Use of reboxetine for the treatment of narcolepsy

Abstract

Described herein are methods of treating narcolepsy with cataplexy, the methods comprising administering reboxetine to a human in need thereof. Reboxetine can also be used in the manufacture of a medicament for the treatment of narcolepsy with cataplexy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine, and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human.

Description

[0001] This application is a divisional application of Chinese patent application No. 201980067756.9 (filed on October 14, 2019, invention title: Use of reboxetine for the treatment of narcolepsy).

[0002] Cross-references to related applications

[0003] 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

[0004] Narcolepsy is a severe and debilitating neurological disorder that causes disruption of the sleep-wake cycle and is clinically characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted nocturnal sleep. It is estimated that narcolepsy affects an estimated 185,000 individuals in the United States. Cataplexy is observed in an estimated 70% of narcolepsy patients and is characterized by a sudden decrease or loss of muscle tone while the patient is awake, usually triggered by intense emotions such as laughter, fear, anger, tension, or excitement. Type 1 narcolepsy includes cataplexy, while type 2 narcolepsy does not. Narcolepsy interferes with cognitive, psychological, and social functioning, increases the risk of work-related and driving-related accidents, and is associated with a 1.5 times higher mortality rate. Up to 57% of patients have been reported to have depression. In the United States, it is estimated that nearly 200,000 people with this condition are debilitated by the effects of narcolepsy. Narcolepsy interferes with psychological and social functioning, increases work-related and driving-related accidents, and nearly doubles the mortality rate. Unfortunately, currently approved treatments are rarely used for this underdiagnosed orphan condition and are limited by efficacy variability among patients, tolerability issues, and the need for DEA regulation. Summary of the Invention

[0005] This article describes a method for treating cataplexy-type narcolepsy, which includes administering reboxetine to the person in need.

[0006] Some implementations include the use of reboxetine in the manufacture of a medicament for the treatment of cataplexy-type narcolepsy.

[0007] Some implementations include a kit containing a pharmaceutical composition comprising reboxetine, and instructions for use of the pharmaceutical composition for treating cataplexy-like narcolepsy in humans.

[0008] In some implementations, reboxetine is administered at least once daily for at least three weeks. In some implementations, as a result of treatment, the person experiences a decrease in the number of cataplexy episodes, a decrease in the Epworth Sleepiness Scale score, or a decrease in the Stay Awake Test score within three weeks of treatment initiation. Detailed Implementation

[0009] Reboxetine has the potential to treat symptoms of narcolepsy and lacks DEA regulation, which would represent a significant benefit to patients suffering from this condition.

[0010] If criteria A and B are met, a person may have type 1 narcolepsy:

[0011] A. The patient has an irrepressible daily need for sleep or experiences periods of daytime sleepiness that have persisted for at least 3 months.

[0012] B. One or both of the following exist:

[0013] 1. Cataplexy on the mean sleep latency test (MSLT) performed according to standard techniques (as defined under the basic characteristics), a mean sleep latency of <8 minutes, and ≥2 sleep onset REM periods (SOREMP). One SOREMP on a previous laboratory-based polysomnography (PSG) test (within 15 minutes of sleep onset) may be substituted for one SOREMP on the MSLT.

[0014] 2. CSF hypothalamic secretin-1 concentration measured by immunoreactivity is <110 pg / mL or <⅓ of the mean obtained in normal subjects using the same assay.

[0015] In young children, narcolepsy sometimes manifests as prolonged nighttime sleep or the return of previously interrupted daytime naps. If type 1 narcolepsy is strongly suspected clinically but the B2 criteria are not met, a possible strategy is repeated MSLT (Massage-Lapse Thromboplasty).

[0016] Some patients treated with reboxetine may have and / or may be selected to have an uncontrollable daily need for sleep or periods of daytime sleepiness lasting for at least approximately 3 months, 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 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 2 years, or at least Approximately 3 years, at least approximately 4 years, at least approximately 5 years, at least approximately 10 years, at least approximately 15 years, at least approximately 20 years, at least approximately 25 years, at least approximately 30 years, at least approximately 40 years, at least approximately 50 years, at least approximately 60 years, approximately 3-9 months, approximately 9-18 months, approximately 18 months to approximately 2 years, approximately 2-5 years, approximately 5-10 years, approximately 10-15 years, approximately 15-20 years, approximately 20-25 years, approximately 25-30 years, approximately 30-35 years, approximately 35-40 years, approximately 40-50 years, approximately 50-60 years or longer.

[0017] Some patients treated with boxetine may have and / or may be selected to have an average 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 0.1-1 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 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes.

[0018] Some patients treated with anti-reboxetine may have and / or may be selected to have at least 2, at least 3, or at least 4 SOREMPs on the MSLT (Mean Sleep Latency Test) performed according to standard techniques. A SOREMP occurring within 15 minutes of sleep onset on the PSG during the previous night may replace one of the SOREMPs on the MSLT.

[0019] Some patients treated with reboxetine may have and / or may be selected to have CSF hypothalamic secretin-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.

[0020] Some patients treated with reboxetine may have and / or may be selected to have CSF hypothalamic secretin-1 concentrations, as measured by immunoreactivity, that are 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 average obtained in normal subjects using the same assay.

[0021] Some patients treated with reboxetine may be, and / or may be selected from, young children who exhibit excessively long nighttime sleep.

[0022] Some patients treated with reboxetine may be, and / or may be selected, young children who show signs of recovery from previously interrupted daytime naps.

[0023] Some patients treated with reboxetine may have and / or may be selected to have a cataplexy score on the Ullanlinna 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 and 11.

[0024] Some patients treated with reboxetine may have and / or may be selected to have a score on the Epworth Sleepiness Scale (ESS) of 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, at least about 24, about 10-11, about 11-12, about 12-13, 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.

[0025] Some patients treated with reboxetine may have and / or may be selected to have a duration 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, less than about 17 minutes, 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, or about Stay Awake Test (MWT) scores for 3-4 minutes, approximately 4-5 minutes, approximately 5-6 minutes, approximately 6-7 minutes, approximately 7-8 minutes, approximately 8-9 minutes, approximately 9-10 minutes, approximately 10-11 minutes, approximately 11-12 minutes, approximately 12-13 minutes, approximately 13-14 minutes, approximately 14-15 minutes, approximately 15-16 minutes, approximately 16-17 minutes, approximately 17-18 minutes, approximately 18-19 minutes, approximately 19-20 minutes, approximately 0-4 minutes, approximately 4-8 minutes, approximately 8-12 minutes, approximately 12-16 minutes, approximately 16-20 minutes, or approximately 0-19 minutes.

[0026] In some implementations, prior to treatment with reboxetine, the patient has had and / or may have had symptoms of narcolepsy for approximately 1–5 years, approximately 5–10 years, approximately 10–15 years, approximately 15–20 years, approximately 20–25 years, approximately 25–30 years, approximately 30–35 years, approximately 35–40 years, approximately 40–45 years, approximately 45–50 years, approximately 50–55 years, approximately 55–60 years, approximately 60–65 years, approximately 65–70 years, approximately 70–75 years, or longer than 75 years.

[0027] In some implementations, prior to treatment with reboxetine, the patient has and / or may be selected to be approximately 0–5 years old, approximately 5–10 years old, approximately 10–15 years old, approximately 15–20 years old, approximately 20–25 years old, approximately 25–30 years old, approximately 30–35 years old, approximately 35–40 years old, approximately 40–45 years old, approximately 45–50 years old, approximately 50–55 years old, approximately 55–60 years old, approximately 60–65 years old, approximately 65–70 years old, approximately 70–75 years old, or older than 75 years old.

[0028] Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may be and / or may be selected to be female.

[0029] Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may be male and / or may be selected to be male.

[0030] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have any clinically significant conditions that could cause EDS. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have any clinically significant mental disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have any type of depression not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have any somnolence caused by depression not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having emotional disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having mental disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having brain dysfunction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having motor disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having dementia. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected not to have motor neuron disease.

[0031] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having neurodegenerative diseases. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having epileptic disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having headaches. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having major depressive disorder. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected not to have anti-treatment depression.

[0032] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having treatment-resistant bipolar depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having bipolar disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cyclothymic affective disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having seasonal affective disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having mood disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have chronic depression (e.g., dysphoric mood).

[0033] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having postpartum depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having premenstrual anxiety disorder (PMDD). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having situational depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having atypical depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having mania. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of anxiety disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of attention deficit disorder (ADD).

[0034] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having attention deficit hyperactivity disorder (ADDH). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having attention deficit / hyperactivity disorder (AD / HD). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having manic symptoms. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having obsessive-compulsive disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having bulimia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have obesity or weight gain. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have chronic fatigue syndrome.

[0035] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having premenstrual syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having substance addiction or abuse. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having nicotine addiction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having psychosexual dysfunction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having pseudobulbar affect. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected to not have mood instability.

[0036] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having anxiety disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having phobias. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having generalized anxiety disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having social anxiety disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having panic disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having agoraphobia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having obsessive-compulsive disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having post-traumatic stress disorder (PTSD). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having mania.

[0037] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having bipolar disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having hypomania. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having unipolar depression. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having stress disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having somatic symptom disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having personality disorders.

[0038] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having schizophrenia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having paranoid disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having schizoaffective disorder. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having schizophrenic pathology. Some patients using reboxetine to treat narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be non-aggressive. Some patients using reboxetine to treat narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be non-aggressive in Alzheimer's disease. Some patients using reboxetine to treat narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be non-aggressive in Alzheimer's disease.

[0039] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having drug dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cocaine addiction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having psychostimulant addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having climacteric addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have cocaine addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have fast-acting pill addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have methamphetamine addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have nicotine addiction or dependence.

[0040] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have, and / or may be selected not to have, alcohol addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have, and / or may be selected not to have, opioid addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have, and / or may be selected not to have, addiction to or dependence on anti-anxiety and / or hypnotics. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have, and / or may be selected not to have, cannabis (cannabis / marijuana) addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have amphetamine addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have hallucinogen addiction or dependence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have phencyclidine addiction or dependence.

[0041] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have volatile solvent addiction or dependence on volatile solvents. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have volatile nitrite addiction or dependence on volatile nitrites. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having memory loss. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having amnesia / amnesia syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having epilepsy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having disturbances of consciousness.

[0042] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having coma. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having decreased attention. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having speech disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having vocal spasms. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Parkinson's disease. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected not to have Lennox-Gastaut syndrome.

[0043] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having autism. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having ADHD. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having schizophrenia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having stroke. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cerebral infarction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cerebral hemorrhage. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cerebral arteriosclerosis. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having cerebral venous thrombosis. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having traumatic brain injury.

[0044] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having akinesia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having choreoathetosis. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having ataxia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having ballismus. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having hemispheric ballism. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be without bradykinesia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be without cerebral palsy.

[0045] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having chorea. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Huntington's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having rheumatic chorea. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Siddenham's chorea. Some patients treated with anti-reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having motor disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of tardive dyskinesia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of dystonia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of blepharospasm.

[0046] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having spasmodic torticollis. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having dopamine-responsive dystonia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having restless legs syndrome (RLS). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having tremor. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having essential tremor. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Tourette's syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Wilson's disease.

[0047] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having vascular dementia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Lewy body dementia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having mixed dementia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having frontotemporal dementia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Creutzfeldt-Jakob disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have normobaric hydrocephalus.

[0048] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Pick's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having progressive bulbar palsy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having primary lateral sclerosis (PLS). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having progressive muscular atrophy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having post-polio syndrome (PPS). Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected not to have spinal muscular atrophy (SMA).

[0049] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having spinal motor atrophy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Tay-Sach's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Sandhof's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having hereditary spastic paraplegia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of prion-related disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of cerebellar ataxia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free of spinocerebellar ataxia (SCA).

[0050] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having spinal muscular atrophy (SMA). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having bulbar muscular atrophy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Friedrich's ataxia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Lewy body disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have multiple sclerosis (MS). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have multiple system atrophy.

[0051] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Shy-Drager syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having corticobasal degeneration. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having progressive supranuclear palsy.

[0052] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Wilson's disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Menkes disease. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have adrenoleukodystrophy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have autosomal dominant cerebral arteriosclerosis (CADASIL) with subcortical infarction and leukoencephalopathy. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected not to have muscular dystrophy.

[0053] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have Chuck-Maley-Duss disease (CMT). Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have familial spastic paraplegia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have neurofibromatosis. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected not to have pontocerebellar atrophy or degeneration. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have striatal nigrostriatum degeneration. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have Guillain-Barré syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have spastic paraplegia. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have non-epileptic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having epilepsy. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having febrile seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having partial seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having simple partial seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Jacksonian seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to not have complex partial status epilepticus.Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from generalized tonic-clonic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from generalized tonic-clonic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from absence seizures.

[0054] Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having atonic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having myoclonic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having juvenile myoclonic seizures. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having infantile spasms. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having status epilepticus. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having Rett syndrome. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having tinnitus. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having impaired consciousness. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having sexual dysfunction. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having voice disorders due to uncontrolled laryngeal muscle spasms. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from abducens spasmodic voice disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from adductor spasmodic voice disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from tonic voice disorders. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from voice tremor. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected to be free from diabetic neuropathy. Some patients treated with reboxetine for narcolepsy (such as cataplexy and / or EDS narcolepsy) may not have and / or may be selected to be free from chemotherapy-induced neurotoxicity.Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having methotrexate neurotoxicity. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having stress urinary incontinence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having urge urinary incontinence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having fecal incontinence. Some patients treated with reboxetine for narcolepsy (e.g., cataplexy and / or EDS-type narcolepsy) may not have and / or may be selected as not having erectile dysfunction.

[0055] Cataplexy involves a sudden reduction or loss of muscle tone while the patient is awake. This can affect specific parts of the body or the entire body, such as eyelid drooping, head drooping, facial drooping and / or twitching, slurred speech, jaw weakness, weakness in the arms, shoulders, or hands, and / or knee flexion. Cataplexy can be a specific symptom of narcolepsy. Cataplexy can be triggered by strong emotions (such as laughter, elation, surprise, or anger). Cataplexy can be partial or localized (approximately 75% of cases) and usually has a short duration. The frequency of cataplexy can vary widely. Cataplexy-related narcolepsy can lead to social disability and social isolation.

[0056] Some patients being treated with reboxetine may have and / or may be selected to have cataplexy-type narcolepsy (Type 1), an autoimmune disorder that leads to the loss of neurons in the CNS that produce hypothalamic orexin (orexin) peptides. Hypothalamic orexin peptides are hypothalamic-specific peptides with excitatory activity. Patients being treated with reboxetine for cataplexy-type narcolepsy are, and may be selected to be, susceptible individuals with specific genetic markers, including human leukocyte antigen (HLA DQB1-06:02) and / or T-cell receptor alpha variants. Some patients being treated with reboxetine may not have and may be selected to not have narcolepsy associated with the loss of hypothalamic orexin neurons. Some patients being treated with reboxetine may have or may be selected to have narcolepsy in genetically susceptible individuals caused by seasonal streptococcal infection, H1N1 influenza, and / or H1N1 vaccination.

[0057] Current treatments for narcolepsy only address some of the symptoms, offer variable efficacy, and have significant side effects. Furthermore, all existing treatments are controlled substances.

[0058] According to the FDA, "there is a continued need for additional effective and tolerable treatment options for patients to improve their 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)

[0059] In some embodiments, administration of reboxetine may reduce daytime sleepiness by at least about 1%, at least about 5%, at least about 10%, or at least about 20% compared to, for example, baseline, placebo, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybate, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or selective norepinephrine reuptake inhibitors (SNRIs)). 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%.

[0060] In some implementations, administration of reboxetine may reduce cataplexy by at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, compared to, for example, baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0061] In some embodiments, administration of reboxetine may reduce the number of cataplexy episodes 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 95% compared to, for example, baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs). Approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, approximately 50-60%, approximately 60-70%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 1-25%, approximately 25-50%, approximately 50-75%, or approximately 75-100%, at least once per week, at least twice per week, at least three times per week, at least four times per week, at least five times per week, at least six times per week, at least seven times per week, at least eight times per week, at least Approximately 9 times / week, at least 10 times / week, at least 12 times / week, at least 14 times / week, at least 16 times / week, at least 18 times / week, at least 20 times / week, at least 22 times / week, at least 24 times / week, at least 26 times / week, at least 28 times / week, at least 30 times / week, at least 40 times / week, at least 50 times / week, approximately 1-2 times / week, approximately 2-3 times / week, approximately 3-4 times / week, approximately 4-5 times / week, approximately 5-6 times / week, approximately 6-7 times / week, approximately 7-8 times / week. Approximately 8-9 times / week, approximately 9-10 times / week, approximately 10-11 times / week, approximately 11-12 times / week, approximately 12-13 times / week, approximately 13-14 times / week, approximately 14-15 times / week, approximately 15-16 times / week, approximately 16-17 times / week, approximately 17-18 times / week, approximately 18-19 times / week, approximately 19-20 times / week, approximately 1-10 times / week, approximately 10-20 times / week, approximately 20-30 times / week, approximately 30-40 times / week, approximately 40-50 times / week, approximately 50-60 times / week or more.

[0062] In some embodiments, administration of reboxetine may result in a reduction in the 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 60-70%, 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, about 7-8, about 8-9 Approximately 9-10, Approximately 10-11, Approximately 11-12, Approximately 12-13, Approximately 13-14, Approximately 14-15, Approximately 15-16, Approximately 16-17, Approximately 17-18, Approximately 18-19, Approximately 19-20, Approximately 20-21, Approximately 21-22, Approximately 22-23, Approximately 23-24, Approximately 1-4, Approximately 4-8, Approximately 8-12, Approximately 12-16, Approximately 16-20, Approximately 20-24, Approximately 1-12, or Approximately 12-24.

[0063] In some implementations, administration of reboxetine may result in a reduction in the MWT 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%, or at least [amount missing] compared to baseline, placebo, or some other suitable control (including active controls such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs). Approximately 95%, approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-50%, approximately 50-60%, approximately 60-70%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 1-25%, approximately 25-50%, approximately 50-75%, or approximately 75-100%, at least approximately 1 minute, at least approximately 2 minutes, at least approximately 3 minutes, at least approximately 4 minutes, at least approximately 5 minutes, at least approximately 6 minutes, at least approximately 7 minutes, at least approximately 8 minutes, to At least 9 minutes, at least 10 minutes, at least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 16 minutes, at least 17 minutes, at least 18 minutes, at least 19 minutes, at least 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 Approximately 12-13 minutes, approximately 13-14 minutes, approximately 14-15 minutes, approximately 15-16 minutes, approximately 16-17 minutes, approximately 17-18 minutes, approximately 18-19 minutes, approximately 19-20 minutes, approximately 20-21 minutes, approximately 21-22 minutes, approximately 22-23 minutes, approximately 23-24 minutes, approximately 24-26 minutes, approximately 1-4 minutes, approximately 4-8 minutes, approximately 8-12 minutes, approximately 12-16 minutes, approximately 16-20 minutes, approximately 1-10 minutes, or approximately 10-20 minutes.

[0064] In some implementations, administration of reboxetine may result in a reduction in cataplexy score on the UNS 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 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40- 50%, approximately 50-60%, approximately 60-70%, approximately 70-80%, approximately 80-90%, approximately 90-100%, approximately 1-25%, approximately 25-50%, approximately 50-75%, or approximately 75-100%, at least approximately 1, at least approximately 2, at least approximately 3, at least approximately 4, at least approximately 5, at least approximately 6, at least approximately 7, at least approximately 8, at least approximately 9, at least approximately 10, approximately 11, approximately 2-3, approximately 3-4, approximately 4-5, approximately 5-6, approximately 6-7, approximately 7-8, approximately 8-9, approximately 9-10, approximately 2-4, approximately 4-6, approximately 6-8, approximately 8-10, approximately 10-11, approximately 2-6, or approximately 6-10, approximately 5-11.

[0065] In some implementations, administration of reboxetine may result in a prolongation of sleep latency on the MSLT by 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%, for 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, or at least about 10 minutes, compared to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs). At least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 16 minutes, at least 17 minutes, at least 18 minutes, at least 19 minutes, at least 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, approximately 11-12 minutes, approximately 12-13 minutes, approximately 13-14 minutes, approximately 14-15 minutes, approximately 15-16 minutes, approximately 16-17 minutes, approximately 17-18 minutes, approximately 18-19 minutes, approximately 19-20 minutes, approximately 1-4 minutes, approximately 4-8 minutes, approximately 8-12 minutes, approximately 12-16 minutes, approximately 16-20 minutes, approximately 1-10 minutes, or approximately 10-20 minutes.

[0066] In some embodiments, administration of reboxetine may reduce nightmares or unpleasant dreams (e.g., frequent nightmares or frequent unpleasant dreams) by at least about 1%, at least about 10%, at least about 20%, at least about 30%, or to [a certain percentage] compared to baseline, placebo, or some other suitable control (including active controls, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs). Less than 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, about 1-10%, about 10-20%, about 20-30%, about 30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%.

[0067] In some embodiments, administration of reboxetine may reduce 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 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%, compared to baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0068] In some embodiments, administration of reboxetine may reduce 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 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% compared to, for example, baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0069] In some implementations, administration of reboxetine may reduce nocturnal sleep disturbances by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, 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%, compared to baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0070] In some implementations, administration of reboxetine may reduce narcolepsy-related incidents 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 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%, compared to baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0071] In some implementations, administration of reboxetine may reduce narcolepsy-related impairment 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 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%, compared to, for example, baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine), modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0072] In some implementations, administration of reboxetine may reduce narcolepsy-related deaths 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 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% compared to, for example, baseline, placebo, or some other suitable control (including active control, such as stimulants (e.g., methylphenidate, amphetamine, modafinil, armodafinil, sodium oxybutyrate, tricyclic antidepressants, SSRIs, or SNRIs).

[0073] Reboxetine (with the structure shown below) is a highly selective and potent norepinephrine reuptake inhibitor with the potential to resolve key symptoms of narcolepsy, such as cataplexy or EDS. Unlike existing narcolepsy treatments, reboxetine is not a controlled substance. Therefore, treatment with reboxetine will be scheduled.

[0074] (Ripoxetine)

[0075] Unless otherwise stated, any reference to the compounds described herein (e.g., reboxetine) by structure, name, or any other means includes pharmaceutically acceptable salts; free acids or bases; alternating solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; enantiomers; deuterated compounds, such as deuterated reboxetine; or any chemical substance that can be rapidly converted into the compounds described herein under the conditions of use of the compounds as described herein.

[0076] In some embodiments, reboxetine is in salt form, free base form, or may contain an excess (e.g., at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (+)-reboxetine; 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.

[0077] For the treatment of narcolepsy, reboxetine can be administered in a manner that results in 1) a first local maximum plasma concentration of reboxetine and 2) a second local maximum plasma concentration of reboxetine.

[0078] There are many potential routes of reboxetin administration that could lead to a first local maximum and a second local maximum plasma concentration. The local maximums described herein refer to the maximum plasma concentration in an individual patient within a time period of interest, and these maximums are not necessarily C... 最大 The local maximum can be lower than or equal to C. 最大One potential route of administration of reboxetine in a manner that results in a first local maximum and a second local maximum plasma concentration of reboxetine is to administer a first formulation containing reboxetine, followed by a second formulation containing reboxetine at a later time. The dose is administered at the time that results in both the first and second local maximum plasma concentrations of reboxetine. For example, the second formulation may be administered less than half a day after the first formulation, such as approximately 1–8 hours, approximately 8–12 hours, approximately 2–6 hours, approximately 1–2 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–5 hours, approximately 5–6 hours, approximately 6–7 hours, approximately 7–8 hours, approximately 1–3 hours, approximately 2–4 hours, approximately 3–5 hours, approximately 4–6 hours, approximately 5–7 hours, approximately 6–8 hours, or approximately 7–10 hours after the first formulation, or at any time within the range defined by any of these values.

[0079] Another method involves administering a single dosage form comprising a first releasing component and a second releasing component. Both the first and second releasing components comprise reboxetine.

[0080] In some implementations, the first dosage form administered during the day (either the only dosage form administered during the day or the first of two or more dosage forms administered during the day) is administered shortly after waking up, for example, within about 3 hours, about 2 hours, about 1.5 hours, about 1 hour, about 30 minutes, or about 15 minutes after waking up from overnight sleep.

[0081] For a single dosage form containing a first-releasing component and a second-releasing component administered throughout the day, the first-releasing component may release reboxetine, may initiate the release of reboxetine, or may cause a first local maximum plasma concentration of reboxetine at approximately 0–30 minutes, approximately 30–60 minutes, approximately 60–90 minutes, or approximately 90–120 minutes after oral administration of the dosage form, or at any time within the range defined by any of these values. The second releasing component may release reboxine after the first releasing component has released reboxine; or may cause an increase in reboxine plasma concentration or a second local maximum of reboxine plasma concentration at approximately 1–10 hours, approximately 2–6 hours, approximately 1–2 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–5 hours, approximately 5–6 hours, approximately 6–7 hours, approximately 1–3 hours, approximately 2–4 hours, approximately 3–5 hours, approximately 4–6 hours, approximately 5–7 hours, approximately 6–8 hours, or approximately 7–10 hours after the first local maximum of reboxine plasma concentration, or at any time within the range of any of these values.

[0082] The first and second releasing components can be incorporated into a single dosage form (e.g., pills, tablets, capsules, pouches, or chewing gum). In one embodiment, the first releasing component will be located in one of the outer layers of the dosage form, and the second releasing component will be located in one of the inner layers of the same dosage form.

[0083] In another embodiment, the first releasing component is located in a first layer of the dosage form, and the second releasing component is located in a second layer of the same dosage form. These two layers are distinct and may or may not be in contact with each other. In some embodiments, the two layers are stacked on top of each other and physically bonded in a bilayer structure (e.g., the maximum surfaces of the two layers are in contact with each other, or the layer is thinner compared to its other dimensions). In some embodiments, the two layers are placed adjacent to each other and physically bonded in a bilayer structure (e.g., the layer is thicker compared to its other dimensions).

[0084] In another embodiment, the first releasing component and the second releasing component can be constructed separately in the form of their own specific particles, etc., wherein the first releasing component particles are formulated to release reboxine before the second releasing component particles release reboxine, and wherein the first releasing component particles and the second releasing component particles are combined together into a single dosage form, such as capsules, pills, tablets, pouches, chewing gum, etc., and the two releasing components may or may not be physically bound to each other.

[0085] In some embodiments, the first local maximum plasma concentration of reboxetine occurs at approximately 1–30 minutes, approximately 30–60 minutes, approximately 1–2 hours, approximately 2–3 hours, or approximately 3–4 hours after administration of a single or first dosage form, or at any time within the range defined by any of these values. Typically, the second local maximum plasma concentration of reboxetine occurs less than half a day after the first local maximum plasma concentration, for example, at approximately 1–10 hours, approximately 1–2 hours, approximately 2–6 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–5 hours, approximately 5–6 hours, approximately 6–7 hours, approximately 7–8 hours, approximately 1–3 hours, approximately 2–4 hours, approximately 3–5 hours, approximately 4–6 hours, approximately 5–7 hours, approximately 6–8 hours, or approximately 7–10 hours, or at any time within the range defined by any of these values.

[0086] For dosage forms containing a first releasing component and a second releasing component, the first releasing component is associated with a first local maximum plasma concentration of reboxetine because the reboxetine released by the first releasing component contributes to the first local maximum plasma concentration of reboxetine. For example, the first releasing component may release reboxetine faster or more rapidly than the second releasing component, such that most of the reboxetine contributing to the first local maximum plasma concentration of reboxetine is released from the first releasing component.

[0087] For dosage forms containing a first releasing component and a second releasing component, the second releasing component is associated with a second local maximum plasma concentration of reboxetine because the reboxetine released by the second releasing component contributes to this second local maximum. For example, the second releasing component can delay the release of its reboxetine so that when the reboxetine plasma concentration is decreasing after the first local maximum, the second releasing component releases sufficient reboxetine to again increase the reboxetine plasma concentration to reach the second local maximum.

[0088] For dosage forms containing a first-releasing component and a second-releasing component, the first-releasing component may contain any suitable amount of reboxetine, such as about 1-10 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 1-3 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, or about 0.009-0.012 mmol. 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 the range defined by any of these values.

[0089] For dosage forms containing a first-releasing component and a second-releasing component, the second-releasing component may contain any suitable amount of reboxetine, such as approximately 0.1-2 mg, approximately 0.5-1.5 mg, approximately 1-3 mg, approximately 1-2 mg, approximately 1.5-2.5 mg, approximately 2-3 mg, approximately 2.5-3.5 mg, approximately 3-4 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 3.5-4.5 mg, approximately 4-5 mg, approximately 4.5-5.5 mg, approximately 5-6 mg, approximately 4-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 5-7 mg, approximately 7-10 mg, approximately 4 mg, approximately 5 mg, approximately 0.0003-0.006 mmol, approximately 0.006-0.009 mmol, approximately 0.009-0.012 mmol, approximately 0.012-0.015 mmol. 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 the range defined by any of these values.

[0090] The dose of reboxetine can be gradually increased over time (e.g., for 1, 2, 3, 4, 5, 6 or 7 days) to a maintenance dose, which is the total daily dose (e.g., a 10 mg maintenance dose could be a 10 mg dose once daily, or a 5 mg dose twice daily to achieve a total of 10 mg per day). In some embodiments, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, about 14-17 mg, about 17-20 mg, about 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, or about 0.021-0.024 mmol. mmol, approximately 0.024-0.027 mmol, approximately 0.027-0.03 mmol, approximately 0.03-0.033 mmol, approximately 0.033-0.036 mmol, approximately 0.036-0.039 mmol, approximately 0.039-0.042 mmol, approximately 0.042-0.045 mmol, approximately 0.045-0.048 mmol, approximately 0.048-0.051 mmol, approximately 0.051-0.054 mmol, approximately 0.054-0.057 mmol, approximately 0.057-0.06 mmol, approximately 0.06-0.063 mmol, approximately 0.063-0.066 mmol, approximately 0.066-0.069 mmol, approximately 0.006-0.01 mmol, approximately 0.01-0.02 mmol, approximately 0.02-0.03 mmol, approximately 0.03-0.04 mmol, approximately 0.04-0.05 mmol, approximately 0.05-0.06 mmol, approximately 0.06-0.07 mmol, or approximately 0.07-0.08 mmol.The maintenance dose can be administered for at least approximately 2 weeks, at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, at least approximately 6 weeks, at least approximately 7 weeks, at least approximately 8 weeks, at least approximately 9 weeks, at least approximately 10 weeks, at least approximately 11 weeks, at least approximately 12 weeks, at least 4 months, at least 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, at least 1.5 years, at least 2 years, at least approximately 3 years, at least approximately 4 years, at least approximately 5 years, at least approximately 10 years, at least approximately 20 years, or longer.

[0091] In some embodiments, the first releasing component provides immediate release of reboxetine. In some embodiments, the first releasing component provides delayed release of reboxetine. In some embodiments, the first releasing component provides sustained release of reboxetine.

[0092] In some embodiments, the second releasing component provides immediate release of reboxetine. In some embodiments, the second releasing component provides delayed release of reboxetine. In some embodiments, the second releasing component provides sustained release of reboxetine.

[0093] In some embodiments, the first releasing component provides immediate release of reboxetine, and the second releasing component provides delayed release of reboxetine. In some embodiments, the first releasing component provides immediate release of reboxetine, and the second releasing component provides sustained release of reboxetine.

[0094] Regarding the methods of administering reboxetin in both the first and second dosage forms containing reboxetin, the first dosage form may contain any suitable amount of reboxetin, such as about 1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, or about 0.006-0.009 mmol. 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 the range defined by any of these values.

[0095] Regarding the methods of administering reboxetin in both a first dosage form and a second dosage form, the second dosage form may contain any suitable amount of reboxetin, such as approximately 0.1-1 mg, approximately 0.1-2 mg, approximately 0.5-1.5 mg, approximately 1-3 mg, approximately 1-2 mg, approximately 1.5-2.5 mg, approximately 2-3 mg, approximately 2.5-3.5 mg, approximately 3-4 mg, approximately 3.5-4.5 mg, approximately 4-5 mg, approximately 4.5-5.5 mg, approximately 5-6 mg, approximately 6-7 mg, approximately 7-8 mg, approximately 8-9 mg, approximately 9-10 mg, approximately 2-4 mg, approximately 3-5 mg, approximately 4-6 mg, approximately 5-7 mg, approximately 7-10 mg, approximately 4 mg, approximately 5 mg, approximately 0.0003-0.006 mmol, approximately 0.006-0.009 mmol. 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 the range defined by any of these values.

[0096] 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.

[0097] 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.

[0098] For a single dosage form containing both a first releasing component and a second releasing component, in some embodiments, a single dose is administered within two hours of waking from overnight sleep.

[0099] In some implementations that administer more than one dosage form, the first dosage form may be administered within two hours of waking from overnight sleep.

[0100] Many factors can affect the total time required for a drug (e.g., reboxetine) to be completely absorbed and / or reach its maximum plasma concentration in the human body. Some of these factors include the patient's age, weight, sex, stress level, gastric contents, gastric pH level, and the presence of other medications. The time required to reach the maximum plasma concentration of a drug (e.g., reboxetine) can also be affected by the time of day the drug (e.g., reboxetine) is taken and the patient's level of physical activity. Another factor that can affect the time required to reach the maximum plasma concentration of a drug (e.g., reboxetine) is the presence of a controlled-release coating on the drug (e.g., reboxetine).

[0101] Controlled release includes: immediate release of a drug (e.g., reboxetine) at a specific time or in a specific area of ​​the body; delayed release of a drug; sustained release of a drug at a specific time or in a specific location in the body; or extended release of a drug (e.g., reboxetine).

[0102] Reboxetine is typically absorbed rapidly in human patients, reaching peak plasma concentrations in approximately 2–4 hours. To delay the time required to reach peak plasma concentrations, controlled-release coatings or mixtures can be used.

[0103] Delayed release is a general term for drug delivery that describes an oral form of medicine in which the active pharmaceutical ingredient is not immediately released into the patient's mouth or stomach. While there may be many ways to achieve delayed release, delayed release of reboxetine can be achieved by completely or partially surrounding reboxetine (e.g., in a second release component) with a coating or layer that does not immediately dissolve upon swallowing (e.g., an internal controlled-release coating). For example, the material of the coating or layer may slowly dissolve in the stomach and / or slowly disintegrate in the stomach through a chemical reaction (e.g., by hydrolysis) until the layer no longer prevents reboxetine from contacting gastric juices.

[0104] In some embodiments, the delayed-release coating ensures delivery through the stomach and into the intestines. Once in the duodenum, the coating begins to break down and release reboxetine. In some cases, reboxetine may be completely released in the duodenum. In some embodiments, reboxetine may be partially released in the duodenum and partially released in the jejunum. In some cases, reboxetine may be completely released in the jejunum. In some cases, reboxetine may be partially released in the jejunum and partially released in the iliac crest. In some cases, reboxetine may be completely released in the iliac crest. In some cases, reboxetine may be partially released in the duodenum, jejunum, and iliac crest. In some embodiments, reboxetine may be partially released in the iliac crest and partially released in the colon. In some cases, reboxetine may be completely released in the colon.

[0105] The time of delayed release, such as the time between the release of the first and second reboxetine components, can be regulated by using materials that dissolve or disintegrate more or less slowly in the digestive system, adjusting the thickness of the coating layer or coating material (e.g., a thicker layer will provide a longer release time), and / or by using materials with pH-sensitive properties. For example, materials that are less stable at acidic pH or more soluble at acidic pH may dissolve or disintegrate more quickly in the stomach because the stomach pH is lower than the intestinal pH. Conversely, materials that are stable at low pH but less stable at higher pH may dissolve or disintegrate later due to the time it takes for the dosage form to be transported through the gastrointestinal tract.

[0106] 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 coatings), moisture-proof coatings, enteric polymer coatings, etc.

[0107] Depending on the formulation's structure, controlled-release polymers can be used for sustained-release or delayed-release. For example, dispersing reboxetine throughout a controlled-release polymer provides sustained release because the drug is released as long as the polymer is present in the gastrointestinal tract. Delayed release can be achieved by creating a barrier (e.g., a coating) designed to last for a short time (e.g., less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) so that reboxetine is freely released when the barrier is breached. The thickness of the barrier can be used to control the delay time.

[0108] Any suitable controlled-release polymer can be used, such as acrylic acid and methacrylic acid copolymers and their various esters, 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), and glycidyl methacrylate copolymers.

[0109] Other suitable controlled-release polymers include polymerizable quaternary ammonium compounds, such as quaternized aminoalkyl esters and aminoalkylamides of acrylic acid and methacrylic acid, such as β-methacryloyloxyethyltrimethylammonium methyl sulfate, β-acryloyloxypropyltrimethylammonium chloride, and trimethylaminomethacrylamide methyl sulfate. The quaternary ammonium atom can also be part of a heterocycle, as in methacryloyloxyethylmethylmorpholine chloride or the corresponding piperidinium salt, or it can be linked to an acrylic acid group or a methacrylic acid group via a heteroatom-containing group (such as a polyethylene glycol ether group). Other suitable polymerizable quaternary ammonium compounds include quaternized vinyl-substituted nitrogen heterocycles, such as methyl-vinylpyridinium salts, quaternized vinyl esters of aminocarboxylic acids, styryltrialkylammonium salts, etc. Other polymerizable quaternary ammonium compounds include benzyl dimethylammonium ethyl-methacrylate chloride, diethylmethylammonium ethyl-acrylate and methyl methacrylate methyl sulfate, N-trimethylammonium propylmethacrylamide chloride, and N-trimethylammonium-2,2-dimethylpropyl-1-methacrylate chloride.

[0110] Delayed release can also be achieved by using controlled-release polymers targeted to a specific pH, where it should be understood that, with appropriate fasting or feeding, a specific pH can correspond to a specific time after administration.

[0111] For some controlled-release polymers, acrylic or methacrylic polymers include one or more ammonium methacrylate copolymers. Ammonium methacrylate copolymers (such as those sold by Evonik under the trademarks EUDRAGIT® RS and RL) are fully polymerized copolymers of acrylates and methacrylates, wherein the fully polymerized copolymers have a low content of quaternary ammonium groups. The ammonium groups are attached to the ester portion of the methacrylate (as 2-trimethylammonium-ethyl ester). The charged ammonium groups in these polymers make them insoluble and highly permeable, and exhibit pH-independent swelling. These properties make these polymers suitable for customized, time-controlled release of coated drugs. To obtain the desired solubility properties for a given therapeutic agent (such as reboxetine), two or more ammonium methacrylate copolymers with different physical properties can be incorporated. For example, it is known that the permeability of the resulting coating can be modified by changing the molar ratio of a prepolymer containing quaternary ammonium groups to a prepolymer containing uncharged neutral methacrylates or acrylates.

[0112] In other embodiments, the controlled-release coating also includes a pH-dependent polymer, such as anionic polymers synthesized from methacrylic acid and methyl methacrylate. These polymers are commercially available, for example, from Evonik under the trade names EUDRAGIT® L and EUDRAGIT® S. The free carboxyl to ester ratio is known to be 1:1 in EUDRAGIT® L and 1:2 in EUDRAGIT® S. EUDRAGIT® L is insoluble in acids and pure water, but becomes increasingly permeable above pH 5.0. This makes EUDRAGIT® L suitable for targeted release of coated drugs, such as coated reboxetine, in the duodenum and jejunum of the small intestine. Therefore, compared to uncoated or immediate-release drugs (such as reboxetine in the first-release component), EUDRAGIT® L-coated drugs can achieve a maximum plasma concentration delay of about 30 minutes to about 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about 2.5-3 hours, or about 3.5-4 hours.

[0113] EUDRAGIT® S is similar to EUDRAGIT® L, except that it becomes increasingly permeable above pH 7. This makes EUDRAGIT® S suitable for targeted release of coated drugs, such as coated reboxetine, in the ileum of the small intestine and in the colon. Therefore, compared to uncoated or immediately released drugs (such as reboxetine in the first-release fraction), EUDRAGIT® S-coated drugs can achieve a maximum plasma concentration delay of approximately 1–2 hours, approximately 2–3 hours, approximately 3–4 hours, approximately 4–5 hours, approximately 5–6 hours, approximately 6–7 hours, approximately 7–8 hours, approximately 8–9 hours, or approximately 9–10 hours.

[0114] Hydrophobic acrylic polymer coatings may also include polymers based on dimethylaminoethyl methacrylate and neutral methacrylates (e.g., EUDRAGIT® E, commercially available from Evonik). EUDRAGIT® E is insoluble in saliva (making it suitable for masking tastes and odors) but soluble in gastric juices at pH 5 or lower, providing immediate drug release in the stomach. Reboxetine coated with EUDRAGIT® E may release reboxetine, initiate reboxetine release, or result in a first local maximum plasma concentration of reboxetine at approximately 0–30 minutes, 30–60 minutes, 60–90 minutes, or 90–120 minutes after oral administration of this formulation, or at any time within the range defined by any of these values.

[0115] Hydrophobic acrylic polymer coatings may contain neutral copolymers based on polymethacrylates, such as EUDRAGIT® NE (NE = neutral ester), commercially available from Evonik. EUDRAGIT® NE 30D films are insoluble in water and digestive fluids, but are permeable and swellable, thus providing another option for time-controlled release. EUDRAGIT® NE exhibits a pH-independent sustained-release effect, which can release drugs (such as reboxetine) over a period of time, or delay release over a period of time, wherein the release or delay time is approximately 1–24 hours, approximately 1–18 hours, approximately 1–12 hours, approximately 1–8 hours, or approximately 1–6 hours.

[0116] In some embodiments, the controlled-release coating comprises a polymer containing ethyl acrylate and methyl methacrylate in a 2:1 ratio (KOLLICOAT® EMM 30 D, BASF). KOLLICOAT® EMM 30 D has a pH-independent sustained-release effect that can release a drug (such as reboxetine) over a period of time or delay its release over a period of time, wherein the release or delay time is approximately 1–24 hours, approximately 1–18 hours, approximately 1–12 hours, approximately 1–8 hours, or approximately 1–6 hours.

[0117] In some embodiments, the controlled-release coating comprises polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium dodecyl sulfate, such as KOLLICOAT® SR30D (BASF). The solubility properties can be altered by changing the relative amounts of different acrylic resins contained in the coating. Furthermore, the permeation properties (which affect solubility properties) of the resulting coating can be altered by changing the molar ratio of a polymerizable permeation enhancer (e.g., a quaternary ammonium compound) to a neutral methacrylate. KOLLICOAT® SR30D is another coating with a pH-independent sustained-release effect that can release a drug (such as reboxetine) over a period of time or delay its release over a period of time, wherein the release or delay time is approximately 1–24 hours, approximately 1–18 hours, approximately 1–12 hours, approximately 1–8 hours, approximately 1–6 hours, approximately 1–4 hours, or approximately 1–2 hours.

[0118] In some embodiments, the controlled-release coating comprises ethyl cellulose, which can be used as a dry polymer solubilized in an organic solvent before use (e.g., ETHOCEL™, Dow Chemical Company) or as an aqueous dispersion. A suitable commercially available aqueous dispersion of ethyl cellulose is Aquacoat® (Danisco). Aquacoat® ECD (Aqueous Dispersion of Ethyl Cellulose), Aquacoat® ARC (Aqueous Dispersion of Ethyl Cellulose Resistant to Alcohol), and Aquacoat® CPD (Aqueous Dispersion of Cellulose Acetate Phthalate) are all commercially available controlled-release coatings. Another suitable aqueous dispersion of ethyl cellulose is Surelease® (Colorcon, Inc.), which is commercially available. This product can be prepared by incorporating a plasticizer into the dispersion during the manufacturing process. The polymer, plasticizer (e.g., dibutyl sebacate), and stabilizer (e.g., oleic acid) can be hot-melted and prepared into a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion that can be directly applied to a substrate. These coatings have a pH-independent sustained-release effect that can release the drug (such as reboxetine) over a period of time or delay the release over a period of time, wherein the release or delay time is approximately 1–24 hours, approximately 1–18 hours, approximately 1–12 hours, approximately 1–8 hours, approximately 1–6 hours, approximately 1–4 hours, or approximately 1–2 hours.

[0119] Other examples of polymers that can be used in controlled-release coatings include cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogels and gel-forming materials such as carboxyvinyl polymers, sodium alginate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose-based crosslinked polymers (where the degree of crosslinking is low enough to promote water adsorption and swelling of the polymer matrix), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, amylopectin, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular weight from 5 k to 5000 k), polyvinylpyrrolidone (molecular weight from 10 k to 360 k). k), anionic and cationic hydrogels, corn protein, polyamides, polyvinyl alcohol with low acetate residues, swellable mixtures of agar and carboxymethyl cellulose, copolymers of maleic anhydride with styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, gum arabic, ark tartaric acid gum, tragacanth gum, alginic acid gum and guar gum, polyacrylamide, POLYOX® polyoxyethylene (molecular weight 100 k to 5000 k, Dow), AQUA KEEP® acrylate polymers (primarily composed of acrylic polymers and sodium salts), diesters of polydextrose, crosslinked polyvinyl alcohol and poly-N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methylcellulose, sodium or calcium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitrocellulose, carboxymethyl cellulose, cellulose ethers, methylethyl cellulose, ethyl hydroxyethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, amylopectin, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithin, pectin, alginate, ammonium alginate, sodium alginate, calcium alginate, potassium alginate, propylene glycol alginate, agar and gums such as gum arabic, ebony gum, locust bean gum, tragacanth gum, carrageenan, guar gum, xanthan gum, stearin, and mixtures and blends thereof.

[0120] In some embodiments, the dosage form of reboxetine is coated with a polymer to promote mucosal adhesion in the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucosal adhesion include carboxymethyl cellulose, polyacrylic acid, Carbopol™ (Lubrizol), polycarboxylic acid, gelatin, and other natural or synthetic polymers.

[0121] The polymer coating disclosed herein may be any one of the coatings, or a combination of two or more of the coatings, to achieve the desired release characteristics for reboxetine release.

[0122] In addition to the improved release formulations described herein, other improved release technologies known to those skilled in the art can also be used to achieve the improved release formulations of this disclosure, i.e., providing the average T0 of the drug described herein when administered to a human patient (e.g., orally or via other modes of administration). 最大 Formulations with and / or other pharmacokinetic parameters. Such formulations can be formulated into improved release oral formulations in the form of tablets or multiparticles known to those skilled in the art. In either case, the improved release dosage form may optionally include a controlled-release carrier incorporated into the matrix together with the drug, or administered as a controlled-release coating.

[0123] Any dosage form containing an effective amount of reboxetine may also contain binders, lubricants, and other conventional inert excipients.

[0124] Binders (sometimes also called adhesives) can be added to drug-filler mixtures to increase the mechanical strength of granules and tablets during formation. Binders can be added to formulations in different ways: (1) as a dry powder that is mixed with other components before wet agglomeration, (2) as a solution that serves as the agglomeration liquid during wet agglomeration and is referred to as a solution binder, and (3) as a dry powder that is mixed with other components before compaction. In this form, the binder is referred to as a dry binder. Solution binders are a common way to incorporate binders into granules. In some embodiments, the binder used in tablets is in the form of a solution binder. Non-limiting examples of useful binders include hydrogenated vegetable oils, castor oil, paraffin wax, higher fatty alcohols, higher fatty acids, long-chain fatty acids, fatty acid esters, waxy substances such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having a hydrocarbon backbone, and mixtures thereof. Specific examples of water-soluble polymeric binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol, and mixtures thereof. Any suitable amount of binder may be present, for example, about 0.5-5% by weight, about 5-10% by weight, about 10-15% by weight, about 15-20% by weight, about 20-25% by weight, about 0.5-25% by weight, about 0.5-15% by weight, about 1-6% by weight, or about 3% by weight, based on the dry weight of the tablet. In some embodiments, the binder is polyvinyl alcohol.

[0125] Lubricants can be added to pharmaceutical formulations to reduce any friction that occurs between the solid and the mold wall during tablet manufacturing. High friction during tableting can lead to a range of problems, including inadequate tablet quality (tablets being capped or even broken during ejection, and vertical scratches on the tablet edges) and may even halt production. Therefore, lubricants can be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils (e.g., hydrogenated cottonseed oil (STEROTEX®), hydrogenated soybean oil (STEROTEX® HM), and hydrogenated soybean oil and castor wax (STEROTEX® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, suitably 4000 and higher), magnesium stearate, glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymers (e.g., available from Union Carbide, Inc., Danbury, Conn. under the registered trademark CARBOWAX®), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearoyl fumarate, DL-leucine, colloidal silica, mixtures thereof, and other substances known in the art. In some embodiments, the lubricant is glyceryl behenate (e.g., COMPRITOL®). 888). Any suitable amount of binder may be present, for example, about 0.5-5% by weight, about 5-10% by weight, about 10-15% by weight, about 15-20% by weight, about 20-25% by weight, about 0.5-25% by weight, about 0.5-15% by weight, about 1-6% by weight, or about 3% by weight, based on the dry weight of the tablets.

[0126] In some implementations, reboxetine is administered once or twice daily for at least approximately 3 weeks, at least approximately 4 weeks, at least approximately 5 weeks, at least approximately 6 weeks, at least approximately 7 weeks, at least approximately 8 weeks, at least approximately 9 weeks, at least approximately 10 weeks, at least approximately 11 weeks, at least approximately 12 weeks, at least approximately 4 months, at least approximately 5 months, at least approximately 6 months, at least approximately 7 months, at least approximately 8 months, at least approximately 9 months, at least approximately 10 months, at least approximately 11 months, at least approximately 12 months, at least 1.5 years, at least 2 years, at least approximately 3 years, at least approximately 4 years, at least approximately 5 years, approximately 0.1-5 years, approximately 5-10 years, at least approximately 10 years, approximately 10-15 years, at least approximately 15 years, approximately 15-20 years, at least approximately 20 years, or longer.

[0127] Examples of useful compositions for dosage forms containing about 5-10 mg of reboxetine (without attempting to limit the scope of this disclosure) are shown in Table 1 below:

[0128] Table 1. Examples of Reboxetine Dosage Forms

[0129]

[0130] Treatment of cataplexy with reboxetine in the formulations described herein may not have the same significant side effects as existing treatment options. Treatment of cataplexy with reboxetine in the formulations described herein is well tolerated in mammals such as humans.

[0131] Some embodiments include a kit comprising a pharmaceutical composition containing 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 one unit dosage form contains about 0.1-5 mg of reboxetine; and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy.

[0132] Some embodiments include a kit comprising a pharmaceutical composition containing 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 one unit dosage form contains about 5-10 mg of reboxetine; and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy.

[0133] Some embodiments include a kit comprising a pharmaceutical composition containing 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 one unit dosage form contains about 10-15 mg of reboxetine; and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy.

[0134] Some embodiments include a kit comprising a pharmaceutical composition containing 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 one unit dosage form contains about 15-20 mg of reboxetine; and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy.

[0135] Some embodiments include a kit comprising a pharmaceutical composition containing 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 one unit dosage form contains about 5-20 mg of reboxetine; and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy.

[0136] Example

[0137] Example 1

[0138] A 40-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the number of cataplexy episodes decreased by 10-30%.

[0139] Example 2

[0140] A 20-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the number of cataplexy episodes decreased by 30-60%.

[0141] Example 3

[0142] A 60-year-old man was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the number of cataplexy episodes decreased by 60-100%.

[0143] Example 4

[0144] A 50-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the ESS score decreased by 10-30%.

[0145] Example 5

[0146] A 25-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the ESS score had decreased by 30-60%.

[0147] Example 6

[0148] A 47-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the ESS score decreased by 60-100%.

[0149] Example 7

[0150] A 19-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the MWT score decreased by 10-30%.

[0151] Example 8

[0152] A 42-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the MWT score decreased by 30-60%.

[0153] Example 9

[0154] A 33-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After one week of treatment, the MWT score decreased by 60-100%.

[0155] Example 10

[0156] A 54-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the frequency of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the frequency of cataplexy episodes decreased by 10-30%.

[0157] Example 11

[0158] A 27-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the frequency of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the frequency of cataplexy episodes decreased by 30-60%.

[0159] Example 12

[0160] A 52-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the frequency of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the frequency of cataplexy episodes decreased by 60-100%.

[0161] Example 13

[0162] A 66-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the ESS score decreased by 10-30%.

[0163] Example 14

[0164] A 34-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the ESS score decreased by 30-60%.

[0165] Example 15

[0166] A 35-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the ESS score decreased by 60-100%.

[0167] Example 16

[0168] A 19-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the MWT score decreased by 10-30%.

[0169] Example 17

[0170] A 70-year-old woman was diagnosed with cataplexy-type narcolepsy. She was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the MWT score decreased by 30-60%.

[0171] Example 18

[0172] A 57-year-old male was diagnosed with cataplexy-type narcolepsy. He was given reboxetine and instructed to take 5 mg of reboxetine at 8 a.m. and 5 mg of reboxetine at 1 p.m. for three weeks. The patient was assessed before treatment and weekly to determine the number of cataplexy episodes, ESS score, and MWT score. After three weeks of treatment, the MWT score decreased by 60-100%.

[0173] Unless otherwise stated, all figures used in the specification and claims to indicate the quantity, nature (e.g., amount, percentage), etc., of components should in all cases be understood to represent precise values ​​and be modified by the term "about". Therefore, unless indicated to the contrary, the numerical parameters listed in the specification and appended claims are approximate values ​​that may vary depending on the desired properties sought. At the very least, and not in an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be understood at least according to the reported significant number and the application of ordinary rounding.

[0174] In the context of describing embodiments (especially in the context of the appended claims), the use of the terms "a," "an," "the," and similar designations, and the absence of quantifiers, should be understood to cover both singular and plural forms, unless otherwise stated herein or clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise stated herein or clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "for example") provided herein is intended only to better illustrate embodiments and does not constitute a limitation on the scope of any claim. No language in the specification should be construed as indicating that any non-claim element is necessary to implement the claims.

[0175] The grouping of alternative elements or embodiments disclosed herein should not be construed as limiting. Each member of a group may be mentioned and claimed individually or in any combination with other members of that group or other elements found herein. It is foreseeable that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. When any such inclusion or removal occurs, the specification is deemed to include the modified group, thus completing the description of the entire Markush group as used in the appended claims.

[0176] Certain embodiments are described herein, including the best mode known to the inventors for implementing the claimed embodiments. Of course, variations of these described embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors anticipate that those skilled in the art will adopt these modifications as appropriate, and the inventors intend that the claimed embodiments be implemented in ways different from those specifically described herein. Therefore, the claims include all modifications and equivalents of the subject matter described in the claims as permitted by applicable law. Furthermore, any combination of all possible variations of the foregoing elements is contemplated unless otherwise stated herein or clearly contradicted by the context.

[0177] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications may be made within the scope of the claims. Therefore, alternative embodiments may be utilized based on the teachings of this document, rather than as examples or limitations. Consequently, the claims are not limited to the embodiments shown and described precisely.

[0178] This disclosure relates to the following implementation plan:

[0179] 1. A method for treating cataplexy-type narcolepsy, the method comprising administering reboxetine to a person in need, wherein the reboxetine is administered at least once daily for at least three weeks, wherein, as a result of the treatment, within two weeks from the start of treatment, the person experiences a decrease in the number of cataplexy attacks within one week, a decrease in the Epworth Somnolence Scale score, a decrease in the cataplexy subscale score of the Ullanlinna Narcolepsy Scale (NUS), or a decrease in the Stay Awake Test score.

[0180] 2. Use of reboxetine in the manufacture of a medicine for the treatment of cataplexy-type narcolepsy, wherein reboxetine is administered at least once daily for at least three weeks.

[0181] 3. A kit comprising a pharmaceutical composition containing reboxetine, and instructions for use of the pharmaceutical composition for treating cataplexy narcolepsy in humans, wherein reboxetine is administered at least once daily for at least three weeks.

[0182] 4. The method, use, or kit according to item 1, 2, or 3, wherein reboxetine is administered twice daily, wherein the first dosage form is administered in the morning and the second dosage form is administered approximately 2 to approximately 6 hours later.

[0183] 5. The method, use, or kit according to item 4, wherein the second dosage form is administered about 2 to about 3 hours after the first dosage form.

[0184] 6. The method, use, or kit according to item 4, wherein the second dosage form is administered about 3 to about 4 hours after the first dosage form.

[0185] 7. The method, use, or kit according to item 4, wherein the second dosage form is administered about 4 to about 5 hours after the first dosage form.

[0186] 8. The method, use, or kit according to item 4, wherein the second dosage form is administered about 5 to about 6 hours after the first dosage form.

[0187] 9. The method, use, or kit according to claim 1, wherein a single dosage form is administered daily, wherein the single dosage form comprises a first releasing component containing reboxetin and a second releasing component containing reboxetin, wherein the first releasing component provides a first local maximum plasma concentration of reboxetin, and the second releasing component provides a second local maximum plasma concentration of reboxetin, wherein the first local maximum plasma concentration of reboxetin occurs approximately 2 to approximately 6 hours prior to the second local maximum plasma concentration of reboxetin.

[0188] 10. The method, use, or kit according to item 9, wherein the second local maximum of reboxetine plasma concentration occurs approximately 2 to 3 hours after the first local maximum of reboxetine plasma concentration.

[0189] 11. The method, use, or kit according to item 9, wherein the second local maximum of reboxetine plasma concentration occurs approximately 3 to approximately 4 hours after the first local maximum of reboxetine plasma concentration.

[0190] 12. The method, use, or kit according to item 9, wherein the second local maximum of reboxetine plasma concentration occurs approximately 4 to 5 hours after the first local maximum of reboxetine plasma concentration.

[0191] 13. The method, use, or kit according to item 9, wherein the second local maximum of reboxetine plasma concentration occurs approximately 5 to 6 hours after the first local maximum of reboxetine plasma concentration.

[0192] 14. The method, use, or kit according to items 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the person is selected as not suffering from depression.

[0193] 15. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.006 mmol to about 0.01 mmol.

[0194] 16. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.01 mmol to about 0.02 mmol.

[0195] 17. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.02 mmol to about 0.03 mmol.

[0196] 18. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.03 mmol to about 0.04 mmol.

[0197] 19. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.04 mmol to about 0.05 mmol.

[0198] 20. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.05 mmol to about 0.06 mmol.

[0199] 21. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.06 mmol to about 0.07 mmol.

[0200] 22. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dose of reboxetine is increased for 1 to 7 days and then kept constant at a total daily dose of about 0.07 mmol to about 0.08 mmol.

[0201] 23. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein reboxetine is a dosage form and said dosage form contains about 5 mg of reboxetine.

[0202] 24. The method, use, or kit according to item 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein reboxetine is a dosage form and said dosage form contains about 10 mg of reboxetine.

[0203] 25. The method, use, or kit according to item 23, wherein the dosage form is administered once or twice daily for at least three weeks.

[0204] 26. The method, use, or kit according to item 24, wherein the dosage form is administered once or twice daily for at least three weeks.

[0205] 27. The method, use, or kit according to item 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, wherein the person experiences prolonged sleep latency on a multiple sleep latency test (MSLT).

[0206] 28. The method, use, or kit according to item 27, wherein the person experiences at least 10% prolongation of sleep latency on MSLT.

[0207] 29. The method, use, or kit according to item 27, wherein the person experiences at least 20% prolongation of sleep latency on MSLT.

[0208] 30. The method, use, or kit according to item 27, wherein the person experiences at least 30% prolongation of sleep latency on MSLT.

[0209] 31. The method, use, or kit according to item 27, wherein the person experiences at least 40% prolongation of sleep latency on MSLT.

[0210] 32. The method, use, or kit according to item 27, wherein the person experiences at least 50% prolongation of sleep latency on MSLT.

[0211] 33. The method, use, or kit according to item 27, wherein the person experiences at least 60% prolongation of sleep latency on MSLT.

[0212] 34. The method, use, or kit according to item 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, wherein the person experiences at least a 15% reduction in burst score on the UNS.

[0213] 35. The method, use, or kit according to item 34, wherein the person experiences at least a 20% reduction in burst score on the UNS.

[0214] 36. The method, use, or kit according to item 34, wherein the person experiences at least a 30% reduction in burst score on the UNS.

[0215] 37. The method, use, or kit according to item 34, wherein the person experiences at least a 40% reduction in burst score on the UNS.

[0216] 38. The method, use, or kit according to item 34, wherein the person experiences at least a 50% reduction in burst score on the UNS.

[0217] 39. The method, use, or kit according to item 34, wherein the person experiences at least a 60% reduction in burst score on the UNS.

[0218] 40. The method, use, or kit according to item 34, wherein the person experiences at least a 70% reduction in burst score on the UNS.

[0219] 41. The method, use, or kit according to item 34, wherein the person’s sudden death score is about 0.

Claims

1. A method for treating cataplexy-type narcolepsy, the method comprising administering reboxetine to a person in need, wherein the reboxetine is administered at least once daily for at least three weeks, wherein, as a result of the treatment, within two weeks from the start of treatment, the person experiences a reduction in the number of cataplexy attacks within one week, a decrease in the Epworth Somnolence Scale score, a decrease in the cataplexy subscale score of the Ullanlinna Narcolepsy Scale (NUS), or a decrease in the Stay Awake Test score.

2. Use of reboxetine in the manufacture of a medicine for the treatment of cataplexy-type narcolepsy, wherein reboxetine is administered at least once daily for at least three weeks.

3. A kit comprising a pharmaceutical composition containing reboxetine, and instructions for use of the pharmaceutical composition for treating cataplexy-type narcolepsy in humans, wherein reboxetine is administered at least once daily for at least three weeks.

4. The method, use, or kit according to claim 1, 2, or 3, wherein reboxetine is administered twice daily, wherein the first dosage form is administered in the morning and the second dosage form is administered approximately 2 to approximately 6 hours later.

5. The method, use, or kit according to claim 4, wherein the second dosage form is administered about 2 to about 3 hours after the first dosage form.

6. The method, use, or kit according to claim 4, wherein the second dosage form is administered about 3 to about 4 hours after the first dosage form.

7. The method, use, or kit of claim 1, wherein a single dosage form is administered daily, wherein the single dosage form comprises a first releasing component comprising reboxine and a second releasing component comprising reboxine, wherein the first releasing component provides a first local maximum plasma concentration of reboxine, and the second releasing component provides a second local maximum plasma concentration of reboxine, wherein the first local maximum plasma concentration of reboxine occurs approximately 2 to approximately 6 hours prior to the second local maximum plasma concentration of reboxine.

8. The method, use, or kit according to claim 7, wherein the second local maximum of reboxetine plasma concentration occurs approximately 3 to approximately 4 hours after the first local maximum of reboxetine plasma concentration.

9. The method, use, or kit of claim 7, wherein the second local maximum of reboxetine plasma concentration occurs approximately 4 to 5 hours after the first local maximum of reboxetine plasma concentration.

10. The method, use, or kit of claim 7, wherein the second local maximum of reboxetine plasma concentration occurs approximately 5 to 6 hours after the first local maximum of reboxetine plasma concentration.

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