KR20210071046A - Uses of Reboxetine for the Treatment of Narcolepsy - Google Patents

Abstract

Described herein is a method of treating narcolepsy with cataplexy comprising administering to a human in need thereof reboxetine. Reboxetine may also be used in the manufacture of a medicament for treating narcolepsy with cataplexy. Also disclosed herein is a kit comprising a pharmaceutical composition comprising reboxetine and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human.

Description

Uses of Reboxetine for the Treatment of Narcolepsy

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of US Provisional Application No. 62/745,956, filed on October 15, 2018, which is incorporated herein by reference in its entirety.

Narcolepsy is a serious and debilitating neurological condition that causes dysregulation of the sleep-wake cycle and is clinically characterized by excessive daytime sleepiness (EDS), cataplexy, hypnotic hallucinations, sleep paralysis, and disturbances of nocturnal sleep. Narcolepsy is estimated to afflict approximately 185,000 people in the United States. Cataplexy occurs in about 70% of patients with narcolepsy, and is a sudden decrease or loss of muscle tone while the patient is awake, usually triggered by strong emotions such as laughter, fear, anger, stress, or excitement. Narcolepsy type 1 includes cataplexy, whereas narcolepsy type 2 does not include cataplexy. Narcolepsy interferes with cognitive, psychological, and social functioning, increases the risk of work- and driving-related accidents, and is associated with a 1.5-fold higher mortality rate. Depression is reported in up to 57% of patients. The debilitating effects of narcolepsy affect approximately 200,000 patients in the United States with this disorder. Narcolepsy interferes with mental and social functioning, increases work- and driving-related accidents, and results in an almost two-fold higher mortality rate. Unfortunately, currently approved therapies are few for these underdiagnosed rare conditions and are limited by variability in efficacy from patient to patient, tolerability issues and the need for DEA scheduling.

Described herein is a method of treating narcolepsy with cataplexy comprising administering to a human in need thereof reboxetine.

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

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

In some embodiments, reboxetine is administered at least once per day for at least 3 weeks. In some embodiments, 3 weeks after initiation of treatment, the human experiences a decrease in the number of cataplexy, a decrease in the Epworth Sleepiness Scale score, and a decrease in the maintenance of arousal test score, within 1 week as a result of the treatment.

Reboxetine has the potential to treat the symptoms of narcolepsy in combination with the need for no DEA scheduling, which would represent a significant benefit to patients suffering from this condition.

A person may have type 1 narcolepsy if the following criteria A and B are met:

A. The patient has an uncontrollable period in which he must sleep daily or during the day for at least 3 months.

B. The presence of one or both of the following:

1. Catalytic seizures ( as defined in Essential Characteristics ), and mean sleep latency of < 8 min, sleep onset REM duration (SOREMP) of ≥ 2 in the mean sleep latency test (MSLT) performed according to standard techniques. SOREMP (within 15 minutes of onset of sleep) in the preceding laboratory-based polysomnography (PSG) may replace one of the SOREMPs in MSLT.

2. CSF hypocretin-1 concentration measured by immunoreactivity of <100 pg/mL or <1/3 of the mean value obtained in normal subjects with the same assay.

In young children, narcolepsy can sometimes manifest as an excessively long night's sleep or as a resumption of a previously interrupted nap. If type 1 narcolepsy is strongly suspected clinically but criterion B2 is not met, a possible strategy is to repeat the MSLT.

Some patients treated with reboxetine are at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 15 years, at least about 20 years, at least about 25 years, at least about 30 years, at least about 40 years, at least about 50 years, at least about 60 years, about 3 years -9 months, about 9-18 months, about 18 months to about 2 years, about 2-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25 -30 years, about 30-35 years, about 35-40 years, about 40-50 years, about 50-60 years, or longer have uncontrollable periods of having to sleep every day or during the daytime and/or may be selected as a patient with

Some patients treated with reboxetine have 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 minute, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1 minute, Patients may be selected to have and/or have a mean sleep latency of about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes.

Some patients treated with reboxetine may have, and/or may be selected as patients with, at least 2, at least 3, or at least 4 SOREMPs in MSLT (Mean Sleep Latency Test) performed according to standard techniques. SOREMPs within 15 minutes of onset of sleep in the preceding night PSG can replace one of the SOREMPs in MSLT.

Some patients treated with reboxetine have 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, A patient may be selected for having and/or having a CSF hypocretin-1 concentration measured by an immunoreactivity of less than about 100 pg/mL and less than about 110 pg/mL.

Some patients treated with reboxetine have 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, about 1 of the mean values obtained in normal subjects in the same assay. A patient may be selected for having and/or having a CSF hypocretin-1 concentration measured by an immunoreactivity of less than /5, less than about one-quarter, or less than about one-third.

Some patients treated with reboxetine may be young children with excessively long nights of sleep and/or may be selected as young children.

Some patients treated with reboxetine may be young children resuming previously interrupted naps and/or may be selected as young children.

Some patients treated with reboxetine have 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 on the Ullanlinna Narcolepsy Scale (UNS). , 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 between 1 and 11 A patient may be selected to have and/or have a cataplexy item score that is a number of

Some patients treated with reboxetine are 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 Epworth Drowsiness Scale (ESS) scores can be selected for and/or have an Epworth Sleepiness Scale (ESS) score.

Some patients treated with reboxetine have 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 9 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, about 19 less than a minute, less than about 20 minutes, about 0-1 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 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15 -16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 0-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes Minutes, about 16-20 minutes, or about 0-19 minutes may be selected as patients with and/or have a maintenance of arousal test (MWT) score.

In some embodiments, the patient has about 1-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years before receiving reboxetine for treatment. years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, Patients may be selected for having and/or having symptoms of narcolepsy for about 70-75, or at least 75 years.

In some embodiments, the patient is about 0-5 years old, about 5-10 years old, about 10-15 years old, about 15-20 years old, about 20-25 years old, about 25-30 years old before receiving reboxetine for treatment. about 30-35 years old, about 35-40 years old, about 40-45 years old, about 45-50 years old, about 50-55 years old, about 55-60 years old, about 60-65 years old, about 65-70 years old, about 70-75 years of age, or greater than 75 years of age, and/or may be selected as a patient of said age.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may be and/or may be selected to be female.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may be male and/or may be selected to be male.

Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may or may not have any clinically significant condition potentially causing EDS. can be chosen. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have any clinically significant psychiatric disorder. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have and/or may be selected to not have any type of depression not due to narcolepsy. . Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may or may not have any drowsiness due to depression not attributable to narcolepsy. can be Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no affective disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no psychiatric disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected as patients without brain dysfunction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no movement disorders. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have dementia and/or may be selected as not having dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no motor neuron disease.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no neurodegenerative disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no seizure disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may and/or may be selected to have no headache. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have depression and/or may be selected as not having depression. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have major depression. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have treatment-resistant depression.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no treatment-resistant bipolar depression. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have bipolar disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no circulatory disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as patients without, seasonal affective disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no mood disorders. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have and/or may be selected to not have chronic depression (e.g., dysthymia). have. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected for not having psychotic depression.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have postpartum depression. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no premenstrual dysphoric disorder (PMDD). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have situational depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as not having, atypical depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have mania and/or may be selected as not having mania. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have, and/or may be selected as patients without, an anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have attention deficit disorder (ADD).

Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may or may not have attention deficit disorder with hyperactivity (ADDH); can Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have, and/or will be selected as not having, attention deficit/hyperactivity disorder (AD/HD). can Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no manic condition. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected to have, no obsessive compulsive disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no bulimia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have obesity or weight gain and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no chronic fatigue syndrome.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected to do not have, premenstrual syndrome. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have drug addiction or abuse. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have nicotine addiction. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no mental sexual dysfunction. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have emotional incontinence and/or may be selected as not having emotional incontinence. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no emotional instability.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have, and/or may be selected as patients without, an anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no phobias. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no generalized anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no social anxiety disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as patients without, panic disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no agoraphobia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected to have, no obsessive compulsive disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected as patients without post-traumatic stress disorder (PTSD). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have mania and/or may be selected as not having mania.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have bipolar disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no hypomania. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no unipolar depression. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no stress disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no somatic disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no personality disorder. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no psychosis.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have schizophrenia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no delusional disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as patients without, schizoaffective disorder. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no schizophrenia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not and/or may be selected as non-aggressive patients. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected for not having aggression in Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no agitation. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected as patients who do not have agitation in Alzheimer's disease.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have drug dependence and/or may be selected as not having drug dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have cocaine addiction and/or may be selected as patients without cocaine addiction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have psychostimulant addiction or dependence, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have drug addiction or dependence and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have cocaine addiction or dependence, and/or may be selected as not having cocaine addiction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, do not have rate addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have methamphetamine addiction or dependence, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have nicotine addiction or dependence.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have alcoholism or dependence and/or may be selected as patients without alcoholism. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have opiate addiction or dependence, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have, and/or may be selected as not having, anxiolytic and/or hypnotic addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have cannabis (marijuana) addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have amphetamine addiction or dependence. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have hallucinogen addiction or dependence, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have phencyclidine addiction or dependence and/or may be selected as patients without.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have volatile solvent intoxication or dependence. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have volatile nitrite intoxication or dependence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have senile dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have Alzheimer's type dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have memory loss and/or may be selected to have no memory loss. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no forgetfulness/amnesia syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have epilepsy and/or may be selected as patients without epilepsy. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have impaired consciousness and/or may be selected as patients without.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or be selected to not have coma. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no attention deficit. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no speech impairment. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have negative convulsions. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Parkinson's disease, and/or may be selected as not having Parkinson's disease. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Lennox-Gastaut syndrome and/or may be selected to not have it.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no autism. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have, and/or may be selected as not having, hyperkinetic syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have schizophrenia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or be selected as patients without a history of stroke. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have cerebral infarction. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no cerebral hemorrhage. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no cerebral atherosclerosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no cerebral vein thrombosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no head trauma.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no apnea. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no ataxia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have ataxia and/or may be selected as not having ataxia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no ballismus. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no hemiballismus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as patients without, dyskinesia. Some patients who are treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have cerebral palsy and/or may be selected as not having cerebral palsy.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have chorea and/or may be selected as not having chorea. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Huntington's disease and/or may be selected as not having Huntington's disease. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have rheumatoid chorea. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no Sidnam's chorea. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no movement disorders. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have tardive dyskinesia and/or may be selected as patients without tardive dyskinesia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have dystonia and/or may be selected as patients without dystonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have blepharospasm, and/or may be selected as not having blepharospasm.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have spasmodic torticollis. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no dopamine-responsive dystonia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have restless legs syndrome (RLS) and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have tremor and/or may be selected as not having tremor. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no essential tremor. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Tourette's syndrome and/or may be selected as patients without Tourette's syndrome. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Wilson's disease and/or may be selected as not having Wilson's disease.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have vascular dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Lewy body dementia, and/or may be selected as not having dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have mixed dementia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have frontotemporal dementia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Creutzfeldt-Jakob disease and/or may be selected as patients without Creutzfeldt-Jakob disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no normotensive hydrocephalus. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have Wernicke-Korsakoff Syndrome.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have Pick's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no progressive medulla oblongata. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected as patients without primary lateral sclerosis (PLS). Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no progressive muscular atrophy. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have post polio syndrome (PPS). Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no spinal muscular atrophy (SMA).

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no spinal motor atrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Tay-Sachs disease and/or may be selected as patients without Tay-Sachs disease. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have Sandhoff's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as not having, hereditary spastic paraplegia. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no prion-associated disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no cerebellar ataxia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no spinal cerebellar ataxia (SCA).

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no spinal muscular atrophy (SMA). Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have, and/or may be selected as not having, myelodystrophy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Friedrich's ataxia and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Lewy body disease and/or may be selected as not having Lewy body disease. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have, and/or may be selected to not have, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). have. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have multiple sclerosis (MS). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no multiple system atrophy.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no Shay Drager syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, do not have corticobasal degeneration. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no progressive supranuclear palsy.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have Wilson's disease and/or may be selected as not having Wilson's disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to not have Menkes' disease. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, do not have adrenoleukemia. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have cerebral autosomal dominant arteropathy (CADASIL) with subcortical infarction and leukoencephalopathy (CADASIL) and/or , patients who do not have Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no muscular dystrophy.

Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Charcot Marie Tooth disease (CMT) and/or may be selected as patients not having Charcot Marie Tooth disease (CMT). Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no familial convulsive paralysis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no neurofibromatosis. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have olivopontin cerebellar atrophy or cerebellar degeneration, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected for, do not have striatal melanoma. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have Guillain-Barré syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have spastic paraplegia and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no epileptic seizures. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have non-epileptic seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have epilepsy and/or may be selected as patients without epilepsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no febrile seizures. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have partial seizures and/or may be selected as patients without partial seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no simple partial seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no Jackson-type seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no complex partial seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have persistent partial epilepsy and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no generalized seizures. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have, and/or may be selected as not having, generalized tonic-clonic seizures. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have absence seizures.

Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to not have atonic seizures. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have myoclonic seizures, and/or may be selected as not having myoclonic seizures. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may or may not have juvenile myoclonic seizures and/or may be selected as not having them. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have infantile convulsions, and/or may be selected as not having infantile convulsions. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no epilepsy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have Rett's syndrome and/or may be selected as patients without Rett's syndrome. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have tinnitus and/or may be selected as not having tinnitus. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected as patients without disturbance of consciousness. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no sexual dysfunction. Some patients treated with reboxetine for narcolepsy (e.g., with cataplexy and/or EDS) may not have, and/or may be selected as patients without, voice impairment due to uncontrolled laryngeal muscle spasm. have. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have extrovert convulsive dysphonia, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have extrovert convulsive dysphonia, and/or may be selected as patients without. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have dystonia and/or may be selected as patients without dysphonia. Some patients treated with reboxetine for narcolepsy (eg, accompanied by cataplexy and/or EDS) may not have and/or may be selected to have no voice tremor. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have diabetic neuropathy and/or may be selected as patients without diabetic neuropathy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not and/or may be selected to have no neurotoxicity due to chemotherapy. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have methotrexate neurotoxicity, and/or may be selected as not having methotrexate neurotoxicity. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may and/or may be selected to have no tension incontinence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have urge incontinence and/or may be selected as patients without urge incontinence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have fecal incontinence and/or may be selected as not having fecal incontinence. Some patients treated with reboxetine for narcolepsy (eg, with cataplexy and/or EDS) may not have and/or may be selected to have no erectile dysfunction.

Catalytic seizures include a sudden decrease or loss of muscle tone while the patient is awake, such as a fall of the eyelids, head, sagging and/or tremors of the face, slurred speech, weakness in the jaw, weakness in the arms, shoulders, or hands, and/or Or it can affect a specific part of the body or the whole body, such as the buckling of the knee. Catalytic seizures may be a pathological feature of narcolepsy. Catalytic seizures can be triggered by strong emotions such as laughter, excitement, surprise, or anger. Catalytic seizures can be partial or local (in about 75% of cases) and are usually short in duration. The frequency of cataplexy can vary widely. Narcolepsy with cataplexy can be socially incapacitated and isolated.

Some patients treated with reboxetine may have and/or be selected to have narcolepsy with cataplexy (type 1), an autoimmune disease that results in loss of hypocretin (orexin) producing neurons in the CNS. have. Hypocretin (orexin) is a hypothalamus-specific peptide with neuroexcitatory activity. Patients treated with reboxetine for narcolepsy with cataplexy are predisposed individuals with specific genetic markers including human leukocyte antigen (HLA DQB1/06:02) and/or T cell receptor alpha variants, the individual can be selected as Some patients treated with reboxetine may not, and may be selected as patients without, narcolepsy associated with loss of hypocretin neurons. Some patients treated with reboxetine may have, or may be selected for, have, in genetically predisposed individuals, seasonal streptococcal infection, H1N1 influenza, and/or narcolepsy promoted by H1N1 vaccination.

Existing treatments for narcolepsy address only some of its symptoms, provide variable efficacy, and have serious side effects. In addition, all existing treatments are controlled drugs.

According to the FDA, "There is an ongoing need for additional effective and tolerable treatment options to improve patients' day-to-day 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).

In some embodiments, administering reboxetine results in daytime sleepiness, e.g., baseline, placebo, or some other suitable control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate). , including an active control such as a tricyclic antidepressant, a selective serotonin reuptake inhibitor (SSRI), or a selective norepinephrine reuptake inhibitor (SNRI)), 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%.

In some embodiments, administering reboxetine reduces cataplexy, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate) , 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%.

In some embodiments, administering reboxetine reduces the number of cataplexy attacks, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, (including active controls such as sodium oxybate, tricyclic antidepressants, SSRIs, or SNRIs), 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 once per week, at least about twice per week, at least about 3 times per week, at least about 4 times per week, at least about 5 times per week, at least about 6 times per week, at least about 7 times per week , at least about 8 times per week, at least about 9 times per week, at least about 10 times per week, at least about 12 times per week, at least about 14 times per week, at least about 16 times per week, at least about 18 times per week, at least about 20 times per week, per week at least about 22 times, at least about 24 times per week, at least about 26 times per week, at least about 28 times per week, at least about 30 times per week, at least about 40 times per week, at least about 50 times per week, about 1-2 times per week, about 2-3 times a week, about 3-4 times a week, about 4-5 times a week, about 5-6 times a week, about 6-7 times a week, about 7-8 times a week, about 8-9 times a week, about 9 times a week -10 times, about 10-11 times a week, about 11-12 times a week, about 12-13 times a week, about 13-14 times a week, about 14-15 times a week, about 15-16 times a week, about 16 times a week About 17 times a week, about 17-18 times a week, about 18-19 times a week, about 19-20 times a week, about 1-10 times a week, about 10-20 times a week, about 20-30 times a week, about 30- times a week 40 times, about 40-50 times per week, about 50-60 times per week, or more.

In some embodiments, administering reboxetine lowers the ESS score, e.g., at baseline, in a placebo group, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate). , at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% compared to an active control such as a tricyclic antidepressant, SSRI, or SNRI). , 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, about 9-10, 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 1-4, about 4-8, about 8-12, about 12-16, about 16-20, about 20-24, about 1-12 , or about 12-24.

In some embodiments, administering reboxetine increases the MWT score, e.g., at baseline, in a placebo group, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate). , at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% compared to an active control such as a tricyclic antidepressant, SSRI, or SNRI). , 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 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes , at least about 10 minutes, at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes , at least about 20 minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8 -9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17-18 minutes, about 18-19 minutes, about 19-20 minutes, about 20-21 minutes, about 21-22 minutes, about 22-23 minutes, about 23-24 minutes, about 24-26 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes, or about 10-20 minutes.

In some embodiments, administering reboxetine reduces the cataplexy score for the UNS, e.g., baseline, placebo or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil 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, About 11, about 2-3, about 3-4, about 4-5, about 5-6, about 6-7, about 7-8, about 8-9, about 9-10, about 2-4, about 4 -6, about 6-8, about 8-10, about 10-11, about 2-6, or about 6-10, about 5-11.

In some embodiments, administering reboxetine increases sleep latency in MSLT, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-100% , at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 4 minutes, at least about 5 minutes, at least about 6 minutes, at least about 7 minutes, at least about 8 minutes, at least about 9 minutes, at least about 10 minutes , at least about 11 minutes, at least about 12 minutes, at least about 13 minutes, at least about 14 minutes, at least about 15 minutes, at least about 16 minutes, at least about 17 minutes, at least about 18 minutes, at least about 19 minutes, at least about 20 minutes , about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 8-9 minutes, about 9-10 minutes, about 10-11 minutes, about 11-12 minutes, about 12-13 minutes, about 13-14 minutes, about 14-15 minutes, about 15-16 minutes, about 16-17 minutes, about 17- 18 minutes, about 18-19 minutes, about 19-20 minutes, about 1-4 minutes, about 4-8 minutes, about 8-12 minutes, about 12-16 minutes, about 16-20 minutes, about 1-10 minutes , or about 10-20 minutes.

In some embodiments, administering reboxetine reduces nightmares or unpleasant dreams (eg, frequent nightmares and frequent unpleasant dreams), e.g., a baseline, placebo group, or some other appropriate control (stimulant agent (e.g., methylphenidate, amphetamine ), modafinil, amodafinil, sodium oxybate, tricyclic antidepressants, SSRIs, or active controls such as SNRIs), 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%.

In some embodiments, administering reboxetine reduces hallucinations, e.g., at baseline, in a placebo group, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate, 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%.

In some embodiments, administering reboxetine reduces sleep paralysis, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxybate) , at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50% compared to an active control such as a tricyclic antidepressant, SSRI, or SNRI). , 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%.

In some embodiments, administering reboxetine results in disrupted nocturnal sleep, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium 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%.

In some embodiments, administering reboxetine reduces narcolepsy related events, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxy 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%.

In some embodiments, administering reboxetine reduces narcolepsy-related injury, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium oxy 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%.

In some embodiments, administering reboxetine reduces narcolepsy-related fatal events, e.g., baseline, placebo, or some other appropriate control (stimulant (e.g., methylphenidate, amphetamine), modafinil, amodafinil, sodium 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%.

Reboxetine (structure shown below) is a highly selective and potent inhibitor of norepinephrine reuptake that has the potential to address the main symptoms of narcolepsy, such as cataplexy or EDS. Unlike conventional treatments for narcolepsy, reboxetine is not a controlled drug. Therefore, treatment with reboxetine is not scheduled.

(레복세틴)

(reboxetine)

Unless otherwise indicated, reference to a compound herein, such as reboxetine, by structure, name, or any other means refers to a pharmaceutically acceptable salt; free acid or base; alternative solid forms such as polymorphs, solvates, hydrates, and the like; tautomers; enantiomers; deuterium modified compounds such as deuterium modified reboxetine; or any species that can be rapidly converted to a compound described herein under the conditions in which the compound is used as described herein.

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

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

There are many potential ways of administering reboxetine in a manner that results in a first local maximum of reboxetine plasma concentration and a second local maximum of reboxetine plasma concentration. The local maxima described herein are the plasma concentration maxima in an individual patient's period of interest, which need not necessarily be Cmax. The local maximum may be less than or equal to Cmax. One potential way to administer reboxetine in a manner that results in a first local maximum of reboxetine plasma concentration and a second local maximum of reboxetine plasma concentration is to administer a first dose comprising reboxetine. and then administering a second dose comprising reboxetine. The dose is administered at a time that results in a first local maximum of reboxetine plasma concentration and a second local maximum of reboxetine plasma concentration. For example, the second dosage form may be administered less than half a day after the first dosage form, e.g., about 1-8 hours, about 8-12 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2-4 hours, about 3- 5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or any time in a range defined by any value thereof.

Another method involves administering a single dosage form comprising a first release component and a second release component. Both the first release component and the second release component comprise reboxetine.

In some embodiments, the first dosage form administered on a day, the only dosage form administered during the day, or the first dosage form of two or more dosage forms administered during the day is administered immediately after waking, such as waking up from a nocturnal sleep. It is administered within about 3 hours, within about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, or within about 15 minutes after the egg.

In the case of a single dosage form comprising a first release component and a second release component administered on a day, the first release component may release or begin to release reboxetine, or the dosage form may be administered orally. from about 0-30 minutes, about 30-60 minutes, about 60-90 minutes, or about 90-120 minutes after, or any time in the range defined by any of these, in the plasma concentration of reboxetine. 1 may result in a local maximum. The second release component may release reboxetine after the first release component releases reboxetine, or may cause an increase in reboxetine plasma concentration or a second local maximum of the plasma concentration of reboxetine, which About 1-10 hours, about 2-6 hours, about 1-2 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5- hours after the first release of reboxetine from the first release component 6 hours, about 6-7 hours, about 1-3 hours, about 2-4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours after the time, or after the first local maximum in the plasma concentration of reboxetine, or any time in a range defined by any of these.

The first release component and the second release component may be incorporated into one single dosage form (eg, pill, tablet, capsule, caplet, or cachet). In one embodiment, the first release component will be located in one of the outer layers of the dosage form and the second release component will be located in one of the inner layers of the same dosage form.

In other embodiments, the first release component is located in a first layer of the dosage form and the second release component is located in a second layer of the same dosage form. The two layers are distinct and may or may not contact each other. In some embodiments, the two layers are stacked on top of each other and physically bonded in a bilayer structure (eg, when the largest surfaces of the two layers are in contact with each other, or when the layers are thin relative to the other dimensions of the layers). In some embodiments, the two layers are positioned next to each other and physically bonded in a bilayer structure (eg, when the layers are thicker than other dimensions of the layers).

In other embodiments, the first release component and the second release component may be separately composed of their own specific granules, particles, etc., wherein the first release component particles are subjected to prior release of the second release component particles before the release of reboxetine. is formulated to release reboxetine, wherein both the first release component particles and the second release component particles are combined together into a single dosage form, such as a capsule, pill, tablet, caplet, cashew, etc., wherein the two release components physically interact with each other may or may not be bound to

In some embodiments, the first local maximum plasma concentration of reboxetine is about 1-30 minutes, about 30-60 minutes, about 1-2 hours, about 2-3 hours after the single dosage form or the first dosage form is administered. , or after about 3-4 hours, or at any time in a range defined by any value thereof. Generally, the second local maximum plasma concentration of reboxetine is less than half a day after the first local maximum plasma concentration of reboxetine, such as about 1-10 hours, about 1-2 hours, about 1-10 hours after the first local maximum plasma concentration of reboxetine. 2-6 hours, about 2-3 hours, about 3-4 hours, about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 1-3 hours, about 2- 4 hours, about 3-5 hours, about 4-6 hours, about 5-7 hours, about 6-8 hours, or about 7-10 hours, or any time in the range defined by any value thereof Occurs.

For dosage forms containing a first release component and a second release component, the first release component is reboxetine plasma in that the first release component releases reboxetine that contributes to a first local maximum in reboxetine plasma concentration. associated with a first local maximum of concentration. For example, the first releasing component may release reboxetine faster or earlier than the second releasing component, such that most of the reboxetine released from the first releasing component contributes to the first local maximum plasma concentration of reboxetine. do.

For dosage forms containing a first release component and a second release component, the second release component is a reboxetine plasma concentration in that the second release component releases reboxetine that contributes to a second local maximum in reboxetine plasma concentration. associated with a second local maximum of the concentration. For example, the second releasing component may delay the release of its reboxetine so that when the reboxetine plasma concentration decreases after the first local maximum, the second releasing component is sufficient to again increase the plasma concentration of reboxetine. A second local maximum is achieved in reboxetine plasma concentrations due to the release of positive reboxetine.

For dosage forms containing a first release component and a second release component, any suitable amount, 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, 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 Reboxetine in an amount in a range defined by 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 of these values may be present in the first release component.

For dosage forms containing a first release component and a second release component, any suitable amount, such as 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 2-4 mg, about 3-5 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg , about 5-6 mg, about 4-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about Any amount of reboxetine in the range defined by 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any of these may be present in the second release component.

The dose of reboxetine may be increased progressively over time, such as for 1, 2, 3, 4, 5, 6, or 7 days, up to a maintenance dose, which is the total dose given daily. For example, a 10 mg maintenance dose may be a 10 mg dose once daily for a total of 10 mg per day, or a 5 mg dose twice daily).

In some embodiments, the maintenance dose is 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2- 5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, 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, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, about 0.033-0.036 mmol, about 0.036-0.039 mmol, about 0.039-0.042 mmol, about 0.042-0.045 mmol, about 0.045-0.048 mmol, about 0.048-0.051 mmol, about 0.051-0.054 mmol, about 0.054-0.057 mmol, about 0.057-0.06 mmol, about 0.06-0.063 mmol, about 0.063- 0.066 mmol, about 0.066-0.069 mmol, about 0.006-0.01 mmol, about 0.01-0.02 mmol, about 0.02-0.03 mmol, about 0.03-0.04 mmol, about 0.04-0.05 mmol, about 0.05-0.06 mmol, about 0.06-0.07 mmol , or about 0.07-0.08 mmol. The maintenance dose is at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months , at least 1.5 years, at least 2 years, at least about 3 years, at least about 4 years, at least about 5 years, at least about 10 years, at least about 20 years, or longer.

In some embodiments, the first release component provides an immediate release (IR) of reboxetine. In some embodiments, the first release component provides a delayed release (DR) of reboxetine. In some embodiments, the first release component provides a sustained release (SR) of reboxetine.

In some embodiments, the second release component provides immediate release of reboxetine. In some embodiments, the second release component provides delayed release of reboxetine. In some embodiments, the second release component provides sustained release of reboxetine.

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

With respect to the method in which reboxetine is administered in the first dosage form containing reboxetine and the second dosage form containing reboxetine, any suitable amount, 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, about 0.006-0.009 mmol, about 0.009-0.012 mmol, by 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 of these values Any amount of reboxetine within the defined range may be present in the first dosage form.

With respect to the method in which reboxetine is administered in the first dosage form containing reboxetine and the second dosage form containing reboxetine, any suitable amount, such as about 0.1-1 mg, about 0.1-2 mg, about 0.5 -1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any of the ranges defined by any of these An amount of reboxetine may be present in the second dosage form.

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.

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.

With respect to a single dosage form containing both a first release component and a second release component, in some embodiments, the single dosage form is administered within 2 hours of waking up from a nighttime sleep.

In some embodiments in which more than one dosage form is provided, the first dosage form may be administered within 2 hours of waking up from a nocturnal sleep.

There are many factors that can influence the total time required for a pharmacological substance such as reboxetine to be fully absorbed and/or to reach maximum plasma concentrations in humans. Some of these factors include the human patient's age, weight, sex, stress level, gastric contents, gastric pH level, and the presence of other medications. The time required to reach the maximum plasma concentration of a drug such as reboxetine may also be affected by the time the drug such as reboxetine is taken and the level of physical activity of the human patient. Another factor that may affect the time required to reach the maximum plasma concentration of a drug such as reboxetine is the presence or absence of a controlled release coating for a drug such as reboxetine.

Controlled release includes: immediate release of a pharmacological substance such as reboxetine at a specific time or in a specific area of the body; sustained release of pharmacological substances; Extended release (ER) of a pharmacological substance, such as reboxetine, at a specific time or in a specific area of the body.

Reboxetine is generally rapidly absorbed by human patients, reaching maximum plasma concentrations within about 2-4 hours. Controlled release coatings or mixtures may be used to delay the time required to reach maximum plasma concentrations.

Delayed release is a general drug delivery term that describes a form of oral drug that does not immediately release the active drug ingredient in the mouth or stomach of a patient. While there may be many ways to achieve delayed release, delayed release of reboxetine can be achieved by, for example, completely or partially enclosing reboxetine in a second release component with a coating or layer that does not completely dissolve when swallowed. can be achieved. For example, the material of the coating or layer may be slowly dissolved in the stomach and/or degraded slowly by a chemical reaction such as hydrolysis in the stomach until the layer can no longer prevent reboxetine from contacting gastric juices.

In some embodiments, the delayed release coating ensures delivery through the stomach to the intestine. Once in the duodenum, the coating can break down and begin to release reboxetine. In some cases, reboxetine may be completely released from the duodenum. In some embodiments, reboxetine is partially released in the duodenum and may be partially released in the jejunum. In some cases, reboxetine may be completely released from the jejunum. In some cases, reboxetine may be partially released in the jejunum and partially in the ileum. In some cases, reboxetine may be completely released from the ileum. In some cases, reboxetine may be partially released in the duodenum, jejunum, and ileum. In some embodiments, reboxetine may be partially released in the ileum and partially released in the colon. In some cases, reboxetine may be completely released from the colon.

For example, the time of delayed release between the release of the first reboxetine component and the release of the second reboxetine component can be determined by using a material that dissolves or disintegrates more slowly in the digestive system, by adjusting the thickness of the coating layer or coating material (e.g. For example, thicker layers provide longer times), and/or by using materials with pH-sensitive properties. For example, substances that are less stable or more soluble at acidic pH may dissolve or disintegrate more quickly in the stomach because the pH of the stomach is lower than the pH of the intestine. Conversely, substances that are stable at low pH but less stable at high pH may dissolve or disintegrate more slowly because of the time it takes for the dosage form to pass through the gastrointestinal tract.

Controlled release formulations containing reboxetine may be coated with one or more functional or non-functional coatings. Examples of functional coatings include controlled release polymer coatings (ie, controlled release coatings), moisture barrier coatings, enteric polymer coatings, and the like.

Controlled release polymers can be used for both sustained release or delayed release depending on the structure of the dosage form. For example, interspersing reboxetine throughout a controlled release polymer can provide sustained release as the drug is released as long as the polymer is present in the gastrointestinal tract. Delayed release can be achieved by creating a barrier, such as a coating, that is intended to last for a shorter period of time (eg, less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.) Reboxetine is freely released. The thickness of the barrier can be used to control the delay time.

Any suitable controlled release polymer, such as acrylic acid and methacrylic acid copolymers and their various esters, for example methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate Copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic acid) anhydride) and glycidyl methacrylate copolymers.

Other suitable controlled release polymers are polymerizable quaternary ammonium compounds such as quaternized aminoalkyl esters and aminoalkyl amides of acrylic acid and methacrylic acid such as β-methacryloxyethyltrimethylammonium methosulfate, β-acryl oxypropyltrimethylammonium chloride, and trimethylaminomethylmethacrylamide methosulfate. The quaternary ammonium atom may also be part of a heterocycle, as in methacryloxyethylmethylmorpholinium chloride or the corresponding piperidinium salt, or an acrylic or methacrylic acid group via a group containing a heteroatom such as a polyglycol ether group can be coupled to Further suitable polymerizable quaternary ammonium compounds include quaternized vinyl substituted nitrogen heterocycles such as methyl vinyl pyridinium salts, vinyl esters of quaternized amino carboxylic acids, styryltrialkyl ammonium salts, and the like. Other polymerizable quaternary ammonium compounds include benzyldimethylammoniumethylmethacrylate chloride, diethylmethylammoniumethylacrylate and -methacrylate methosulfate, N-trimethylammoniumpropylmethacrylamide chloride, and N-trimethylammonium-2 ,2-dimethylpropyl-1-methacrylate chloride.

It should be understood that delayed release can also be achieved using controlled release polymers that target a specific pH, and with appropriate fasting or feeding, a specific pH can be matched at a specific time after administration.

For some controlled release polymers, the acrylic or methacrylic polymer comprises one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers (eg ^{sold by Evonik under the trade names EUDRAGIT ®} RS and RL) are fully polymerized copolymers of acrylic acid and methacrylic acid esters with a low content of quaternary ammonium groups. An ammonium group is added to the ester portion of the methacrylate (as 2-trimethyl ammonium-ethyl ester). The pH-independent swelling of the charged ammonium groups in these polymers makes the polymers insoluble and highly permeable. These properties make these polymers useful for tailored, time-controlled release of coated drugs. In order to obtain the desired dissolution profile for a given therapeutically active substance such as reboxetine, it is possible to incorporate two or more ammonio methacrylate copolymers with different physical properties. For example, by changing the molar ratio of prepolymerized material containing quaternary ammonium groups to prepolymerized material containing uncharged neutral methacrylic or acrylic ester, the permeability properties of the resulting coating can be altered. is known

In another embodiment, the controlled release coating further comprises a polymer whose permeability is pH dependent, such as an anionic polymer synthesized from methacrylic acid and methacrylic acid methyl ester. These polymers are sold by Evonik under the trade names EUDRAGIT ^® L and EUDRAGIT ^{® S.} The ratio of free carboxyl groups to ester 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 gradually increases in permeability above pH 5.0. Therefore, EUDRAGIT ^® L is suitable for targeted release of coated pharmacological substances such as coated reboxetine in the jejunum of the duodenum and small intestine. Thus, the EUDRAGIT ^® L coated pharmacological agent is about 30 minutes to about 1 hour, about 1-1.5 hours, about 1.5-2 compared to an uncoated or immediate release pharmacological agent (eg, reboxetine of the first release component). A maximum plasma concentration delay of about 2-2.5 hours, about 2.5-3 hours, or about 3.5-4 hours can be achieved.

EUDRAGIT ^® S is ^{similar to EUDRAGIT ®} L, but with a gradual increase in permeability above pH 7. EUDRAGIT ^® S is therefore suitable for targeted release of coated pharmacological substances such as coated reboxetine in the ileum and colon of the small intestine. Thus, the EUDRAGIT ^® S coated pharmacological agent is about 1-2 hours, about 2-3 hours, about 3-4 hours compared to an uncoated or immediate release pharmacological agent (eg, reboxetine of the first release component). Maximum plasma concentration delays of about 4-5 hours, about 5-6 hours, about 6-7 hours, about 7-8 hours, about 8-9 hours, or about 9-10 hours can be achieved.

The hydrophobic acrylic polymer coating may comprise a polymer based on dimethylaminoethyl methacrylate and a neutral methacrylic acid ester (eg EUDRAGIT ^® E available from Evonik). EUDRAGIT ^® E is not soluble in saliva (useful for taste and odor masking), but dissolves in gastric juices with a pH of 5 or less and immediately releases the drug product in the stomach. Reboxetine ^{surrounded by the EUDRAGIT ®} E coating is administered orally in a dosage form about 0-30 minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after, or in a range defined by any of these. At any time it may release reboxetine, begin to release reboxetine, or reach a first local maximum in the plasma concentration of reboxetine.

The hydrophobic acrylic polymer coating may comprise a polymethacrylate based neutral copolymer such as ^{EUDRAGIT ® NE (NE = neutral ester) available from Evonik.} EUDRAGIT ^® NE 30D Lacquer Film is insoluble in water and digestive fluids, but its permeability and swelling properties provide another option for time-controlled release. EUDRAGIT ^® NE has a pH-independent delayed release effect that can release a pharmacological substance such as reboxetine over a period of time, or delay the release for a period of time, where the release or delay time is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the control-releasing coat comprises a polymer comprising ethyl acrylate and methyl methacrylate in a 2:1 ratio (KOLLICOAT ^® EMM 30 D, BASF). OLLICOAT ^® EMM 30 D has a pH-independent delayed release effect that can release a pharmacological substance such as reboxetine over a period of time, or delay the release for a period of time, where the release or delay time is about 1 -24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, or about 1-6 hours.

In some embodiments, the control releasing coat comprises polyvinyl pyrrolidone and sodium lauryl sulfate as a stabilizing polyvinyl acetate, such as KOLLICOAT ^® SR30D (BASF). Altering the dissolution profile can be accomplished by changing the relative amount of different acrylic resin lacquers included in the coating. Also, by changing the molar ratio of the polymerizable permeation promoter (eg, quaternary ammonium compound) to the neutral methacrylic ester, the permeability properties (affecting the dissolution profile) of the resulting coating can be altered. KOLLICOAT ^® SR30D has a pH-independent delayed-release effect that can release a pharmacological substance such as reboxetine over a period of time, or delay the release for a period of time, where the release or delay time is about 1-24 hours, about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

In some embodiments, the control-releasing coat comprises ethylcellulose, which can be used as an aqueous dispersion or as a dry polymer (eg, ETHOCEL™, Dow Chemical Company) solubilized in an organic solvent prior to use. One suitable commercially available aqueous dispersion of ethylcellulose is Aquacoat ^® (Danisco). Aquacoat ^® ECD (ethylcellulose aqueous dispersion), Aquacoat ^® ARC (alcoholic resistant ethylcellulose aqueous dispersion), and Aquacoat ^® CPD (cellulose acetate phthalate aqueous dispersion) are all commercially available controlled release coatings. Another suitable aqueous dispersion of ethylcellulose ^{is commercially available as Surelease ®} (Colorcon, Inc.). These products can be prepared by incorporating plasticizers into the dispersion during the manufacturing process. A homogeneous mixture is prepared by mixing a hot melt of the polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleic acid), which can then be diluted with an alkaline solution and applied directly to the substrate. An aqueous dispersion is obtained. Such coatings have a pH-independent delayed release effect that can release a pharmacological substance such as reboxetine over a period of time, or delay the release for a period of time, wherein the release or delay time is about 1-24 hours. , about 1-18 hours, about 1-12 hours, about 1-8 hours, about 1-6 hours, about 1-4 hours, or about 1-2 hours.

Other examples of polymers that can be used in controlled release coatings are cellulose acetate phthalate, cellulose acetate trimalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate, shellac, hydrogel and gel formation. substances such as carboxyvinyl polymer, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and absorption of water and of the polymer matrix. Cellulose-based cross-linked polymers with low degree of cross-linking to promote swelling, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, cross-linked starch, microcrystalline cellulose, chitin, pullulan, collagen , casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymer) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000 k), polyvinylpyrrolidone (molecular weight 10 k to 360 k) , anionic and cationic hydrogels, zein, polyamide, 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, acacia, karaya, tragacanth, algin and guar, polyacrylamide, POLYOX ^® polyethylene oxide (molecular weight 100 k to 5000 k, Dow), AQUA KEEP ^® acrylate Polymers (consisting mainly of acrylic acid polymers, sodium salts), diesters of polyglucans, cross-linked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium carboxymethyl cellulose or calcium Carboxymethyl Cellulose, Hydroxypropyl Methyl Cellulose, Hydroxypropyl Cellulose, Hydroxyethyl Cellulose, Nitro Cell cellulose, carboxymethyl cellulose, cellulose ether, methyl ethyl cellulose, ethyl hydroxy ethyl cellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinylpyrrolidone, polyvinyl alcohol , polyvinyl acetate, glycerol fatty acid ester, polyacrylamide, polyacrylic acid, natural gum, lecithin, pectin, alginate, ammonia alginate, sodium, calcium, potassium alginate, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, scloglucan and mixtures and blends thereof.

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 carboxymethylcellulose, polyacrylic acid, Carbopol™ (Lubrizol), polycarbophil, gelatin, and other natural or synthetic polymers.

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

In addition to the modified release dosage forms described herein, other modified release technologies known to those skilled in the art include the modified release formulations of the present disclosure, i.e., those described herein when administered orally or by other modes of administration, for example, to a human patient. It can be used to achieve formulations that provide mean Tmax and/or other pharmacokinetic parameters of the drug. Such dosage forms can be prepared as modified release oral dosage forms in suitable tablet or multiparticulate dosage forms known to those skilled in the art. In either case, the modified release dosage form may optionally include a controlled release carrier incorporated into a matrix with the drug or applied as a controlled release coating.

Any dosage form comprising an effective amount of reboxetine may further comprise binders, lubricants, and other conventional inert excipients.

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

Lubricants may be added to the pharmaceutical formulation to reduce any friction that occurs between the solid and the die wall during tablet manufacture. High friction during tableting can cause a series of problems including inadequate tablet quality (capping or even fragmentation of tablets during ejection, vertical scratching of tablet edges), and may even stop production. Accordingly, lubricants may be added to tablet formulations. Non-limiting examples of useful lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as 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 polymer (e.g., Danbury, CT; (available under the registered trademark CARBOWAX ^® from Union Carbide, Inc.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof and known in the art including other things that have been In some embodiments, the lubricant is glyceryl behenate (eg, COMPRITOL ^® 888). Any suitable amount, such as about 0.5-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5-25% by weight of the dry weight of the tablet. %, about 0.5-15 wt%, about 1-6 wt%, or about 3 wt% binder may be present.

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

Examples of useful compositions for dosage forms containing about 5-10 mg of reboxetine, which are not intended to limit the scope of the present disclosure, are shown in Table 1 below:

Examples of Reboxetine Dosage Forms ingredient Amount (wt/wt) reboxetine 30-70% slush 1-10% diluent 20-70% disintegrant 1-10%

Treatment of narcolepsy with cataplexy with reboxetine in the dosage form described herein may not have the severe side effects of existing treatment options. Treatment of narcolepsy with cataplexy with reboxetine in the dosage form described herein is well tolerated in mammals such as humans.

Some embodiments include one or more units of the dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720). a kit comprising a pharmaceutical composition comprising a dosage form of units) and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein the unit of dosage form is about 0.1-5 mg of reboxetine.

Some embodiments include one or more units of the dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720). a kit comprising a pharmaceutical composition comprising a dosage form of units) and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein the unit of dosage form is about 5-10. mg of reboxetine.

Some embodiments include one or more units of the dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720). a kit comprising a pharmaceutical composition comprising a dosage form of units) and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein the unit of dosage form is about 10-15 mg of reboxetine.

Some embodiments include one or more units of the dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720). a kit comprising a pharmaceutical composition comprising a dosage form of units) and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein the unit of dosage form is about 15-20 mg of reboxetine.

Some embodiments include one or more units of the dosage form (e.g., about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720). a kit comprising a pharmaceutical composition comprising a dosage form of units) and instructions for using the pharmaceutical composition to treat narcolepsy with cataplexy in a human, wherein the unit of dosage form is about 5-20 mg of reboxetine.

Example

Example 1

A 40-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the number of cataplexy decreased by 10-30%.

Example 2

A 20-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the number of cataplexy decreased by 30-60%.

Example 3

A 60-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the number of cataplexy decreased by 60-100%.

Example 4

A 50-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated prior to treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the ESS score decreased by 10-30%.

Example 5

A 25-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the ESS score decreased by 30-60%.

Example 6

A 47-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the ESS score decreased by 60-100%.

Example 7

A 19-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the MWT score decreased by 10-30%.

Example 8

A 42-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the MWT score decreased by 30-60%.

Example 9

A 33-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 1 week of treatment, the MWT score decreased by 60-100%.

Example 10

A 54-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the number of cataplexy decreased by 10-30%.

Example 11

A 27-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the number of cataplexy decreased by 30-60%.

Example 12

A 52-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the number of cataplexy decreased by 60-100%.

Example 13

A 66-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the ESS score decreased by 10-30%.

Example 14

A 34-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the ESS score decreased by 30-60%.

Example 15

A 35-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the ESS score decreased by 60-100%.

Example 16

A 19-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the MWT score decreased by 10-30%.

Example 17

A 70-year-old woman was diagnosed with narcolepsy with cataplexy. She was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the MWT score decreased by 30-60%.

Example 18

A 57-year-old man was diagnosed with narcolepsy with cataplexy. He was given reboxetine and was instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at 1 pm for 3 weeks. This patient was evaluated before treatment and weekly to determine the number of cataplexy, ESS score, and MWT score. After 3 weeks of treatment, the MWT score decreased by 60-100%.

Unless otherwise indicated, all numbers expressing quantities, properties, such as amounts, percentages, etc., of ingredients used in the specification and claims represent the exact values indicated in all instances, and are to be understood as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations which may vary depending upon the desired properties sought. At the very least, it is not intended to limit the application of the doctrine of equivalents to the scope of the claims, and each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding methods.

As used in the context of describing embodiments, singular terms ("a," "an" "the") and similar referents (especially in the context of a claim) refer to the singular and plural unless otherwise indicated herein or otherwise clearly contradicted by context. should be construed as inclusive of all. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as" and "such as") provided herein is merely to better illuminate the invention and to add limitations to the scope of any claims. I never do that. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the claims.

Groupings of alternative components or embodiments disclosed herein are not to be construed as limiting. Each group member may be referred to and claimed individually or in any combination with other members or other components found herein. It is contemplated that one or more members of a group may be included in or deleted from the group for reasons of convenience and/or expedited proceedings. Where any such inclusion or deletion occurs, the specification is deemed to include modified groups, thereby satisfying the stated description of all Markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the claimed embodiments. Of course, modifications to these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventor intends the claimed embodiments to be practiced otherwise than as specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Also, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it is to be understood that the embodiments described herein are illustrative of the principles of the claims. Other variations that may be used are within the scope of the claims. Thus, by way of non-limiting example, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments precisely shown and described.

Claims (32)

A pharmaceutical composition for treating narcolepsy with cataplexy comprising reboxetine in a human in need of treatment for narcolepsy accompanied by cataplexy, wherein reboxetine is administered at least once a day for at least 3 weeks, and starting treatment 2 After a week, the human was treated as a result of a decrease in the number of cataplexy episodes during the week, a decrease in the Epworth Sleepiness Scale score, and a decrease in the cataplexy item score on the Ullanlinna Narcolepsy Scale (NUS). A pharmaceutical composition that experiences a decrease, a decrease in arousal maintenance test score. The pharmaceutical composition of claim 1 , wherein the reboxetine is administered twice a day, the first dosage form is administered in the morning, and the second dosage form is administered about 2 hours to about 6 hours later. The dosage form of claim 1 , wherein the reboxetine is a daily administered dosage form, the dosage form contains a first release component comprising reboxetine and a second release component comprising reboxetine, wherein the first release component is a dosage form of reboxetine. wherein the second release component provides a second local maximum in the plasma concentration of reboxetine and the first local maximum in the plasma concentration of reboxetine provides a first local maximum in the plasma concentration of reboxetine 2 A pharmaceutical composition that occurs about 2 to 6 hours before a local maximum. 4. The pharmaceutical composition of claim 3, wherein the second local maximum in the plasma concentration of reboxetine occurs about 4 hours to about 6 hours after the first local maximum of reboxetine. The pharmaceutical composition according to claim 1, wherein the human is selected as a human not suffering from depression. The pharmaceutical composition of claim 1 , wherein the dose of reboxetine is increased for 1 to 7 days and then maintained constant at a total daily dose of about 0.006 mmol to about 0.08 mmol. The pharmaceutical composition of claim 1 , wherein the reboxetine is a dosage form, wherein the dosage form contains about 5 mg of reboxetine. The pharmaceutical composition of claim 1 , wherein the reboxetine is a dosage form and the dosage form contains about 10 mg of reboxetine. The pharmaceutical composition according to claim 7, wherein the dosage form is administered once a day or twice a day for at least 3 weeks. 9. The pharmaceutical composition of claim 8, wherein the dosage form is administered once a day or twice a day for at least 3 weeks. The pharmaceutical composition of claim 1 , wherein the human experiences an increase in sleep latency in the Multiple Sleep Latency Test (MSLT). The pharmaceutical composition of claim 11 , wherein the human experiences an increase in sleep latency of at least 10% in MSLT. The pharmaceutical composition of claim 11 , wherein the human experiences an increase in sleep latency from about 20% to about 60% in MSLT. The pharmaceutical composition of claim 1 , wherein the human experiences a reduction of at least 15% in the cataplexy item score in the UNS. 15. The pharmaceutical composition of claim 14, wherein the human experiences a reduction of about 20% to about 70% of the cataplexy item score in the UNS. 15. The pharmaceutical composition of claim 14, wherein the human has a cataplexy item score of about 0 after administration of reboxetine. A kit comprising a pharmaceutical composition for the treatment of narcolepsy with cataplexy comprising reboxetine and instructions for using the pharmaceutical composition for the treatment of narcolepsy with cataplexy in a human, wherein reboxetine is administered in at least 1 dose for at least 3 weeks. A kit administered at least once a day. 18. The kit of claim 17, wherein the reboxetine is administered twice daily, the first dosage form is administered in the morning and the second dosage form is administered about 2 hours to about 6 hours later. 18. The method of claim 17, wherein the reboxetine is a daily administered dosage form, wherein the dosage form contains a first release component comprising reboxetine and a second release component comprising reboxetine, wherein the first release component is a dosage form of reboxetine. wherein the second release component provides a second local maximum in the plasma concentration of reboxetine and the first local maximum in the plasma concentration of reboxetine provides a first local maximum in the plasma concentration of reboxetine 2 Kits that occur about 2 to 6 hours before the local maximum. The kit of claim 19 , wherein the second local maximum in the plasma concentration of reboxetine occurs about 4 hours to about 6 hours after the first local maximum of reboxetine. 18. The kit of claim 17, wherein the human is selected as a human not suffering from depression. 18. The kit of claim 17, wherein the dose of reboxetine is increased for 1 to 7 days and then remains constant at a total daily dose of about 0.006 mmol to about 0.08 mmol. 18. The kit of claim 17, wherein the reboxetine is a dosage form, wherein the dosage form contains about 5 mg of reboxetine. 18. The kit of claim 17, wherein the reboxetine is a dosage form, wherein the dosage form contains about 10 mg of reboxetine. 24. The kit of claim 23, wherein the dosage form is administered once a day or twice a day for at least 3 weeks. The kit of claim 24 , wherein the dosage form is administered once a day or twice a day for at least 3 weeks. The kit of claim 17 , wherein the human experiences an increase in sleep latency in the Multiple Sleep Latency Test (MSLT). The kit of claim 27 , wherein the human experiences an increase in sleep latency in MSLT of at least 10%. The kit of claim 27 , wherein the human experiences an increase in sleep latency from about 20% to about 60% in MSLT. 18. The kit of claim 17, wherein the human experiences a decrease of at least 15% in the cataplexy item score in the UNS. 31. The kit of claim 30, wherein the human experiences a reduction of about 20% to about 70% of the cataplexy item score in the UNS. 31. The kit of claim 30, wherein the human has a cataplexy item score of about 0 after administration of reboxetine.