Pharmaceutical composition comprising reboxetine

Abstract

To provide a pharmaceutical composition for use in a method of treating narcolepsy with cataplexy.SOLUTION: The present invention provides a pharmaceutical composition for use in a method of treating narcolepsy with cataplexy, the method comprising administering the pharmaceutical composition once a day to a human being in need of treatment thereof, the pharmaceutical composition comprising reboxetine and hydroxypropyl methylcellulose.SELECTED DRAWING: None

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 October 15, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Narcolepsy is a serious and morbid neurological condition that causes dysregulation of the sleep-wake cycle and is characterized by excessive daytime sleepiness (EDS), cataplexy, hypnotic hallucinations, sleep paralysis, and nocturnal sleep disruption. Narcolepsy affects an estimated 185,000 people in the United States. Cataplexy, seen in an estimated 70% of narcolepsy patients, 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, but type 2 narcolepsy does not. Narcolepsy leads to cognitive, psychological, and social dysfunction, increases the risk of work- and driving-related accidents, and is associated with a 1.5-fold increase in mortality. Depressive symptoms are reported in approximately 57% of patients. Narcolepsy is debilitating for nearly 200,000 patients in the United States with this disorder. Narcolepsy causes mental and social dysfunction, increases work- and driving-related accidents, and is associated with a nearly two-fold higher mortality rate. Unfortunately, as an underdiagnosed and rare disease, there are few approved treatments, limited by patient-to-patient variability, tolerability issues, and the need for DEA scheduling. Summary of the Invention [Means for solving the problem]

[0003] Described herein are methods for treating narcolepsy with cataplexy, comprising administering reboxetine to a human in need of treatment for narcolepsy with cataplexy.

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

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

[0006] In some embodiments, reboxetine is administered at least once daily for at least three weeks. In some embodiments, after three weeks of treatment, the human experiences a decrease in the number of cataplexy attacks per week, a decrease in the Epworth Sleepiness Scale score, or a decrease in the Maintenance of Wakefulness Test score. DETAILED DESCRIPTION OF THE INVENTION

[0007] Reboxetine has the potential to improve the symptoms of narcolepsy and is not a DEA controlled substance, which is of great benefit to narcolepsy patients.

[0008] A person may have type 1 narcolepsy if they meet criteria A and B. A. You have been experiencing irresistible sleepiness every day or have been falling asleep during the day for more than three months. B. Having one or both of the following symptoms: 1. Cataplexy (as defined in the Essential Features) with a mean sleep latency of less than 8 minutes and two or more sleep-onset rapid eye movement periods (SOREMPs) on a standardized multiple sleep latency test (MSLT). A SOREMP (within 15 minutes of sleep onset) on a recent laboratory-based polysomnography (PSG) may be substituted for one of the two or more SOREMPs on the MSLT. 2. The CSF hypocretin-1 concentration measured by immune reaction is less than 110 pg / mL or less than one-third of the average value of healthy individuals measured by the same method.

[0009] In infants with narcolepsy, excessive nighttime sleep duration and resumption of previously interrupted daytime napping may occur, and repeated MSLT may be a viable strategy in cases where there is a strong clinical suspicion for type 1 narcolepsy but criterion B2 is not met.

[0010] Patients receiving reboxetine treatment experience daily irresistible sleepiness and daytime sleepiness for a duration of at least about 3 months, 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 about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 40 years, or at least about 50 years. This may include patients whose condition has persisted for at least about 60 years, about 3-9 months, about 9-18 months, about 18 months to 2 years, about 2-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-50 years, about 50-60 years, or longer, or patients selected for such conditions.

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

[0012] Patients receiving reboxetine treatment may include those with, or selected for, at least two, at least three, or at least four SOREMPs on a standardized MSLT (multiple sleep latency test). A SOREMP within 15 minutes of sleep onset on the previous night's PSG may replace one of at least two SOREMPs on the MSLT.

[0013] Patients receiving reboxetine treatment may include those with CSF hypocretin-1 concentrations of less than about 40 pg / mL, less than about 50 pg / mL, less than about 60 pg / mL, less than about 70 pg / mL, less than about 80 pg / mL, less than about 90 pg / mL, less than about 100 pg / mL, or less than about 110 pg / mL as measured by immunoreactivity, 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 about 1 / 10, less than about 1 / 9, less than about 1 / 8, less than about 1 / 7, less than about 1 / 6, less than about 1 / 5, less than about 1 / 4, or less than about 1 / 3 of the mean value in healthy individuals using the same assay, or patients selected for such symptoms.

[0015] Patients receiving reboxetine treatment may include young children whose symptom is excessive nighttime sleep duration, or patients selected for such a symptom.

[0016] Patients treated with reboxetine may include young children whose daytime naps have resumed after a previous interruption, or patients selected for such symptoms.

[0017] Patients receiving reboxetine treatment may include those with a cataplexy subscore on the Uranylunsine Narcolepsy Scale (UNS) of 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 1-11, or patients selected for such symptoms.

[0018] Patients receiving reboxetine treatment are expected to have an Epworth Sleepiness Scale (ESS) score of about 10 or more, about 11 or more, about 12 or more, about 13 or more, about 14 or more, about 15 or more, about 16 or more, about 17 or more, about 18 or more, about 19 or more, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, about 10-11, about 11-12, about 15-16, about 17-18, about 18-19, about 20-21, about 21-22, about 22-23, about 23-24, about 24-25, about 25-26, about 26-27, about 27-28, about 28-30, about 28-31, about 28-32, about 28-33, about 28-34, about 29-30, about 30-31, about 31-32, about 31-33, about 32-34, about 33-35, about 34-35, about 35-36, about 36-37, about 37-38, about 38-39, about 39-40, about 40-41, about 41-42, about 42-43, about 43-44, about 44-45, about 45-46, about 46-47, about 47-48, about 48-49, about 49-50, about 51-52, about 52-53, about 53-54, about 54-55, about 55-56, about 57-58, about 58-59, about 59 Patients scoring 2-13, about 13-14, about 14-15, about 15-16, about 16-17, about 17-18, about 18-19, about 19-20, about 20-21, about 21-22, about 22-23, about 23-24, about 10-13, about 13-16, about 16-19, about 19-22, or about 22-24, or patients selected for such symptoms, may be included.

[0019] Patients receiving reboxetine treatment had a Maintenance of Wakefulness Test (MWT) score of less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, less than about 9 minutes, less than about 10 minutes, less than about 11 minutes, less than about 12 minutes, less than about 13 minutes, less than about 14 minutes, less than about 15 minutes, less than about 16 minutes, or less than about 17 minutes. These may include patients whose blood pressure is less than about 18 minutes, less than about 19 minutes, less than about 20 minutes, about 0-1 minute, 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 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, or about 0-19 minutes, or patients selected for such symptoms.

[0020] In some embodiments, patients may include patients who have had symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, about 70-75 years, or more than 75 years prior to receiving reboxetine treatment, or patients selected for such symptoms.

[0021] In some embodiments, patients may include patients who, prior to receiving reboxetine treatment, were about 0-5 years old, about 5-10 years old, about 10-15 years old, about 15-20 years old, about 20-25 years old, about 25-30 years old, about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old, about 60-65 years old, about 65-70 years old, about 70-75 years old, or 75 years old or older, or patients selected for such conditions.

[0022] Patients receiving reboxetine treatment for narcolepsy (eg, with cataplexy and / or EDS) may include patients who are female or selected for being female.

[0023] Patients receiving reboxetine treatment for narcolepsy (eg, with cataplexy and / or EDS) may include patients who are male or selected for male identity.

[0024] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit clinically significant symptoms that could potentially cause EDS, 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 clinically significant psychiatric disorders, 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 any type of depression not caused by narcolepsy, 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 sleepiness due to depression not caused by narcolepsy, 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 affective disorders or who are 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 are 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 are 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 movement disorders or who are 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 dementia or who are 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 neuron disease or who are selected for not exhibiting such symptoms.

[0025] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit a neurodegenerative disease or who are 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 a seizure disorder or who are 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 headaches or who are 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 depression or who are 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 major depression or who are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit treatment-resistant depression or who are selected for not exhibiting such symptoms.

[0026] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit treatment-resistant bipolar depression or who are 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 bipolar disorder or who are 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 cyclothymia or who are 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 seasonal mood disorder or who are 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 mood disorders or who are 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 depression (e.g., dysthymia) or who are 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 psychotic depression or who are selected for not exhibiting 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 are 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 are 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 are 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 are 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 mania or who are 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 are 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 are 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 (ADDH) or who are 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 (AD / HD) or who are 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 states or who are 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 are 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 are 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 are 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 are 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 or who are 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 substance dependence or abuse or who are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit mania or who are 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 are 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 states or who are 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 stimulant addiction or dependence or who are 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 crack addiction or dependence or who are 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 on cocaine, or who are 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 on speed, or who are 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 on methamphetamine, or who are 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 on nicotine, or who are 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 on alcohol, or who are 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 on opioids, or who are 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 on anxiolytics and / or hypnotics, or who are 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 on cannabis (marijuana), or who are 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 on amphetamines or who are 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 on hallucinogens or who are 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 on phencyclidine or who are 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 addiction or dependence on volatile solvents or who are 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 on volatile nitrites or who are 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 are 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 dementia of the Alzheimer's type or who are 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 are 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 / amnestic syndrome or who are 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 are 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 are 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 coma or who are 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 deficits or who are 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 are 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 voice spasms or who are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Parkinson's disease or who are selected for not having such conditions.Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not have Lennox-Gastaut syndrome or who are selected for not having such conditions.

[0037] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit autism or who are 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 are 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 are 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 are 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 cerebral infarction or who are 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 cerebral hemorrhage or who are 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 cerebral arteriosclerosis or who are 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 cerebral venous thrombosis or who are selected for not having such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not present with head trauma or who are 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 are 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 are 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 are 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 ballismus or who are 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 hemiballismus or who are 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 bradykinesia or who are 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 are 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 exhibit chorea or who are 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 Huntington's disease or who are 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 rheumatic chorea or who are 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 Sydenham chorea or who are 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 movement disorders or who are 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 tardive dyskinesia or who are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit blepharospasm or who are 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 are 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 are 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 are 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 are 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 are 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's syndrome or who are 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 are 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 exhibit vascular dementia or who are 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 Lewy body dementia or who are 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 mixed dementia or who are 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 frontotemporal dementia or who are 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 Creutzfeldt-Jakob disease or who are 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 normal pressure hydrocephalus or who are 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 Wernicke-Korsakoff syndrome or who are selected for not exhibiting such symptoms.

[0042] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit Pick's disease or who are 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 bulbar palsy or who are 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 primary lateral sclerosis (PLS) or who are 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 muscular atrophy or who are 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-polio syndrome (PPS) or who are 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 spinal muscular atrophy (SMA) or who are selected for not exhibiting 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 are 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-Zach's disease or who are 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 Sandov's disease or who are 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 are 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 are 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 prion-related disease or who are 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 cerebellar ataxia or who are 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 spinocerebellar ataxia (SCA) or who are selected for not exhibiting such symptoms.

[0044] Patients receiving reboxetine treatment for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit spinal muscular atrophy (SMA) or who are 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 bulbar muscular atrophy or who are 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 Friedrich's ataxia or who are 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 Lewy body disease or who are 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 amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) or who are 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 are 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 are 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 are 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 are 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 are 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 exhibit Wilson's disease or who are 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 Menkes disease or who are 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 adrenoleukodystrophy or who are 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 autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or who are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit muscle atrophy or who are 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 exhibit Charcot-Marie-Tooth disease (CMT) or who are 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 familial spastic paraplegia or who are 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 neurofibromatosis or who are 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 olivopontine cerebellar atrophy or degeneration or who are 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 striatonigral degeneration or who are 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 are 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 are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit non-epileptic seizures or who are 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 are 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 are 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 are 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 are 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 are 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 are 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 epilepsy continuum or who are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit generalized tonic-clonic seizures or who are selected for not exhibiting such symptoms.Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit absence seizures or who are selected 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 are 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 are 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 are 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 are 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 are 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 are 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 are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit sexual dysfunction or who are 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 uncontrollable laryngeal muscle spasms or who are 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 spasmodic dysphonia or who are 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 spasmodic dysphonia or who are 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 who are 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 are 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 are 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 are 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 are selected for not exhibiting such symptoms. Patients treated with reboxetine for narcolepsy (e.g., with cataplexy and / or EDS) may include patients who do not exhibit stress urinary incontinence or who are 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 urge urinary incontinence or who are 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 fecal incontinence or who are 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 erectile dysfunction or who are selected for not exhibiting such symptoms.

[0049] Cataplexy is a sudden decrease or loss of muscle tone while the patient is awake and can affect specific body parts or the entire body, including eyelids, drooping of the head, facial sagging and / or twitching, slurred speech, jaw weakness, arm, shoulder, or hand weakness, and / or flexed knees. Cataplexy may be the etiology of narcolepsy. Cataplexy can be triggered by strong emotions such as laughter, elation, surprise, or anger. Cataplexy is localized or focal in approximately 75% of cases and is usually short-lived. The incidence of cataplexy varies greatly. Narcolepsy with cataplexy can be socially disabling and isolating.

[0050] Patients receiving reboxetine treatment may include those with, or selected for, narcolepsy with cataplexy (type 1), an autoimmune disorder resulting in loss of hypocretin (orexin)-producing neurons in the CNS. Hypocretin (orexin) is a neuroexcitatory peptide specifically present in the hypothalamus. Patients receiving reboxetine treatment for narcolepsy with cataplexy may include those predisposed to, or selected for, certain genetic markers, including human leukocyte antigen (HLADQB1 / 06:02) and / or T-cell receptor alpha variants. Patients receiving reboxetine treatment may include those without, or selected for, hypocretin neuron loss-associated narcolepsy. Patients receiving reboxetine treatment may include those with, or selected for, narcolepsy induced by seasonal streptococcal infection, H1N1 influenza, and / or H1N1 vaccination in genetically predisposed individuals.

[0051] Existing treatments for narcolepsy only partially address the symptoms, are inconsistent in their effectiveness, have significant side effects, and are all controlled substances.

[0052] According to the FDA, "There is a continuing 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, administration of reboxetine results in a reduction in daytime sleepiness of at least about 1%, at least about 5%, at least about 1% or at least about 1% when compared to, for example, a baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, a selective serotonin reuptake inhibitor (SSRI), or a selective norepinephrine reuptake inhibitor (SNRI)). The decrease may be 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, administration of reboxetine results in a reduction in cataplexy of at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 3%, or at least about 4%, compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). The decrease may be 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, administration of reboxetine reduces the number of cataplexy attacks by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 105%, at least about 110%, at least about 125%, at least about 130%, at least about 145%, at least about 150%, at least about 160%, at least about 175%, at least about 180%, at least about 195%, at least about 200%, at least about 215%, at least about 225%, at least about 230%, at least about 245%, at least about 250%, at least about 265%, at least about 275%, at least about 285%, at least about 295%, at least about 300%, at least about 310%, at least about 325%, at least about 330%, at least about 345%, at least about 350%, at least about 360%, at least about 375%, at least about 385%, at least about 395%, at least about 400%, at least about 410%, at least about 425%, at least about 430%, at least about 445%, at least about 450%, at least about 465%, at least about 475%, at least about 485%, at least about 495%, at least about 500%, at least about 510%, at least about 525%, at least about 530%, at least about 545%, at least about 550%, at least about 560%, at least about 575%, at least about 585%, at least about 595%, at least about 600%, at least about 610%, at least about 625%, at least about %, 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 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 10 times a week, at least about 12 times a week, or at least 14 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. This may decrease to about 8-9 times per week, about 9-10 times per week, about 10-11 times per week, about 11-12 times per week, about 12-13 times per week, about 13-14 times per week, about 14-15 times per week, about 15-16 times per week, about 16-17 times per week, about 17-18 times per week, about 18-19 times per week, about 19-20 times per week, about 1-10 times per week, about 10-20 times per week, about 20-30 times per week, about 30-40 times per week, about 40-50 times per week, about 50-60 times per week, or more.

[0056] In some embodiments, administration of reboxetine results in an improvement in ESS score of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60%, or about 75% compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, tricyclic antidepressant, SSRI, SNRI, etc.). about 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, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, about 24, about 1-2, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7. It may decrease by about 7 to 8, about 8 to 9, about 9 to 10, about 10 to 11, about 11 to 12, about 12 to 13, about 13 to 14, about 14 to 15, about 15 to 16, about 16 to 17, about 17 to 18, about 18 to 19, about 19 to 20, about 20 to 21, about 21 to 22, about 22 to 23, about 23 to 24, about 1 to 4, about 4 to 8, about 8 to 12, about 12 to 16, about 16 to 20, about 20 to 24, about 1 to 12, or about 12 to 24.

[0057] In some embodiments, administration of reboxetine improves or decreases the MWT score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% when compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.). Also 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 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 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, or 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, 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 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 20-21 minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about 24-25 minutes, about 25-26 minutes, about 26-27 minutes, about 27-28 minutes, about 28-30 minutes, about 29-31 minutes, about 30-31 minutes, about 31-32 minutes, about 32-33 minutes, about 33-34 minutes, about 34-35 minutes, about 35-36 minutes, about 37-38 minutes, about 38-39 minutes, about 40-41 minutes, about 42-43 minutes, about 44-45 minutes, about 46-47 minutes, about 48-49 minutes, about 49-50 minutes, about 50-51 minutes, about 52-53 minutes, about 54-55 minutes, about 56-57 minutes, about 57-58 minutes, about 58-59 minutes, about 60-61 minutes, about 61-62 minutes, about 62-63 minutes, about 63-64 minutes, about 64 It may be reduced by 3 minutes, about 13 to 14 minutes, about 14 to 15 minutes, about 15 to 16 minutes, about 16 to 17 minutes, about 17 to 18 minutes, about 18 to 19 minutes, about 19 to 20 minutes, about 20 to 21 minutes, about 21 to 22 minutes, about 22 to 23 minutes, about 23 to 24 minutes, about 24 to 26 minutes, about 1 to 4 minutes, about 4 to 8 minutes, about 8 to 12 minutes, about 12 to 16 minutes, about 16 to 20 minutes, about 1 to 10 minutes, or about 10 to 20 minutes.

[0058] In some embodiments, administration of reboxetine results in an improvement in the cataplexy score on the UNS of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least about 70% compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). 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, or at least about 9. It may be decreased 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, administration of reboxetine results in an improvement in sleep latency on the MSLT of at least about 30%, 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 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-100%, at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, or at least about 7 minutes when compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). 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 , about 6 to 7 minutes, about 7 to 8 minutes, about 8 to 9 minutes, about 9 to 10 minutes, about 10 to 11 minutes, about 11 to 12 minutes, about 12 to 13 minutes, about 13 to 14 minutes, about 14 to 15 minutes, about 15 to 16 minutes, about 16 to 17 minutes, about 17 to 18 minutes, about 18 to 19 minutes, about 19 to 20 minutes, about 1 to 4 minutes, about 4 to 8 minutes, about 8 to 12 minutes, about 12 to 16 minutes, about 16 to 20 minutes, about 1 to 10 minutes, or about 10 to 20 minutes, may increase.

[0060] In some embodiments, administration of reboxetine reduces nightmares or unpleasant dreams (e.g., frequent nightmares and frequent unpleasant dreams) by at least about 1%, at least about 10%, at least about 20%, or both when compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). The concentration may be reduced by about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 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%.

[0061] In some embodiments, administration of reboxetine reduces hallucinations 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%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 220%, at least about 240%, at least about 280%, at least about 300%, at least about 320%, at least about 360%, at least about 380%, at least about 400%, at least about 420%, at least about 440%, at least about 480%, at least about 490%, at least about 500%, at least about 510%, at least about 520%, at least about 530%, at least about 540%, at least about 550%, at least about 560%, at least about 570%, at least about 580%, at least about 590%, at least about 600%, at least about 610%, at least about 620%, at least about 630%, at least about 640%, at least about 650%, at least about 660%, at least about 670%, at least about 680%, at least about 690%, at least about 700%, at least about 710%, at least about 720%, at least about 730%, at least about 750%, at least about 760%, at least about 770%, at least about 780%, at least about 790%, at least about 800%, at least about 810%, at least about 820%, at least about 830%, at least about 840%, at least about 850%, at least about 860%, at least about 870%, at least The decrease may be 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, administration of reboxetine reduces or eliminates sleep paralysis 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%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, at least about 140%, at least about 160%, at least about 220%, at least about 240%, at least about 280%, at least about 300%, at least about 320%, at least about 360%, at least about 380%, at least about 400%, at least about 420%, at least about 440%, at least about 480%, at least about 490%, at least about 500%, at least about 510%, at least about 520%, at least about 530%, at least about 540%, at least about 550%, at least about 560%, at least about 570%, at least about 580%, at least about 590%, at least about 600%, at least about 610%, at least about 620%, at least about 630%, at least about 640%, at least about 650%, at least about 660%, at least about 670%, at least about 680%, at least about 690%, at least about 700%, at least about 710%, at least about 720%, at least about 730%, at least about 750%, at least about 760%, at least about 770%, at least about 780%, at least about 790%, at least about 800%, at least about 810%, at least about 820%, at least about 830%, at least about 840%, at least about 850%, at least about 860%, at least about 870%, The decrease may be 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, administration of reboxetine may result in a reduction in nighttime sleep disturbance of 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% when compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

[0064] In some embodiments, administration of reboxetine reduces narcolepsy-related incidents by at least about 1%, at least about 10%, at least about 20%, at least about 30%, or less when compared to baseline, placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.). The decrease may be at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 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, administration of reboxetine reduces narcolepsy-related injury by at least about 1%, at least about 10%, at least about 20%, at least about 30%, or less when compared to baseline, a placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). The decrease may be at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 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, administration of reboxetine reduces narcolepsy-related fatalities by at least about 1%, at least about 10%, at least about 20%, at least about 30%, or less when compared to baseline, placebo, or other suitable control (including an active control such as a stimulant (e.g., methylphenidate, amphetamine), modafanil, armodafanil, sodium oxybate, tricyclic antidepressants, SSRIs, SNRIs, etc.). The decrease may be at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 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 below) is a highly selective and potent norepinephrine reuptake inhibitor that may improve the core symptoms of narcolepsy, including cataplexy and EDS. Unlike existing medications for narcolepsy, reboxetine is not a controlled substance. Therefore, treatment with reboxetine is not scheduled.

[0068] [ka]

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

[0070] In some embodiments, the reboxetine may be in the form of a salt, free base, or may contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (+)-reboxetine, or an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (-)-reboxetine.

[0071] In treating narcolepsy, reboxetine may be administered in a manner that results in 1) a first local maximum in reboxetine plasma concentrations, and 2) a second local maximum in reboxetine plasma concentrations.

[0072] There are many potential ways to administer reboxetine in a manner that results in a first local maximum of reboxetine plasma concentration and a second local maximum of reboxetine plasma concentration. The local maxima referred to herein are the maximum values ​​of plasma concentration in an individual patient over a period of time of interest, and are not necessarily C max The local maximum is C max One potential method of administering reboxetine in a manner that results in a first local maximum of reboxetine plasma concentration 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, with these doses administered at times that result in the first local maximum of reboxetine plasma concentration and the second local maximum of reboxetine plasma concentration, respectively. For example, the second dosage form may be administered within half a day after the administration of the first dosage form, and may be administered, for example, about 1 to 8 hours, about 8 to 12 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 7 to 8 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 administration of the first dosage form, or any time within any of these ranges.

[0073] In another method, a single dosage form is administered that contains a first-release component and a second-release component, both of which contain reboxetine.

[0074] In some embodiments, the first dosage form administered in a given day, the only dosage form administered that day, or the first of two or more dosage forms administered during the day is administered shortly after waking, e.g., within about 3 hours, within about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes after waking from a night's sleep.

[0075] When a single dosage form comprising a first-release component and a second-release component is administered on a given day, the first-release component may release reboxetine, initiate release of reboxetine, or provide a first local maximum in reboxetine plasma concentration, which may be about 0 to 30 minutes, about 30 to 60 minutes, about 60 to 90 minutes, or about 90 to 120 minutes after the dosage form is orally administered, or any time within any of these ranges. The second-release component may release reboxetine after the first-release component has released reboxetine or may increase the reboxetine plasma concentration or a second local maximum in 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 initial release of reboxetine from the first-release component or after the first local maximum in reboxetine plasma concentration, or any time period within any of these ranges.

[0076] The first-release component and the second-release component may be contained in one single dosage form (such as a tablet, capsule, caplet, or pastille), hi one embodiment, the first-release component is located in one of the outer layers of the dosage form and the second-release component is located in one of the inner layers of the same dosage form.

[0077] In another embodiment, the first release component is disposed in a first layer of the dosage form, and the second release component is disposed in a 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 thin compared to the thickness of the other two layers). In some embodiments, the two layers are disposed side by side and are physically bonded in a two-layer structure (e.g., the two layers are thick compared to the thickness of the other layers).

[0078] In another embodiment, the first release component and the second release component may be separately configured into their own particular granules, particles, etc., where the first release component particles are configured to release reboxetine before the second release component particles release reboxetine, and both the first release component particles and the second release component particles are combined together into a single dosage form such as a capsule, pill, tablet, caplet, pastille, etc., and the two release components may or may not be physically associated with each other.

[0079] In some embodiments, the first local maximum reboxetine plasma concentration is reached about 1-30 minutes, about 30-60 minutes, about 1-2 hours, about 2-3 hours, or about 3-4 hours, or any time within any of these ranges, after administration of the single dosage form or the first dosage form. Typically, the second local maximum reboxetine plasma concentration is reached within half a day after the first local maximum reboxetine plasma concentration is reached, e.g., about 1-10 hours, about 1-2 hours, about 2-6 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, about 7-10 hours, etc., or any time within any of these ranges.

[0080] In a dosage form comprising 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 the first-release component releases reboxetine that contributes to the first local maximum of reboxetine plasma concentration. For example, the first-release component may release reboxetine faster or more immediately than the second-release component, so that most of the reboxetine released from the first-release component that contributes to the first local maximum of reboxetine plasma concentration is released from the first-release component.

[0081] In dosage forms comprising a first-release component and a second-release component, the second-release component is associated with the first local maximum of reboxetine plasma concentration in that the second-release component 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 release of reboxetine so that the second-release component 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 dosage forms comprising a first-release component and a second-release component, the first-release component may be present in any suitable amount, for example, about 1 to 10 mg, about 0.1 to 2 mg, about 0.5 to 1.5 mg, about 1 to 2 mg, about 1.5 to 2.5 mg, about 2 to 3 mg, about 2.5 to 3.5 mg, about 3 to 4 mg, about 3.5 to 4.5 mg, about 4 to 5 mg, about 4.5 to 5.5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 1 to 3 mg, about 2 to 4 mg, about 3 to 5 mg, about 4 to 6 mg, about 5 to 7 mg, about 7 to 10 mg, about 8 ... mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount of reboxetine within any of these ranges.

[0083] In dosage forms comprising a first release component and a second release component, the second release component may be present in any suitable amount, for example, about 0.1 to 2 mg, about 0.5 to 1.5 mg, about 1 to 3 mg, about 1 to 2 mg, about 1.5 to 2.5 mg, about 2 to 3 mg, about 2.5 to 3.5 mg, about 3 to 4 mg, about 2 to 4 mg, about 3 to 5 mg, about 3.5 to 4.5 mg, about 4 to 5 mg, about 4.5 to 5.5 mg, about 5 to 6 mg, about 4 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 5 to 7 mg, about 7 to 10 mg, about The dosage form may contain 4 mg, about 5 mg, about 0.0003 to 0.006 mmol, about 0.006 to 0.009 mmol, about 0.009 to 0.012 mmol, about 0.012 to 0.015 mmol, about 0.015 to 0.018 mmol, about 0.018 to 0.021 mmol, about 0.021 to 0.024 mmol, about 0.024 to 0.027 mmol, about 0.027 to 0.03 mmol, about 0.03 to 0.033 mmol, or any amount of reboxetine within any of these ranges.

[0084] The dose of reboxetine can be gradually increased over a period of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, etc., to a maintenance dose that is a total daily dose (e.g., a 10 mg maintenance dose refers to a daily dose of 10 mg administered once daily or a daily dose of 5 mg administered twice daily for a total of 10 mg). In some embodiments, the maintenance dose is 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 ... mg, 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 3 mmol, about 0.063 to 0.066 mmol, about 0.066 to 0.069 mmol, about 0.006 to 0.01 mmol, about 0.01 to 0.02 mmol, about 0.02 to 0.03 mmol, about 0.03 to 0.04 mmol, about 0.04 to 0.05 mmol, about 0.05 to 0.06 mmol, about 0.06 to 0.07 mmol, or about 0.07 to 0.08 mmol.The maintenance dose is administered for at least about 2 weeks, 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 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 about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years, or more.

[0085] In some embodiments, the first release component releases reboxetine immediately. In some embodiments, the first release component releases reboxetine delayed. In some embodiments, the first release component releases reboxetine in a sustained manner.

[0086] In some embodiments, the second release component releases reboxetine immediately. In some embodiments, the second release component releases reboxetine delayed. In some embodiments, the second release component releases reboxetine in a sustained manner.

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

[0088] In methods in which reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any suitable amount of reboxetine may be administered, for example, about 1 to 10 mg, about 0.1 to 1 mg, about 0.1 to 2 mg, about 0.5 to 1.5 mg, about 1 to 3 mg, about 1 to 2 mg, about 1.5 to 2.5 mg, about 2 to 3 mg, about 2.5 to 3.5 mg, about 3 to 4 mg, about 3.5 to 4.5 mg, about 4 to 5 mg, about 4.5 to 5.5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 2 to 4 mg, about 3 to 5 mg, about 4 to 5 mg, about 4.5 to 5.5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 2 to 4 mg, about 3 to 5 mg, about 4 to 5 mg, about 4 to 5 mg, about 5 ... The first dosage form may contain about 0.0003 to 0.006 mmol, about 0.006 to 0.009 mmol, about 0.009 to 0.012 mmol, about 0.012 to 0.015 mmol, about 0.015 to 0.018 mmol, about 0.018 to 0.021 mmol, about 0.021 to 0.024 mmol, about 0.024 to 0.027 mmol, about 0.027 to 0.03 mmol, about 0.03 to 0.033 mmol, or any amount within a range of any of these values.

[0089] In methods in which reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any suitable amount of reboxetine may be administered, for example, about 0.1 to 1 mg, about 0.1 to 2 mg, about 0.5 to 1.5 mg, about 1 to 3 mg, about 1 to 2 mg, about 1.5 to 2.5 mg, about 2 to 3 mg, about 2.5 to 3.5 mg, about 3 to 4 mg, about 3.5 to 4.5 mg, about 4 to 5 mg, about 4.5 to 5.5 mg, about 5 to 6 mg, about 6 to 7 mg, about 7 to 8 mg, about 8 to 9 mg, about 9 to 10 mg, about 2 to 4 mg, about 3 to 5 mg, about 4 to 6 mg , about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount within any of these ranges.

[0090] In some embodiments, the first dosage form provides immediate release of reboxetine. In some embodiments, the first dosage form provides delayed release of reboxetine. In some embodiments, the first dosage form provides sustained release of reboxetine.

[0091] In some embodiments, the second dosage form provides immediate release of reboxetine. In some embodiments, the second dosage form provides delayed release of reboxetine. In some embodiments, the second dosage form provides sustained release of reboxetine.

[0092] In some embodiments, in a single dosage form that includes both a first-release component and a second-release component, the single dosage form is administered within two hours of waking from a night's sleep.

[0093] In some embodiments where more than one dosage form is given, the first dosage form may be administered within two hours of waking from a night's sleep.

[0094] Various factors affect the time it takes for a drug, such as reboxetine, to be completely absorbed and / or to reach its maximum plasma concentration in humans. For example, these factors include the age, weight, sex, stress level, gastric contents, gastric pH, and the presence of other medications of the human patient. The time required to reach the maximum plasma concentration of a drug, such as reboxetine, can also be affected by the time of day the drug, such as reboxetine, is taken and the patient's level of physical activity. Another factor that can affect the time it takes for a drug, such as reboxetine, to reach its maximum plasma concentration is whether or not the drug, such as reboxetine, is coated with a controlled-release coating.

[0095] Controlled release includes methods of immediate release of a drug such as reboxetine at a specific time or at a specific location in the body, methods of delayed release of a drug, methods of sustained release of a drug at a specific time or at a specific location in the body, and methods of extended release of a drug such as reboxetine.

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

[0097] Delayed-release is a common drug delivery term that describes an oral medication form that does not immediately release its active drug ingredient in the patient's mouth and stomach. While there are many ways to achieve delayed release, delayed-release of reboxetine can be achieved by fully or partially covering reboxetine (e.g., a second-release component) with a coating or layer (e.g., an inner release-controlling coating) that does not dissolve immediately upon swallowing. For example, the coating or layer material may slowly dissolve in the stomach and / or slowly degrade in the stomach by chemical reactions, such as hydrolysis, until the layer can no longer prevent reboxetine from contacting gastric fluids.

[0098] In some embodiments, the delayed-release coating ensures transport from the stomach to the intestine. Upon entering the duodenum, the coating degrades 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 throughout the intestine. 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 duration of delayed release, e.g., the time between the release of a first reboxetine component and the release of a second reboxetine component, can be adjusted by using materials that dissolve or degrade more or less slowly in the digestive system, adjusting the thickness of the coating layer or coating material (e.g., thicker layers provide longer release times), and / or using materials with pH-sensitive properties. For example, materials that are less stable or more soluble at acidic pH will dissolve or degrade more quickly in the stomach because the stomach pH is lower than the intestinal pH. Conversely, materials that are stable at low pH but less stable at high pH will experience delayed dissolution or degradation as the dosage form takes longer to transit the digestive tract.

[0100] Controlled-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 coats), moisture barrier coatings, enteric polymer coatings, etc.

[0101] Controlling-release polymers can be used for both sustained and delayed release, depending on the structure of the dosage form. For example, dispersing reboxetine throughout a controlled-release polymer allows for sustained release, as the drug is released as long as the polymer is present in the GI tract. Delayed release can be achieved by forming a barrier, such as a coating, intended to provide sustained release over a shorter period of 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 when the barrier is penetrated. The thickness of the barrier can be used to control the delay time.

[0102] Any suitable release-controlling polymer may be used, for example, acrylic and methacrylic acid copolymers and various esters thereof, such as methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polyacrylamide, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and the like.

[0103] Other suitable release-controlling polymers include polymerizable quaternary ammonium compounds, such as quaternary aminoalkyl esters and aminoalkylamides of acrylic and methacrylic acid, such as β-methacryloxyethyltrimethylammonium methosulfate, β-acryloxypropyltrimethylammonium chloride, and trimethylaminomethylmethacrylamide methosulfate. The quaternary ammonium atom may also be part of a heterocycle, such as methacryloxyethylmethylmorpholinium chloride or the corresponding piperidinium salt, or may be bonded to the acrylic or methacrylic acid group via a heteroatom-containing group, such as a polyglycol ether group. Further suitable 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 methylacrylate and -methacrylate methosulfate, N-trimethylammonium propyl methacrylamide chloride, N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride, and the like.

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

[0105] In some controlled-release polymers, the acrylic or methacrylic polymer contains one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers (such as those sold by Evonik under the trademark EUDRAGIT® RS and RL) contain a low content of quaternary ammonium groups and are fully polymerized copolymers of acrylic and methacrylic acid esters. The ammonium groups are attached to the ester moiety of methacrylic acid (e.g., 2-trimethylammonium-ethyl ester). The charged ammonium groups contained in these polymers make them insoluble, pH-independently swellable, and highly moisture-permeable. These properties make them useful for customized, time-controlled release of coated drugs. Two or more ammonio methacrylate copolymers with different physical properties can be included to achieve a desired release profile for a given therapeutically active substance, such as reboxetine. For example, it is known that the moisture permeability properties of the resulting coating can be altered by changing the molar ratio of prepolymerized raw materials containing uncharged neutral methacrylate or acrylate esters to prepolymerized raw materials containing quaternary ammonium groups.

[0106] In other embodiments, the controlled-release coat further comprises a polymer whose permeability is pH-dependent, such as an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester. Such polymers are commercially available, for example, from Evonik under the trade 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 becomes increasingly permeable above pH 5.0. This makes EUDRAGIT® L suitable for releasing coated drug substances, such as coated reboxetine, in the duodenum and jejunum of the small intestine. Thus, a drug substance coated with EUDRAGIT® L can delay the attainment of maximum plasma concentrations by about 30 minutes to about 1 hour, about 1 to 1.5 hours, about 1.5 to 2 hours, about 2 to 2.5 hours, about 2.5 to 3 hours, or about 3.5 to 4 hours compared to an uncoated drug substance or an immediate-release drug substance (e.g., reboxetine in a first-release component).

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

[0108] Hydrophobic acrylic polymer coatings also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylate esters (such as EUDRAGIT® E, available from Evonik). EUDRAGIT® E is insoluble in saliva (a property that also aids in taste and odor masking) but soluble in gastric juices at pH 5 or below, resulting in immediate drug release in the stomach. EUDRAGIT® E-coated reboxetine releases, begins to release reboxetine, or reaches a first local maximum in reboxetine plasma concentrations approximately 0-30 minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after oral administration of the dosage form, or any time within these ranges.

[0109] Hydrophobic acrylic polymer coatings include polymethacrylate-based neutral copolymers, such as EUDRAGIT® NE (NE = neutral ester), available from Evonik. EUDRAGIT® NE 30D lacquer film is insoluble in water and digestive fluids, but is permeable and swellable, providing another option for time-controlled release. EUDRAGIT® NE provides a pH-independent sustained-release effect, allowing for the release or delayed release of a drug substance, such as reboxetine, over a period of about 1 to 24 hours, about 1 to 18 hours, about 1 to 12 hours, about 1 to 8 hours, or about 1 to 6 hours.

[0110] In some embodiments, the controlled-release coat comprises a polymer containing ethyl acrylate to methyl methacrylate in a ratio of 2:1 (KOLLICOAT® EMM30D, BASF). KOLLICOAT® EMM30D provides a pH-independent sustained-release effect, allowing for the release or delayed release of a drug substance, such as reboxetine, over a period of about 1 to 24 hours, about 1 to 18 hours, about 1 to 12 hours, about 1 to 8 hours, or about 1 to 6 hours.

[0111] In some embodiments, the controlled-release coat comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate, such as KOLLICOAT® SR30D (BASF). The dissolution profile can be altered by varying the relative amounts of different acrylic resin lacquers in the coating. The permeability characteristics of the resulting coating, which affect the dissolution profile, can also be altered by varying the molar ratio of polymerizable permeation enhancer (e.g., a quaternary ammonium compound) to neutral methacrylic acid ester. KOLLICOAT® SR30D provides a pH-independent sustained-release effect, allowing for the release or delayed release of a drug substance, such as reboxetine, over a period of about 1 to 24 hours, about 1 to 18 hours, about 1 to 12 hours, about 1 to 8 hours, about 1 to 6 hours, about 1 to 4 hours, or about 1 to 2 hours.

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

[0113] Other examples of polymers that can be used in the controlled release coat include cellulose acetate phthalate, cellulose acetate trimalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogel and gel-forming materials such as carboxyvinyl polymers, sodium alginate, carmellose sodium, carmellose calcium, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, cellulosic cross-linked polymers that are lightly cross-linked to facilitate water absorption and swelling of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly Hydrophilic polymers such as (hydroxyalkyl methacrylate) (molecular weight 5k-5000k), polyvinylpyrrolidone (molecular weight 10k-360k), anionic and cationic hydrogels, zein, polyamide, polyvinyl alcohol with low residual acetate, swellable mixture of agar and carboxymethylcellulose, copolymer of maleic anhydride and styrene, ethylene, propylene, and isobutylene, pectin (molecular weight 30k-300k), agar, acacia, karaya, tragacanth, algin, and guar, polyacrylamide, POLYOX® polyethylene oxide (molecular weight 100k-5000k, manufactured by Dow), AQUAKEEP® acrylate polymer (acrylic acid polymer, primarily composed of sodium salt), diesters of polyglucan, cross-linked polyvinyl alcohol, poly(N-vinyl-2-pyrrolidone), and polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.Included are hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, methylethyl cellulose, ethylhydroxyethyl cellulose, 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, scleroglucan, and mixtures and blends thereof.

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

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

[0116] In addition to the modified release dosage forms described herein, modified release formulations of the present disclosure, i.e., formulations that, when administered to a human patient, e.g., orally or via other modes of administration, exhibit a mean T of the drug and / or other pharmacokinetic parameters described herein. maxOther modified release technologies known to those skilled in the art can be used to achieve a formulation that provides. Such formulations can be made as modified release oral formulations in suitable tablets or multi-dose formulations known to those skilled in the art. In either case, the modified release dosage form can optionally include a controlled release carrier that is incorporated into a matrix with the drug or applied as a controlled release coating.

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

[0118] Binders (sometimes called adhesives) can be added to a drug-filler mixture to enhance the mechanical strength of granules and tablets during formulation. Binders can be added to formulations in a variety of ways: (1) as a dry powder mixed with other ingredients before wet granulation; (2) as a solution used as a granulating fluid during wet granulation; and (3) as a dry powder mixed with other ingredients before compression. In this form, the binder is referred to as a dry binder. Solution binders are a common method of incorporating binders into granules. In certain embodiments, the binder used in tablets is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long-chain fatty acids, fatty acid esters, fatty alcohols, fatty acid esters, waxy substances such as fatty acid glycerides, hydrogenated fats, hydrocarbons, conventional waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with hydrocarbon backbones, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropylmethylcellulose (HPMC) and hydroxypropylcellulose (HPC)), polyvinyl alcohol, and mixtures thereof. Any suitable amount of binder may be present, such as about 0.5-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or about 3% by weight of the tablet dry weight. In some embodiments, the binder is polyvinyl alcohol.

[0119] Lubricants can be added to pharmaceutical formulations to reduce friction between the solid and the die wall during tablet production. High friction during tablet production can cause a series of problems, including poor tablet quality (capping or fragmentation of tablets during ejection and vertical scratches on the tablet edges), which can lead to production stoppages. Therefore, lubricants may be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils (hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM), hydrogenated soybean oil & castor wax (STEROTEX® K)), etc. Lubricants include those known in the art, such as stearyl alcohol, leucine, polyethylene glycol (MW 1450, preferably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymers (e.g., those available under the registered trademark CARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof, etc. In some embodiments, the lubricant is glyceryl behenate (e.g., COMPRITOL® 888). Any suitable 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 tablet dry weight.

[0120] In some embodiments, reboxetine is administered 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, once daily or twice daily, 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 more.

[0121] Without intending to limit the scope of this disclosure, examples of compositions useful for dosage forms containing about 5-10 mg of reboxetine are shown in Table 1 below.

[0122] [Table 1]

[0123] Treatment of narcolepsy with cataplexy with the reboxetine dosage forms described herein may not be associated with the significant side effects of existing therapies, and treatment of narcolepsy with cataplexy with the reboxetine dosage forms described herein may be well tolerated in mammals, such as humans.

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

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

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

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

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

[0129] (Example) Example 1 A 40-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, the number of cataplexy attacks 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, the number of cataplexy attacks decreased by 30-60%.

[0131] Example 3 A 60-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, the number of cataplexy attacks 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, ESS score decreased by 10-30%.

[0133] Example 5 A 25-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, ESS score decreased by 60-100%.

[0135] Example 7 A 19-year-old male was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after the start of treatment, MWT scores 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after starting treatment, MWT scores decreased by 30-60%.

[0137] Example 9 A 33-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. One week after starting treatment, MWT scores decreased by 60-100%.

[0138] Example 10 A 54-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, the number of cataplexy attacks 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, the number of cataplexy attacks decreased by 30-60%.

[0140] Example 12 A 52-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated pre-treatment and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, the number of cataplexy attacks 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, ESS score decreased by 10-30%.

[0142] Example 14 A 34-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, ESS score decreased by 60-100%.

[0144] Example 16 A 19-year-old male was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, MWT scores 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 of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, MWT scores decreased by 30-60%.

[0146] Example 18 A 57-year-old man was diagnosed with narcolepsy with cataplexy. He was prescribed reboxetine and instructed to take 5 mg of reboxetine at 8:00 AM and 5 mg of reboxetine at 1:00 PM for three weeks. The patient was evaluated before and weekly for the number of cataplexy attacks, ESS score, and MWT score. Three weeks after the start of treatment, MWT scores decreased by 60-100%.

[0147] Unless otherwise indicated, all numbers expressing properties, percentages, and the like, such as amounts of ingredients, should be understood in all instances to refer both to the exact value as stated and as modified by the term "about." Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained. While not limiting the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed as based on at least the number of reported significant digits and by applying ordinary rounding techniques.

[0148] As used in the context of describing the present embodiments (particularly in the context of the claims below), the terms "a," "an," "the," and similar reference words are to be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or illustrative language (e.g., "etc.") herein is merely to further clarify the embodiments and does not limit the scope of any claims. Nothing in the specification should be construed as indicating any non-claimed element essential to the practice of a claim.

[0149] Groupings of alternative elements or embodiments described herein should not be construed as limitations. Each group member may be referenced and claimed individually or in any combination with other members of the group or elements described herein. For purposes of convenience and / or patentability, one or more members of a group may be included in, or deleted from, a group. When such inclusion or deletion occurs, the specification is considered to include the group so modified, thereby satisfying the description requirement of all Markush groups used in the appended claims.

[0150] Certain embodiments are described herein, including the best mode contemplated by the inventors for carrying out the claimed embodiments. Of course, variations on the claimed embodiments will be apparent to those skilled in the art in light of the foregoing description. The inventors expect that those skilled in the art will adopt such variations as appropriate, and intend that the claimed embodiments may be practiced other than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the claimed subject matter as permitted by applicable law. Moreover, any combination of the above-described elements is contemplated in all possible variations of the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0151] Finally, it should be understood that the embodiments described herein are intended to illustrate the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not limitation, alternative embodiments may be employed in accordance with the teachings herein. Accordingly, the claims should not be limited to the exact embodiments shown and disclosed.

[0152] (Addendum) (Appendix 1) administering reboxetine to a human being in need of treatment for narcolepsy with cataplexy, Reboxetine is administered at least once daily for at least 3 weeks, and wherein, after two weeks of treatment, the treatment results in a reduction in the number of cataplexy attacks per week, the Epworth Sleepiness Scale score, the cataplexy subscore of the Uranium Nasal Narcolepsy Scale (UNS), or the Maintenance of Wakefulness Test score in a human. A method for treating narcolepsy with cataplexy.

[0153] (Appendix 2) 1. A method of using reboxetine in the manufacture of a medicine for treating narcolepsy with cataplexy, comprising administering reboxetine at least once daily for at least three weeks.

[0154] (Appendix 3) a pharmaceutical composition comprising reboxetine; instructions for using said pharmaceutical composition to treat narcolepsy with cataplexy in a human; and A kit comprising: Reboxetine is administered at least once daily for at least 3 weeks. kit.

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

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

[0157] (Appendix 6) 5. The method of treatment, use, or kit of claim 4, wherein the second dosage form is administered from about 3 to about 4 hours after the first dosage form.

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

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

[0160] (Appendix 9) A single dosage form is administered daily; the single dosage form comprises a first-release component comprising reboxetine and a second-release component comprising reboxetine; the first release component results in a first local maximum in reboxetine plasma concentration, and the second release component results in a second local maximum in reboxetine plasma concentration; 2. The method of claim 1, wherein the time to reach the first local maximum of the reboxetine plasma concentration is about 2 to about 6 hours before the time to reach the second local maximum of the reboxetine plasma concentration.

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

[0162] (Appendix 11) 10. The method of treatment, use, or kit of claim 9, wherein the second local maximum of reboxetine plasma concentration is reached about 3 to about 4 hours after the first local maximum of reboxetine plasma concentration.

[0163] (Appendix 12) 10. The method of treatment, use, or kit of claim 9, wherein the second local maximum of reboxetine plasma concentration is reached about 4 to about 5 hours after the first local maximum of reboxetine plasma concentration.

[0164] (Appendix 13) 10. The method of treatment, use, or kit of claim 9, wherein the second local maximum of reboxetine plasma concentration is reached about 5 to about 6 hours after the first local maximum of reboxetine plasma concentration.

[0165] (Appendix 14) 14. The method of treatment, method of use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the human is not suffering from depression.

[0166] (Appendix 15) 15. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose is maintained constant at about 0.006 mmol to about 0.01 mmol.

[0167] (Appendix 16) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.01 mmol to about 0.02 mmol.

[0168] (Appendix 17) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.02 mmol to about 0.03 mmol.

[0169] (Appendix 18) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.03 mmol to about 0.04 mmol.

[0170] (Appendix 19) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.04 mmol to about 0.05 mmol.

[0171] (Appendix 20) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.05 mmol to about 0.06 mmol.

[0172] (Appendix 21) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.06 mmol to about 0.07 mmol.

[0173] (Appendix 22) 16. The method of treatment, use, or kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased over a period of 1 to 7 days, after which the total daily dose remains constant at about 0.07 mmol to about 0.08 mmol.

[0174] (Appendix 23) 23. The method of treatment, method of use, or kit of claim 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 reboxetine is contained in a dosage form, and the dosage form contains about 5 mg of reboxetine.

[0175] (Appendix 24) 23. The method of treatment, method of use, or kit of claim 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 reboxetine is contained in a dosage form, and the dosage form contains about 10 mg of reboxetine.

[0176] (Appendix 25) 24. The method of treatment, use, or kit of claim 23, wherein the dosage form is administered once daily or twice daily for at least 3 weeks.

[0177] (Appendix 26) 25. The method of treatment, use, or kit of claim 24, wherein the dosage form is administered once daily or twice daily for at least 3 weeks.

[0178] (Appendix 27) 27. The method of treatment, use, or kit of claim 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, which increases sleep latency in a multiple sleep latency test (MSLT) in a human.

[0179] (Appendix 28) 28. The method of treatment, use, or kit of claim 27, which increases sleep latency on the MSLT by at least 10% in a human.

[0180] (Appendix 29) 28. The method of treatment, use, or kit of claim 27, which increases the MSLT sleep latency in a human by at least 20%.

[0181] (Appendix 30) 28. The method of treatment, use, or kit of claim 27, which increases the MSLT sleep latency in a human by at least 30%.

[0182] (Appendix 31) 28. The method of treatment, use, or kit of claim 27, which increases the MSLT sleep latency in a human by at least 40%.

[0183] (Appendix 32) 28. The method of treatment, use, or kit of claim 27, which increases the MSLT sleep latency in a human by at least 50%.

[0184] (Appendix 33) 28. The method of treatment, use, or kit of claim 27, which increases the MSLT sleep latency in a human by at least 60%.

[0185] (Appendix 34) 34. The method of treatment, use, or kit of claim 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, which reduces the cataplexy subscore on the UNS by at least 15% in a human.

[0186] (Appendix 35) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 20%.

[0187] (Appendix 36) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 30%.

[0188] (Appendix 37) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 40%.

[0189] (Appendix 38) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 50%.

[0190] (Appendix 39) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 60%.

[0191] (Appendix 40) 35. The method of treatment, use, or kit of claim 34, which reduces the cataplexy subscore on the UNS in a human by at least 70%.

[0192] (Appendix 41) 35. The method of treatment, use, or kit of claim 34, wherein the human has a cataplexy subscore of about 0.

Claims

1. A pharmaceutical composition comprising reboxetine and hydroxypropyl methylcellulose.

2. 10. The pharmaceutical composition of claim 1 for a method for treating narcolepsy with cataplexy, comprising administering the pharmaceutical composition of claim 1 once daily to a human in need of such treatment.

3. 3. The pharmaceutical composition of claim 1, comprising 1 mg to 10 mg of reboxetine.

4. 4. The pharmaceutical composition of claim 1, further comprising microcrystalline cellulose.

5. 5. The pharmaceutical composition of claim 1, further comprising silicon dioxide.

6. 6. The pharmaceutical composition of claim 1, further comprising magnesium stearate.

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