell receptor alpha variants, or those selected for such conditions. Patients receiving reboxetine treatment may include those who do not exhibit hypocretin neuron deficiency-related narcolepsy, or those selected for not exhibiting such conditions. Patients receiving reboxetine treatment may include those in genetically predisposed individuals whose narcolepsy is induced by seasonal streptococcal infection, H1N1 influenza, and / or H1N1 vaccination, or those selected for such conditions.

[0051] Existing treatments for narcolepsy only address a portion of the symptoms, have inconsistent effectiveness, and carry significant side effects. Furthermore, all existing treatments rely on controlled substances.

[0052] According to the FDA, "There is still a need for more effective and tolerable treatment options to improve patients' daily functioning" (The Voice of the Patient, A series of reports from the US Food and Drug Administration's (FDA's) Patient-Focused Drug Development Initiative, Narcolepsy, June 2014. p.25).

[0053] In some embodiments, for example, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), etc.), administration of reboxetine reduced daytime sleepiness by at least about 1%, at least about 5%, and at least about 1%. It may decrease by 0%, 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%.

[0054] In some embodiments, when administered reboxetine compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), cataplexy was reduced by at least about 1%, at least about 5%, at least about 10%, at least about 20%, and at least about 3%. It may decrease by 0%, 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%.

[0055] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced the number of cataplexy seizures by at least approximately 10%, 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%, and at least approximately 95%. %, approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, 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%, at least about once a week, at least about twice a week, at least about three times a week, at least about four times a week, at least about five times a week, at least about six times a week, at least about seven times a week, at least about eight times a week, at least about nine times a week, at least about ten times a week, at least about twelve times a week, at least fourteen times a week. At least about 16 times a week, at least about 18 times a week, at least about 20 times a week, at least about 22 times a week, at least about 24 times a week, at least about 26 times a week, at least about 28 times a week, at least about 30 times a week, at least about 40 times a week, at least about 50 times a week, about 1-2 times a week, about 2-3 times a week, about 3-4 times a week, about 4-5 times a week, about 5-6 times a week, about 6-7 times a week, about 7-8 times a week. The frequency may decrease to approximately 8-9 times per week, 9-10 times per week, 10-11 times per week, 11-12 times per week, 12-13 times per week, 13-14 times per week, 14-15 times per week, 15-16 times per week, 16-17 times per week, 17-18 times per week, 18-19 times per week, 19-20 times per week, 1-10 times per week, 10-20 times per week, 20-30 times per week, 30-40 times per week, 40-50 times per week, 50-60 times per week, or more.

[0056] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine resulted in ESS scores of at least approximately 10%, 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 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, approximately 50-60%, and 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%, at least approximately 1, at least approximately 2, at least approximately 3, at least approximately 4, at least approximately 5, at least approximately 6, at least approximately 7, at least approximately 8, at least approximately 9, at least approximately 10, at least approximately 11, at least approximately 12, at least approximately 13, at least approximately 14, at least approximately 15, at least approximately 16, at least approximately 17, at least approximately 18, at least approximately 19, at least approximately 20, at least approximately 21, at least approximately 22, at least approximately 23, approximately 24, approximately 1-2, approximately 2-3, approximately 3-4, approximately 4-5, approximately 5-6, approximately 6-7. It may decrease by approximately 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, 17-18, 18-19, 19-20, 20-21, 21-22, 22-23, 23-24, 1-4, 4-8, 8-12, 12-16, 16-20, 20-24, 1-12, or 12-24.

[0057] In some embodiments, when compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine resulted in MWT scores being at least approximately 10%, 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%, and at least approximately 20%. Also approximately 95%, approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, 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%, at least approximately 1 minute, at least approximately 2 minutes, at least approximately 3 minutes, at least approximately 4 minutes, at least approximately 5 minutes, at least approximately 6 minutes, at least approximately 7 minutes, at least approximately 8 minutes, at least approximately 9 minutes, at least approximately 10 minutes, at least approximately 11 minutes, at least approximately 12 minutes, at least approximately 13 minutes. At least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 12-1 It may decrease by 3 minutes, approximately 13-14 minutes, approximately 14-15 minutes, approximately 15-16 minutes, approximately 16-17 minutes, approximately 17-18 minutes, approximately 18-19 minutes, approximately 19-20 minutes, approximately 20-21 minutes, approximately 21-22 minutes, approximately 22-23 minutes, approximately 23-24 minutes, approximately 24-26 minutes, approximately 1-4 minutes, approximately 4-8 minutes, approximately 8-12 minutes, approximately 12-16 minutes, approximately 16-20 minutes, approximately 1-10 minutes, or approximately 10-20 minutes.

[0058] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine resulted in a cataplexy score in UNS of at least approximately 10%, at least approximately 20%, at least approximately 30%, at least approximately 40%, at least approximately 50%, at least approximately 60%, and at least approximately 40%. Also about 70%, at least about 80%, at least about 90%, at least about 95%, 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%, at least about 1, at least about 2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9. It may decrease by at least about 10, about 11, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4, about 4-6, about 6-8, about 8-10, about 10-11, about 2-6, or about 6-10, about 5-11.

[0059] In some embodiments, when administered reboxetine compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), sleep latency in MSLT was reduced by at least approximately 30%, 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 50-60%, approximately 60-70%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 50-75%, or approximately 75-100%, at least approximately 1 minute, at least approximately 2 minutes, at least approximately 3 minutes, at least approximately 4 minutes, at least approximately 5 minutes, and at least approximately 6 minutes. minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes It may increase by approximately 6-7 minutes, 7-8 minutes, 8-9 minutes, 9-10 minutes, 10-11 minutes, 11-12 minutes, 12-13 minutes, 13-14 minutes, 14-15 minutes, 15-16 minutes, 16-17 minutes, 17-18 minutes, 18-19 minutes, 19-20 minutes, 1-4 minutes, 4-8 minutes, 8-12 minutes, 12-16 minutes, 16-20 minutes, 1-10 minutes, or 10-20 minutes.

[0060] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced nightmares or unpleasant dreams (such as frequent nightmares and frequent unpleasant dreams) by at least about 1%, at least about 10%, at least about 20%, and less. Each may decrease by approximately 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, 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%.

[0061] In some embodiments, when administered reboxetine compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), hallucinations were reduced by at least about 1%, at least about 10%, at least about 20%, at least about 30%, and at least about It may decrease by 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 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%.

[0062] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced sleep paralysis by at least about 1%, at least about 10%, at least about 20%, at least about 30%, and at least about It may decrease by 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 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%.

[0063] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (such as methylphenidate, amphetamine), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine may reduce nocturnal sleep disturbances by at least about 1%, 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%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%.

[0064] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced narcolepsy-related incidents by at least approximately 1%, at least approximately 10%, at least approximately 20%, at least approximately 30%, and less than approximately 1%. It may decrease by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 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%.

[0065] In some embodiments, compared to baseline, placebo, or other suitable controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced narcolepsy-related injuries by at least approximately 1%, at least approximately 10%, at least approximately 20%, at least approximately 30%, and less than approximately 20%. It may decrease by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 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%.

[0066] In some embodiments, compared to baseline, placebo, or other appropriate controls (including stimulants (methylphenidate, amphetamine, etc.), modaphanil, almodaphanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.), administration of reboxetine reduced narcolepsy-related deaths by at least approximately 1%, at least approximately 10%, at least approximately 20%, at least approximately 30%, and less than approximately 20%. It may decrease by at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, 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%.

[0067] Reboxetine (structure shown in the diagram below) is a highly selective and potent norepinephrine reuptake inhibitor that may improve major symptoms of narcolepsy, such as cataplexy and EDS. Unlike existing treatments for narcolepsy, reboxetine is not a controlled substance. Therefore, treatment with reboxetine is not scheduled.

[0068] [ka]

[0069] Unless otherwise specified, when compounds such as reboxetine are referred to herein by structure, name, or other means, such references include pharmaceutically acceptable salts, free acids or free bases, alternative solid forms such as polymorphs, solvates, hydrates, tautomers, enantiomers, deuterium-modified compounds such as deuterium-modified reboxetine, or any chemical species that, under the conditions of use of the compound as described herein, can be rapidly converted to the compound described herein.

[0070] In some embodiments, leboxetine may be in the form of a salt, a free base, 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 (+)-leboxetine 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 (-)-leboxetine.

[0071] In the treatment of narcolepsy, reboxetine may be administered in a manner that yields 1) a first local maximum of reboxetine plasma concentration and 2) a second local maximum of reboxetine plasma concentration.

[0072] There are many potential methods of administering reboxetine in a manner that yield a first local maximum and a second local maximum of reboxetine plasma concentration. Local maximums as described herein refer to the maximum plasma concentration in an individual patient during a period of attention, and not necessarily C max No. The local maximum is C max It may be lower or the same. One potential way to administer reboxetine in a manner that yields a first local maximum and a second local maximum of reboxetine plasma concentration is to administer a first dosage form containing reboxetine, followed by a second dosage form containing reboxetine. These dosings are performed when the first and second local maximums of reboxetine plasma concentration are reached, respectively. For example, the second dosage form may be administered within half a day of the first dosage form administration, or, for example, approximately 1-8 hours, 8-12 hours, 2-6 hours, 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 1-3 hours, 2-4 hours, 3-5 hours, 4-6 hours, 5-7 hours, 6-8 hours, or 7-10 hours after the first dosage form administration, or at any time within any of these ranges.

[0073] In another method, a single dosage form containing a first-release component and a second-release component is administered. Both the first-release component and the second-release component contain reboxetine.

[0074] In some embodiments, a first dosage form administered on a given day, the only dosage form administered during that day, or the first of two or more dosage forms administered during the day, is administered immediately after waking up, for example, within approximately 3 hours, 2 hours, 1.5 hours, 1 hour, 30 minutes, or 15 minutes after waking up from nighttime sleep.

[0075] When a single dosage form containing a first-release component and a second-release component is administered on a given day, the first-release component may release reboxetine, initiate the release of reboxetine, or result in a first local maximum of reboxetine plasma concentration, and may occur approximately 0–30 minutes, approximately 30–60 minutes, approximately 60–90 minutes, or approximately 90–120 minutes after oral administration of the dosage form, or at any time within any of these ranges. The second releasing component may release reboxetine after the first releasing component has released reboxetine, or it may increase the reboxetine plasma concentration or the second local maximum of plasma concentration, which may be about 1 to 10 hours, about 2 to 6 hours, about 1 to 2 hours, about 2 to 3 hours, about 3 to 4 hours, about 4 to 5 hours, about 5 to 6 hours, about 6 to 7 hours, about 1 to 3 hours, about 2 to 4 hours, about 3 to 5 hours, about 4 to 6 hours, about 5 to 7 hours, about 6 to 8 hours, or about 7 to 10 hours after the first release of reboxetine from the first releasing component or the first local maximum of reboxetine plasma concentration, or any time within any of these ranges.

[0076] The first and second releasing components may be contained in a single dosage form (such as a tablet, capsule, capre, or oral lozenge). In one embodiment, the first releasing component is located in one of the outer layers of the dosage form, and the second releasing component is located in one of the inner layers of the same dosage form.

[0077] In another embodiment, the first release component is located in the first layer of the dosage form, and the second release component is located in the second layer of the same dosage form. The two layers are separate and may or may not be in contact with each other. In some embodiments, the two layers overlap and are physically bonded in a two-layer structure (e.g., the largest surfaces of the two layers are in contact with each other, or the two layers are thinner than the other two layers). In some embodiments, the two layers are located adjacent to each other and are physically bonded in a two-layer structure (e.g., the two layers are thicker than the other layers).

[0078] In another embodiment, the first and second releasing components may be separately composed of specific granules, particles, etc., and the first releasing component particles are configured to release reboxetine before the second releasing component particles release reboxetine, and both the first and second releasing component particles are combined together to form a single dosage form such as a capsule, tablet, capre, or oral blister, and the two releasing components may or may not be physically bound to each other.

[0079] In some embodiments, the first local maximum of reboxetine plasma concentration is reached approximately 1–30 minutes, 30–60 minutes, 1–2 hours, 2–3 hours, or 3–4 hours after administration of a single dosage form or the first dosage form, or at any time within any of these ranges. Generally, the second local maximum of reboxetine plasma concentration is reached within half a day of reaching the first local maximum of reboxetine plasma concentration, for example, approximately 1–10 hours, 1–2 hours, 2–6 hours, 2–3 hours, 3–4 hours, 4–5 hours, 5–6 hours, 6–7 hours, 7–8 hours, 1–3 hours, 2–4 hours, 3–5 hours, 4–6 hours, 5–7 hours, 6–8 hours, 7–10 hours, or at any time within any of these ranges.

[0080] In a dosage form containing a first-release component and a second-release component, the first-release component is associated with the first local maximum of reboxetine plasma concentration in that it releases reboxetine that contributes to the first local maximum of reboxetine plasma concentration. For example, because the first-release component can release reboxetine faster or more immediately than the second-release component, most of the reboxetine released from the first-release component that contributes to the first local maximum of reboxetine plasma concentration originates from the first-release component.

[0081] In a dosage form containing a first-release component and a second-release component, the second-release component is related to the first local maximum of reboxetine plasma concentration in that it releases reboxetine that contributes to the second local maximum of reboxetine plasma concentration. For example, when the reboxetine plasma concentration is decreasing after the first local maximum, the second-release component delays its own reboxetine release so that it releases a sufficient amount of reboxetine to increase the reboxetine plasma concentration again and reach the second local maximum of reboxetine plasma concentration.

[0082] In a dosage form containing a first-release component and a second-release component, the first-release component is released in any appropriate amount, for example, approximately 1-10 mg, approximately 0.1-2 mg, approximately 0.5-1.5 mg, approximately 1-2 mg, approximately 1.5-2.5 mg, approximately 2-3 mg, approximately 2.5-3.5 mg, approximately 3-4 mg, approximately 3.5-4.5 mg, approximately 4-5 mg, approximately 4.5-5.5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 1-3 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 4-6 mg, approximately 5-7 mg, approximately 7-10 mg It may contain mg, approximately 4 mg, approximately 5 mg, approximately 0.0003-0.006 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, or any amount of reboxetine within any of these ranges.

[0083] In a dosage form containing a first-release component and a second-release component, the second-release component is released in any appropriate amount, for example, approximately 0.1-2 mg, approximately 0.5-1.5 mg, approximately 1-3 mg, approximately 1-2 mg, approximately 1.5-2.5 mg, approximately 2-3 mg, approximately 2.5-3.5 mg, approximately 3-4 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 3.5-4.5 mg, approximately 4-5 mg, approximately 4.5-5.5 mg, approximately 5-6 mg, approximately 4-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 5-7 mg, approximately 7-10 mg, approximately It may contain 4 mg, approximately 5 mg, approximately 0.0003-0.006 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, or any amount of reboxetine within any of these ranges.

[0084] The dose of reboxetine may be gradually increased over a period of time such as 1, 2, 3, 4, 5, 6, or 7 days, until a maintenance dose is reached, which is the total daily dose (for example, a maintenance dose of 10 mg means a total daily dose of 10 mg, either administered once daily or twice daily at 5 mg doses). In some embodiments, the maintenance dose is 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 mg, approximately 14~17mg, approximately 17~20mg, approximately 0.006~0.009mmol, approximately 0.009~0.012mmol, approximately 0.012~0.015mmol, approximately 0.015~0.01 8mmol, approximately 0.018~0.021mmol, approximately 0.021~0.024mmol, approximately 0.024~0.027mmol, approximately 0.027~0.03mmol, approximately 0.03~0.033 mmol, approximately 0.033~0.036mmol, approximately 0.036~0.039mmol, approximately 0.039~0.042mmol, approximately 0.042~0.045mmol, approximately 0.045~0.0 48mmol, approximately 0.048~0.051mmol, approximately 0.051~0.054mmol, approximately 0.054~0.057mmol, approximately 0.057~0.06mmol, approximately 0.06~0.06 These are approximately 3 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 0.07–0.08 mmol.The maintenance dose is administered for 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 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 1.5 years, at least approximately 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.

[0085] In some embodiments, the first releasing component immediately releases reboxetine. In some embodiments, the first releasing component releases reboxetine with a delay. In some embodiments, the first releasing component releases reboxetine with a sustained release.

[0086] In some embodiments, the second releasing component immediately releases reboxetine. In some embodiments, the second releasing component delayed the release of reboxetine. In some embodiments, the second releasing component sustainedly releases reboxetine.

[0087] In some embodiments, the first releasing component immediately releases reboxetine, and the second releasing component releases reboxetine with a delay. In some embodiments, the first releasing component immediately releases reboxetine, and the second releasing component releases reboxetine in a sustained manner.

[0088] In a method in which reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any appropriate amount of reboxetine is, for example, 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 The first dosage form may contain ~6 mg, approximately 5~7 mg, approximately 7~10 mg, approximately 4 mg, approximately 5 mg, approximately 0.0003~0.006 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, or any amount within any of these ranges.

[0089] In a method in which reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any appropriate amount of reboxetine is, for example, 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 The second dosage form may contain approximately 5-7 mg, approximately 7-10 mg, approximately 4 mg, approximately 5 mg, approximately 0.0003-0.006 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, or any amount within any of these ranges.

[0090] In some embodiments, the first dosage form releases reboxetine immediately. In some embodiments, the first dosage form releases reboxetine with a delay. In some embodiments, the first dosage form releases reboxetine with a sustained release.

[0091] In some embodiments, the second dosage form releases reboxetine immediately. In some embodiments, the second dosage form releases reboxetine with a delay. In some embodiments, the second dosage form releases reboxetine with a sustained release.

[0092] In a single dosage form containing both a first-release component and a second-release component, in some embodiments, the single dosage form is administered within two hours of waking up from nighttime sleep.

[0093] In some embodiments in which two or more dosage forms are provided, the first dosage form may be administered within two hours of waking up from nighttime sleep.

[0094] Several factors influence the time it takes for drugs such as reboxetine to be fully absorbed by humans and / or reach their maximum plasma concentration. These factors include, for example, the patient's age, weight, sex, stress level, gastric contents, gastric pH, and the presence of other drug treatments. The time required to reach maximum plasma concentration with drugs such as reboxetine can also be influenced by the time of day the drug is taken and the patient's level of physical activity. Another factor that can affect the time to reach maximum plasma concentration with drugs such as reboxetine is the presence or absence of a release-controlled coating on the drug.

[0095] Release control methods include methods for immediately releasing drugs such as reboxetine at a specific time or to a specific site in the body, methods for delayed release of drugs, methods for sustained release of drugs at a specific time or to a specific site in the body, and methods for prolonged release of drugs such as reboxetine.

[0096] Reboxetine is typically absorbed rapidly in humans, reaching peak plasma concentrations in approximately 2–4 hours. To delay the time required to reach peak plasma concentrations, release-controlled coatings or mixtures may be employed.

[0097] Delayed release is a common drug delivery term referring to a form of oral medication that does not immediately release its active drug component in the patient's mouth and stomach. While there are many ways to achieve delayed release, the delayed release of reboxetine can be achieved by completely or partially covering reboxetine (e.g., the second-release component) with a coating or layer (e.g., an inner release-controlled coating) that does not dissolve immediately after ingestion. For example, the materials of the coating or layer may dissolve slowly in the stomach and / or slowly break down in the stomach through chemical reactions such as hydrolysis until the layer can no longer prevent reboxetine from coming into contact with gastric juices.

[0098] In some embodiments, a delayed-release coating ensures transport from the stomach to the intestines. Upon entering the duodenum, the coating breaks down, and reboxetine begins to be released. In some embodiments, reboxetine is completely released in the duodenum. In some embodiments, reboxetine is partially released in the duodenum and partially released in the jejunum. In some embodiments, reboxetine is completely released in the jejunum. In some embodiments, reboxetine is partially released in the jejunum and partially released in the ilium. In some embodiments, reboxetine is completely released in the intestines. In some embodiments, reboxetine is partially released in the duodenum, jejunum, and ilium. In some embodiments, reboxetine is partially released in the ilium and partially released in the large intestine. In some embodiments, reboxetine is completely released in the large intestine.

[0099] The delayed release time, for example, the time between the release of the first and second reboxetine components, can be adjusted by using raw materials that dissolve or decompose slowly, albeit to varying degrees, in the digestive system; by adjusting the thickness of the coating layer or coating material (e.g., a thicker layer provides a longer release time); and / or by using raw materials with pH-sensitive properties. For example, raw materials that are less stable at acidic pH or more soluble at acidic pH will dissolve or decompose more quickly in the stomach because the pH of the stomach is lower than that of the intestines. Conversely, raw materials that are stable at low pH but less stable at high pH will dissolve or decompose more slowly because the dosage form takes longer to pass through the digestive tract.

[0100] Regulated-release formulations containing 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 barrier coatings, and enteric polymer coatings.

[0101] Release-controlled polymers can be used for both sustained-release and delayed-release depending on the structure of the dosage form. For example, by dispersing reboxetine throughout the release-controlled polymer, sustained-release is possible because the drug is released as long as the polymer remains within the GI tube. Delayed release can be achieved by forming a barrier, such as a coating, intended for sustained release over a shorter time (e.g., less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.), allowing reboxetine to be freely released once the barrier has penetrated. The thickness of the barrier can be used to control the delay time.

[0102] As any suitable release-controlled polymer, for example, 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), glycidyl methacrylate copolymer, etc. may be used.

[0103] Other suitable release-controlled polymers include polymerizable quaternary ammonium compounds, such as quaternary aminoalkyl esters and aminoalkylamides of acrylic and methacrylic acids, e.g., β-methacryloxyethyltrimethylammonium methosulfate, β-acryloxypropyltrimethylammonium chloride, and trimethylaminomethylmethacrylamide methosulfate. The quaternary ammonium atom may also be part of a heterocycle, as in methacryloxyethylmethylmorpholinium chloride and the corresponding piperidinium salt, or it may be bonded to the acrylic or methacrylic acid group via a heteroatom-containing group such as a polyglycol ether group. Further preferred polymerizable quaternary ammonium compounds include quaternary vinyl-substituted nitrogen heterocycles such as methylvinylpyridinium salts, vinyl esters of quaternary aminocarboxylic acids, and styryltrialkylammonium salts. Other polymerizable quaternary ammonium compounds include benzyldimethylammonium ethyl methacrylate chloride, diethylmethylammonium methyl acrylate and methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

[0104] Delayed release can be achieved by using release-controlled polymers that target a specific pH, understanding that a specific pH corresponds to a specific time after administration, under appropriate feeding or fasting conditions.

[0105] In some controlled-release polymers, acrylic or methacrylic polymers contain one or more ammoniacete copolymers. Ammoniacete copolymers (such as those marketed by Evonik under the trademark "EUDRAGIT®" RS and RL) are complete polymerization copolymers of acrylic acid esters and methacrylic acid esters with a low quaternary ammonium group content. The ammonium group is added to the ester portion of methacrylic acid (e.g., 2-trimethylammonium-ethyl ester). The charged ammonium group in these polymers makes them insoluble and gives them pH-independent swellability and high water permeability. These properties make these polymers useful for customized, time-controlled release of coated drugs. To obtain a preferred release profile for a given therapeutically effective substance such as reboxetine, two or more ammoniacete copolymers with different physical properties may be included. For example, it is known that the moisture permeability properties of the resulting coating can be altered by changing the molar ratio of prepolymerization raw materials containing a neutral methacrylate or acrylic acid ester with respect to prepolymerization raw materials containing a quaternary ammonium group.

[0106] In other embodiments, controlled-release coatings further include pH-dependent permeability polymers, such as anionic polymers synthesized from methacrylic acid and methyl methacrylate esters. Such polymers are commercially available, for example, from Evonik under the trademark names EUDRAGIT®L and EUDRAGIT®S. The ratio of free carboxyl groups to esters is known to be 1:1 for EUDRAGIT®L and 1:2 for EUDRAGIT®S. EUDRAGIT®L is insoluble in acid and pure water, but its permeability increases above pH 5.0. For this reason, EUDRAGIT®L is suitable for releasing coated drug substances, such as coated reboxetine, into the duodenum and jejunum of the small intestine. Therefore, drug substances coated with EUDRAGIT® L can delay the arrival of maximum plasma concentration by approximately 30 minutes to 1 hour, 1 to 1.5 hours, 1.5 to 2 hours, 2 to 2.5 hours, 2.5 to 3 hours, or 3.5 to 4 hours, compared to uncoated drug substances or immediate-release drug substances (e.g., reboxetine in the first-release component).

[0107] EUDRAGIT® S is similar to EUDRAGIT® L, except that its permeability increases above pH 7. For this reason, EUDRAGIT® S is suitable for releasing coated drug substances, such as coated reboxetine, in the ileum and large intestine of the small intestine. Thus, drug substances coated with EUDRAGIT® S can delay the arrival of maximum plasma concentration by approximately 1-2 hours, 2-3 hours, 3-4 hours, 4-5 hours, 5-6 hours, 6-7 hours, 7-8 hours, 8-9 hours, or 9-10 hours compared to uncoated drug substances or immediate-release drug substances (e.g., reboxetine in the first-release component).

[0108] Hydrophobic acrylic polymer coatings also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylate esters (such as EUDRAGIT® E, commercially available from Evonik). EUDRAGIT® E is insoluble in saliva (this property is also effective for masking taste and odor) but soluble in gastric juice with a pH of 5 or less, so the drug is released immediately in the stomach. Reboxetine coated with EUDRAGIT® E will release reboxetine, begin releasing reboxetine, or reach a first local maximum of reboxetine plasma concentration approximately 0-30 minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after oral administration of the dosage form, or at any time within these ranges.

[0109] Hydrophobic acrylic polymer coatings include polymethacrylate-based neutral copolymers such as EUDRAGIT®NE (NE = neutral ester), commercially available from Evonik. EUDRAGIT®NE30D lacquer film is insoluble in water and digestive fluids but possesses permeability and swelling properties, offering another option for time-controlled release. EUDRAGIT®NE has a pH-independent sustained-release effect, allowing for the release of drug substances such as reboxetine over a period of time, or for a period of time when the release or delay can be approximately 1-24 hours, 1-18 hours, 1-12 hours, 1-8 hours, or 1-6 hours.

[0110] In some embodiments, the controlled-release coating comprises a polymer containing ethyl acrylate to methyl methacrylate in a 2:1 ratio (KOLLICOAT® EMM30D, BASF). KOLLICOAT® EMM30D has a pH-independent sustained-release effect and can release drug substances such as reboxetine over a period of time, or delay the release over a period of time, which is approximately 1 to 24 hours, 1 to 18 hours, 1 to 12 hours, 1 to 8 hours, or 1 to 6 hours.

[0111] In some embodiments, the controlled-release coatings include polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate, such as KOLLICOAT® SR30D (BASF). The dissolution profile can be modified by changing the relative amounts of different acrylic resin lacquers contained in the coating. The penetration properties of the resulting coating (which affect the dissolution profile) can also be modified by changing the molar ratio of polymerizable penetration enhancers (e.g., quaternary ammonium compounds) to neutral methacrylate esters. KOLLICOAT® SR30D has a pH-independent sustained-release effect and can release drug substances such as reboxetine over a period of time, or delay the release over a period of time, such as 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.

[0112] In some embodiments, the controlled-release coating contains ethylcellulose, which can be used as a dry polymer (such as ETHOCEL™ (Dow Chemical Company)) solubilized in an organic solvent before use, or as an aqueous dispersion. A preferred commercially available aqueous ethylcellulose dispersion is Aquacoat® (Danisco). Aquacoat® ECD (ethylcellulose aqueous dispersion), Aquacoat® ARC (alcohol-resistant aqueous ethylcellulose dispersion), and Aquacoat® CPD (cellulose acetate phthalate aqueous dispersion) are all commercially available controlled-release coating agents. Another preferred aqueous ethylcellulose dispersion is commercially available as Surelease® (Colorcon, Inc.). This product can be prepared by incorporating a plasticizer into the dispersion during the manufacturing process. A hot melt of the polymer, plasticizer (such as dibutyl sebacate), and stabilizer (such as oleic acid) can be mixed and prepared as a homogeneous mixture, which can then be diluted with an alkaline solution to obtain an aqueous dispersion, which can be directly applied to a substrate. These coatings have a pH-independent sustained-release effect, allowing drug substances such as reboxetine to be released over a period of time, or to be delayed for a period of time, with release or delay periods being approximately 1-24 hours, 1-18 hours, 1-12 hours, 1-8 hours, 1-6 hours, 1-4 hours, or 1-2 hours.

[0113] Other examples of polymers that can be used in controlled release coatings include cellulose acetate phthalate, cellulose acetate trimarate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethylcellulose, methylcellulose, ethylcellulose, gelatin, starch, cellulose-based crosslinked polymers with a low degree of crosslinking to facilitate water adsorption and polymer matrix expansion, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethylcellulose, (swellable hydrophilic polymer) poly (Hydroxyalkyl methacrylate) (molecular weight 5k~5000k), polyvinylpyrrolidone (molecular weight 10k~360k), anionic and cationic hydrogels, zein, polyamide, polyvinyl alcohol with low acetic acid content, swelling mixture of agar and carboxymethylcellulose, copolymer of maleic anhydride and styrene, ethylene, propylene, isobutylene, pectin (molecular weight 30k~300k), agar, polysaccharides such as acacia, karaya, tragacanth, algin, guar, polyacrylamide, POLYOX® polyethylene oxide (molecular weight 100k~5000k, manufactured by Dow), etc., AquaKeep® acrylate polymer (acrylic acid polymer, mainly composed of sodium salt), polyglucan diester, crosslinked polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose,This includes hydroxyethylcellulose, nitrocellulose, carboxymethylcellulose, cellulose ethers, methylethylcellulose, ethylhydroxyethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerin fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithin, pectin, alginates, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan gum, scleroglucan, and mixtures and blends thereof.

[0114] In some embodiments, the dosage form of reboxetine is coated with a polymer to promote mucosal adhesion within the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucosal adhesion include carboxymethylcellulose, polyacrylic acid, Carbopol® (Lubrizol), polycarbophil, gelatin, and other natural or synthetic polymers.

[0115] The polymer coating of this disclosure may be any one of the coatings described herein, or a combination of two or more of the coatings described herein, in order to achieve a desired release profile of reboxetine release.

[0116] In addition to the modified release formulations described herein, the modified release formulations disclosed herein, i.e., when administered to a human patient, for example, orally or by other means, the mean T of the drug and / or other pharmacokinetic parameters described herein. maxTo realize formulations that provide the desired effect, other modified release techniques known to those skilled in the art can be used. Such formulations can be manufactured as modified-release oral formulations of suitable tablets or multi-drug formulations known to those skilled in the art. In any case, the modified-release dosage form may optionally include a controlled-release carrier that is incorporated into the matrix with the drug or applied as a controlled-release coating.

[0117] Any dosage form containing an effective amount of reboxetine further includes binders, lubricants, and other conventional inactive excipients.

[0118] Binders (sometimes called adhesives) can be added to mixtures of drugs and fillers to increase the mechanical strength of granules or tablets during formulation. Binders can be added to formulations in various ways, including (1) as a dry powder, mixed with other components before wet granulation; (2) as a solution, used as a granulating solution during wet granulation; and (3) as a dry powder, mixed with other components before compression molding. In this form, the binder is called a dry binder. Solution binders are a common method of incorporating binders into granules. In certain embodiments, binders used in tablets are in the form of solution binders. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin, waxy substances such as higher aliphatic alcohols, higher aliphatic acids, long-chain fatty acids, fatty acid esters, fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, ordinary waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with hydrocarbon backbone, and mixtures thereof. Specific examples of water-soluble polymer 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, for example, about 0.5–5% by weight, about 5–10% by weight, about 10–15% by weight, about 15–20% by weight, about 20–25% by weight, about 0.5–25% by weight, about 0.5–15% by weight, about 1–6% by weight, or about 3% by weight of the dry weight of the tablet. In some embodiments, the binder is polyvinyl alcohol.

[0119] To reduce friction between the solid and the mold walls during tablet manufacturing, lubricants can be added to pharmaceutical formulations. High friction during tablet manufacturing can lead to a range of problems, including poor tablet quality (capping or fragmentation of tablets during ejection, and vertical scratches on the tablet edges), and can cause manufacturing stoppages. Therefore, lubricants may 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 (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM), and hydrogenated soybean oil & castor oil (STEROTEX® K)). This includes stearyl alcohol, leucine, polyethylene glycol (MW1450, preferably 4000 and above), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymer (e.g., available as registered trademark CARBOWAX® of UnionCarbide, Inc., registered trademark CARBOWAX® of Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, and mixtures thereof, as known in the art. In some embodiments, the lubricant is glyceryl behenate (e.g., COMPRITOL® 888). Any appropriate amount of binder may be included, for example, 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% of the dry weight of the tablet.

[0120] In some embodiments, reboxetine is administered once or twice daily for at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least 1.5 years, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, about 0.1 to 5 years, about 5 to 10 years, at least about 10 years, about 10 to 15 years, at least about 15 years, about 15 to 20 years, at least about 20 years or longer.

[0121] Without attempting to limit the scope of this disclosure, Table 1 below shows examples of compositions useful for dosage forms containing approximately 5 to 10 mg of reboxetine.

[0122] [Table 1]

[0123] Treatment of narcolepsy with cataplexy using the reboxetine formulation described herein may not involve the serious side effects associated with existing treatments. Treatment of narcolepsy with cataplexy using the reboxetine formulation described herein may be well-tolerated in mammals such as humans.

[0124] In some embodiments, a kit includes a pharmaceutical composition comprising one or more dosage forms (e.g., dosage forms of about 1 to 30, about 30 to 60, about 60 to 90, about 90 to 120, about 120 to 180, about 180 to 360, or about 360 to 720 units), wherein one unit of the dosage form contains reboxetine in an amount of about 0.1 to 5 mg, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0125] In some embodiments, a kit includes a pharmaceutical composition comprising one or more dosage forms (e.g., dosage forms of about 1 to 30, about 30 to 60, about 60 to 90, about 90 to 120, about 120 to 180, about 180 to 360, or about 360 to 720 units), wherein one unit of the dosage form comprises reboxetine in an amount of about 5 to 10 mg, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0126] In some embodiments, a kit includes a pharmaceutical composition comprising one or more dosage forms (e.g., dosage forms of about 1 to 30, about 30 to 60, about 60 to 90, about 90 to 120, about 120 to 180, about 180 to 360, or about 360 to 720 units), wherein one unit of the dosage form comprises reboxetine in an amount of about 10 to 15 mg, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0127] In some embodiments, a kit includes a pharmaceutical composition comprising one or more dosage forms (e.g., dosage forms of about 1 to 30, about 30 to 60, about 60 to 90, about 90 to 120, about 120 to 180, about 180 to 360, or about 360 to 720 units), wherein one unit of the dosage form comprises reboxetine in an amount of about 15 to 20 mg, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0128] In some embodiments, a kit includes a pharmaceutical composition comprising one or more dosage forms (e.g., dosage forms of about 1 to 30, about 30 to 60, about 60 to 90, about 90 to 120, about 120 to 180, about 180 to 360, or about 360 to 720 units), wherein one unit of the dosage form comprises reboxetine in an amount of about 5 to 20 mg, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in humans.

[0129] (Examples) (Example 1) A 40-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after starting treatment, the number of cataplexy episodes decreased by 10–30%.

[0130] (Example 2) A 20-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after starting treatment, the number of cataplexy episodes decreased by 30–60%.

[0131] (Example 3) A 60-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, the number of cataplexy episodes decreased by 60–100%.

[0132] (Example 4) A 50-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, her ESS score decreased by 10–30%.

[0133] (Example 5) A 25-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, the ESS score decreased by 30–60%.

[0134] (Example 6) A 47-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, her ESS score decreased by 60–100%.

[0135] (Example 7) A 19-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, the MWT score decreased by 10–30%.

[0136] (Example 8) A 42-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, her MWT score decreased by 30–60%.

[0137] (Example 9) A 33-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. One week after the start of treatment, the MWT score decreased by 60–100%.

[0138] (Example 10) A 54-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, the number of cataplexy episodes decreased by 10–30%.

[0139] (Example 11) A 27-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, the number of cataplexy episodes decreased by 30–60%.

[0140] (Example 12) A 52-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, the number of cataplexy episodes decreased by 60–100%.

[0141] (Example 13) A 66-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, her ESS score decreased by 10–30%.

[0142] (Example 14) A 34-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, the ESS score decreased by 30–60%.

[0143] (Example 15) A 35-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, her ESS score decreased by 60–100%.

[0144] (Example 16) A 19-year-old male was diagnosed with narcolepsy with cataplexy. The patient was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, the MWT score decreased by 10–30%.

[0145] (Example 17) A 70-year-old woman was diagnosed with narcolepsy with cataplexy. She was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, her MWT score decreased by 30–60%.

[0146] (Example 18) A 57-year-old male was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg at 8:00 AM and 5 mg at 1:00 PM for three weeks. The patient's cataplexy episode frequency, ESS score, and MWT score were measured and evaluated before treatment and weekly. Three weeks after the start of treatment, his MWT score decreased by 60–100%.

[0147] Unless otherwise stated, all figures used in the specification and claims to represent component amounts, quantities, and other properties, as well as percentages, should be understood in all cases to represent both the exact value as indicated and a value modified by the term "approximately." Therefore, unless otherwise stated, the numerical parameters described in the specification and the attached claims are approximations that may vary depending on the desired properties to be obtained. While the doctrine of equivalents is not limited to the claims, each numerical parameter should at least be interpreted as having been rounded using the usual rounding method, based on at least the number of significant figures recorded.

[0148] In the context describing this embodiment (particularly in the context of the following claims), the terms “a,” “an,” “the,” and similar reference terms are to be interpreted as covering both singular and plural forms unless otherwise stated herein or unless the context clearly contradicts them. All methods described herein can be performed in any appropriate order unless otherwise indicated herein or unless the context clearly contradicts them. The use of any examples or illustrative statements in this specification (e.g., “e.g., “etc.”) is solely for the purpose of further clarifying the embodiments and is not intended to limit them to any of the claims. Nothing described herein should be interpreted as indicating any element not described in the claims that is essential for the implementation of the claims.

[0149] The grouping of alternative elements or embodiments described herein should not be construed as limiting. Each group member may be referenced and described in the claims individually or in any combination with other members of that group or with elements described herein. For convenience and / or patentability, one or more members of a group may be included in or removed from a group. If such inclusion or removal occurs, this specification is considered to include the thus modified group and thus satisfies the description requirements of all Markush groups used in the appended claims.

[0150] Several embodiments are described herein, including the best mode for the inventors when carrying out the embodiments described herein. Naturally, variations of the embodiments described herein are obvious to those skilled in the art who have read the foregoing. The inventors expect that those skilled in the art will appropriately adopt such variations and intend that embodiments of the embodiments described herein other than those specifically described herein will be carried out. Therefore, the claims include all variations and equivalents of the subject matter described herein, to the extent permitted by applicable law. Furthermore, unless otherwise specified herein and in accordance with the context, any combination of the above elements is conceivable in all possible variations of the present invention.

[0151] Finally, the embodiments described herein should be understood as being for illustrative purposes only, illustrating the principles of the claims. Other possible modifications are also included within the claims. Therefore, alternative embodiments may be adopted, for example, in accordance with the teachings herein, but not limited thereto. Thus, the claims are not strictly limited to the embodiments presented and disclosed herein.

[0152] (Note) (Note 1) This includes administering reboxetine to a person who requires treatment for narcolepsy with cataplexy, Reboxetine is administered at least once a day for at least three weeks. Two weeks after the start of treatment, the results of the treatment reduce the number of cataplexy attacks per week, the Epworth Sleepiness Scale score, the cataplexy subscore of the Uranolina Narcolepsy Scale (UNS), or the Arousal Maintenance Test score in humans. Treatment methods for narcolepsy accompanied by cataplexy.

[0153] (Note 2) A method for using reboxetine in the manufacture of a pharmaceutical product for the treatment of narcolepsy with cataplexy, comprising administering reboxetine at least once a day for at least three weeks.

[0154] (Note 3) A pharmaceutical composition containing reboxetine, Instructions for use of the pharmaceutical composition for treating narcolepsy with cataplexy in humans, A kit that includes, Reboxetine is administered at least once a day for at least three weeks. kit.

[0155] (Note 4) Reboxetine is administered twice a day. The treatment method, method of use, or kit described in Appendix 1, 2, or 3, wherein the first dosage form is administered in the morning, and the second dosage form is administered approximately 2 to 6 hours later.

[0156] (Note 5) The treatment method, method of use, or kit described in Appendix 4, wherein the second dosage form is administered approximately 2 to 3 hours after the first dosage form.

[0157] (Note 6) The treatment method, method of use, or kit described in Appendix 4, wherein the second dosage form is administered approximately 3 to 4 hours after the first dosage form.

[0158] (Note 7) The treatment method, method of use, or kit described in Appendix 4, wherein the second dosage form is administered approximately 4 to 5 hours after the first dosage form.

[0159] (Note 8) The treatment method, method of use, or kit described in Appendix 4, wherein the second dosage form is administered approximately 5 to 6 hours after the first dosage form.

[0160] (Note 9) A single dosage form is administered daily. The single dosage form comprises a first-release component containing reboxetine and a second-release component containing reboxetine, The first released component results in a first local maximum of reboxetine plasma concentration, and the second released component results in a second local maximum of reboxetine plasma concentration. The treatment method, method of use, or kit described in Appendix 1, wherein the time to reach the first local maximum of the reboxetine plasma concentration is approximately 2 to approximately 6 hours before that of the second local maximum of the reboxetine plasma concentration.

[0161] (Note 10) The treatment method, method of use, or kit described in Appendix 9, wherein the second local maximum of the reboxetine plasma concentration is reached approximately 2 to 3 hours after the first local maximum of the reboxetine plasma concentration.

[0162] (Note 11) The treatment method, method of use, or kit described in Appendix 9, wherein the second local maximum of the reboxetine plasma concentration is reached approximately 3 to 4 hours after the first local maximum of the reboxetine plasma concentration.

[0163] (Note 12) The treatment method, method of use, or kit described in Appendix 9, wherein the second local maximum of the reboxetine plasma concentration is reached approximately 4 to 5 hours after the first local maximum of the reboxetine plasma concentration.

[0164] (Note 13) The treatment method, method of use, or kit described in Appendix 9, wherein the second local maximum of the reboxetine plasma concentration is reached approximately 5 to 6 hours after the first local maximum of the reboxetine plasma concentration.

[0165] (Note 14) A treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, selected for a person who does not suffer from depression.

[0166] (Note 15) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is kept constant at approximately 0.006 mmol to approximately 0.01 mmol.

[0167] (Note 16) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.01 mmol to approximately 0.02 mmol.

[0168] (Note 17) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.02 mmol to approximately 0.03 mmol.

[0169] (Note 18) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.03 mmol to approximately 0.04 mmol.

[0170] (Note 19) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.04 mmol to approximately 0.05 mmol.

[0171] (Note 20) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.05 mmol to approximately 0.06 mmol.

[0172] (Note 21) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.06 mmol to approximately 0.07 mmol.

[0173] (Note 22) The treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over 1 to 7 days, and thereafter the total daily dose is maintained constant at approximately 0.07 mmol to approximately 0.08 mmol.

[0174] (Note 23) A method of treatment, method of use, or kit as described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the dosage form contains reboxetine, and the dosage form contains approximately 5 mg of reboxetine.

[0175] (Note 24) A method of treatment, method of use, or kit as described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the dosage form contains reboxetine, and the dosage form contains approximately 10 mg of reboxetine.

[0176] (Note 25) The treatment method, method of use, or kit described in Appendix 23, wherein the dosage form is administered once or twice daily for at least three weeks.

[0177] (Note 26) The treatment method, method of use, or kit described in Appendix 24, wherein the dosage form is administered once or twice daily for at least three weeks.

[0178] (Note 27) A treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 that increases sleep latency in humans as measured by multiple sleep latency tests (MSLT).

[0179] (Note 28) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency by at least 10% in humans as measured by MSLT.

[0180] (Note 29) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency by at least 20% in humans as measured by MSLT.

[0181] (Note 30) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency by at least 30% in humans as measured by MSLT.

[0182] (Note 31) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency by at least 40% in humans as measured by MSLT.

[0183] (Note 32) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency by at least 50% in humans as measured by MSLT.

[0184] (Note 33) A treatment method, method of use, or kit described in Appendix 27 that increases sleep latency in MSLT by at least 60% in humans.

[0185] (Note 34) A treatment method, method of use, or kit described in Appendix 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 that reduces the cataplexy subscore on the UNS by at least 15% in humans.

[0186] (Note 35) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 20% in humans.

[0187] (Note 36) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 30% in humans.

[0188] (Note 37) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 40% in humans.

[0189] (Note 38) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 50% in humans.

[0190] (Note 39) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 60% in humans.

[0191] (Note 40) A treatment method, method of use, or kit described in Appendix 34 that reduces the cataplexy subscore on the UNS by at least 70% in humans.

[0192] (Note 41) A treatment method, method of use, or kit described in Appendix 34 for a human being with a cataplexy subscore of approximately 0.

Claims

1. A pharmaceutical composition comprising reboxetine or a pharmaceutically acceptable salt thereof for use in reducing the frequency of cataplexy attacks in humans with narcolepsy accompanied by cataplexy, The pharmaceutical composition is administered to a person in need once or twice daily for at least two weeks, with a total daily dose of reboxetine of approximately 4 mg to approximately 14 mg administered to the person, and for two weeks after the start of treatment, the person will, compared to baseline, 1) experience at least 7 fewer cataplexy attacks per week, and 2) experience at least 30% fewer cataplexy attacks. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein, starting on the 8th day of treatment, the person receives a total daily dose of reboxetine or a pharmaceutically acceptable salt thereof in a total dose of approximately 10 mg to approximately 14 mg.

3. The pharmaceutical composition according to claim 2, wherein the total daily dose of approximately 10 mg to approximately 14 mg is achieved by administering the pharmaceutical composition twice a day.

4. A pharmaceutical composition according to any one of claims 1 to 3, further comprising microcrystalline cellulose.

5. A pharmaceutical composition according to any one of claims 1 to 4, further comprising silicon dioxide.

6. A pharmaceutical composition according to any one of claims 1 to 5, further comprising magnesium stearate.

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