AU2023200917A1

AU2023200917A1 - Use of reboxetine to treat narcolepsy

Info

Publication number: AU2023200917A1
Application number: AU2023200917A
Authority: AU
Inventors: Herriot TABUTEAU
Original assignee: Axsome Therapeutics Inc
Current assignee: Axsome Therapeutics Inc
Priority date: 2018-10-15
Filing date: 2023-02-16
Publication date: 2023-03-23
Also published as: JP2022504975A; IL282311A; SG11202103588WA; PE20211199A1; KR20210071046A; EP3866768A1; CA3115983A1; WO2020081461A1; CN112888430A; AU2019361915A1; ECSP21031200A; CL2021000924A1; CR20210514A; EP3866768A4; MX2021004207A; BR112021007019A2; CO2021004681A2

Abstract

The present invention relates to methods of treating narcolepsy with cataplexy, comprising administering reboxetine to a human being in need thereof. Reboxetine may also be used in the manufacture of a medicament for the treatment of narcolepsy with cataplexy. Also disclosed herein are kits comprising a pharmaceutical composition comprising reboxetine and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

Description

USE OF REBOXETINE TO TREAT NARCOLEPSY

Inventor: HerriotTabuteau

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 62/745,956, filed

October 15, 2018, which is incorporated by reference herein in its entirety.

BACKGROUND

Narcolepsy is a serious and debilitating neurological condition that causes

dysregulation of the sleep-wake cycle and is characterized clinically by excessive daytime

sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis, and disrupted

nocturnal sleep. Narcolepsy is estimated to afflict an estimated 185,000 individuals in the U.S.

Cataplexy is seen in an estimated 70% of narcolepsy patients and is a sudden reduction or loss

of muscle tone while a patient is awake, typically triggered by strong emotions such as

laughter, fear, anger, stress, or excitement. Type 1 narcolepsy includes cataplexy, while Type

2 narcolepsy 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 are far reaching for the estimated nearly

200,000 patients living with this disorder in the United States. Narcolepsy interferes with

mental and social functioning, increases work and driving related accidents, and results in a

nearly two-fold higher mortality rate. Unfortunately, currently approved treatments are few

for this under-diagnosed orphan condition and are limited by variability in efficacy from

patient to patient, tolerability issues and the need for DEA scheduling.

SUMMARY

Described herein are methods of treating narcolepsy with cataplexy, comprising

administering reboxetine to a human being in need thereof.

Some embodiments include 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 to use the pharmaceutical composition to treat

narcolepsy with cataplexy in a human being.

In some embodiments, reboxetine is administered at least once daily for at least three weeks. In some embodiments, three weeks from the beginning of treatment, the human being experiences a reduction in the number of cataplexy attacks in a week, a reduction in the Epworth Sleepiness Scale score, or a reduction in the Maintenance of Wakefulness Test score as a result of the treatment.

DETAILED DESCRIPTION

Reboxetine has the potential to treat the symptoms of narcolepsy along with its lack of DEA scheduling would represent a significant benefit to patients living with this condition. A person may have Type 1 narcolepsy if Criteria A and B are met: A. The patient has daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least 3 months B. The presence of one or both of the following: 1. Cataplexy (as defined under Essential Features) and a mean sleep latency of <8 minutes and >2 Sleep-Onset REM Periods (SOREMPs) on a Mean Sleep Latency Test (MSLT) performed according to standard techniques. A SOREMP (within 15 minutes of sleep onset) on the preceding laboratory-based polysomnography (PSG) may replace one of the SOREMPs on the MSLT 2. CSF hypocretin-1 concentrations measured by immunoreactivity either <110 pg/mL or <3of mean values obtained in normal subjects with the same assay

In young children, narcolepsy may sometimes present as excessively long night sleep or by resumption of previously discontinued daytime napping. If narcolepsy Type 1is strongly suspected clinically but criteria B2 are not met, a possible strategy is to repeat the MSLT Some patients treated with reboxetine may have, and/or may be selected for having, daily periods of irrepressible need to sleep or daytime lapses into sleep occurring for at least about 3 months, at least 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 3-9 months, about 9-18 months, about 18 months to about 2years, about 2-5 years, about5-10years, about 10-15 years, about 15-20years, 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 more. Some patients treated with reboxetine may have, and/or may be selected for having, a mean sleep latency of less than about 1 minute, less than about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5 minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, about 0.1-1minutes, about 1-2 minutes, about 2-3 minutes, about 3-4 minutes, about 4-5 minutes, about 5-6 minutes, about 6-7 minutes, about 7-8 minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, or about 8 minutes. Some patients treated with reboxetine may have, and/or may be selected for having, at least2,atleast3,oratleast 4 SOREMPs on an MSLT (Mean Sleep Latency Test) performed according to standard techniques. A SOREMP within 15 minutes of sleep onset on the preceding nocturnal PSG may replace one of the SOREMPs on the MSLT Some patients treated with reboxetine may have, and/or may be selected for having, CSF hypocretin-1 concentrations measured by immunoreactivity that are less than about 40 pg/mL, less than about 50 pg/mL, less than about 60 pg/mL, less than about 70 pg/mL, less than about 80 pg/mL, less than about 90 pg/mL, less than about 100 pg/mL, less than about 110 pg/mL. Some patients treated with reboxetine may have, and/or may be selected for having, CSF hypocretin-1 concentrations measured by immunoreactivity that are less than about 1/10,less than about1/9,less than about1/8,less than about1/7,less than about1/6,less than about 1/5, less than about 1/4, or less than about 1/3 of mean values obtained in normal subjects with the same assay. Some patients treated with reboxetine may be, and/or may be selected for being, young children presenting with excessively long night sleep. Some patients treated with reboxetine may be, and/or may be selected for being, young children presenting with resumption of previously discontinued daytime napping. Some patients treated with reboxetine may have, and/or may be selected for having, a cataplexy subscore on the Ullanlinna Narcolepsy Score (UNS) that is at least 1, at least about

2, at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least

about8,at least about9,at least about10,about11,about1-2,about 2-3,about3-4,about

4-5,about5-6,about6-7,about7-8,about8-9,about 9-10,about10-11,about 2-4,about4

6, about 6-8, about 8-10, about 2-6, or about 6-10, or any number between 1 and 11.

Some patients treated with reboxetine may have, and/or may be selected for having,

a score on the Epworth Sleepiness Scale (ESS) that is 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,

about13-14,about14-15,about15-16,about16-17,about17-18,about18-19,about19-20,

about20-21,about21-22,about22-23,about23-24,about10-13,about13-16,about16-19,

about19-22,or about22-24.

a Maintenance of Wakefulness Test (MWT) score that is less than about 1 minutes, less than

about 2 minutes, less than about 3 minutes, less than about 4 minutes, less than about 5

minutes, less than about 6 minutes, less than about 7 minutes, less than about 8 minutes, less

than about 9 minutes, less than about 10 minutes, less than about 11minutes, less than about

12 minutes, less than about 13 minutes, less than about 14 minutes, less than about 15

minutes, less than about 16 minutes, less than about 17 minutes, less than about 18 minutes,

less than about 19 minutes, less than about 20 minutes, about 0-1 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, about 16-20, or about 0-19 minutes.

In some embodiments, the patient has had, and/or may be selected for having had,

symptoms of narcolepsy for about 1-5 years, about 5-10 years, about 10-15 years, about 15

20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about

40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years,

about 65-70 years, about 70-75, or more than 75 years prior to receiving reboxetine for

treatment.

In some embodiments, the patient has, and/or may be selected for having, an age of about 0-5 years, about 5-10 years, about 10-15 years, about 15-20 years, about 20-25 years, about 25-30 years, about 30-35 years, about 35-40 years, about 40-45 years, about 45-50 years, about 50-55 years, about 55-60 years, about 60-65 years, about 65-70 years, about 70 75, or more than 75 years prior to receiving reboxetine for treatment. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may be, and/or may be selected for being female. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may be, and/or may be selected for being male. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, any clinically significant conditions potentially causing EDS. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, any clinically significant psychiatric disorders. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, any type of depression that was not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, any sleepiness caused by depression that was not caused by narcolepsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, an affective disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a psychiatric disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral function disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a movement disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or maybe selected for not having, a dementia Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a motor neuron disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a neurodegenerative disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a seizure disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, headaches. Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a

depression. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, major depression. Some patients

treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or

may be selected for not having, a treatment resistant depression.

Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS)

may not have, and/or may be selected for not having, treatment resistant bipolar depression.

Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may

not have, and/or may be selected for not having, a bipolar disorder. Some patients treated

with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be

selected for not having, cyclothymia. Some patients treated with reboxetine for narcolepsy

seasonal affective disorder. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a mood disorder.

not have, and/or may be selected for not having, chronic depression (e.g. dysthymia). Some

patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not

have, and/or may be selected for not having, a psychotic depression.

may not have, and/or may be selected for not having, a postpartum depression. Some

have, and/or may be selected for not having, a premenstrual dysphoric disorder (PMDD).

not have, and/or may be selected for not having, a situational depression. Some patients

may be selected for not having, an atypical depression. Some patients treated with

reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be

selected for not having, a mania. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having, an anxiety disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, attention deficit disorder (ADD).

may not have, and/or may be selected for not having, attention deficit disorder with

hyperactivity (ADDH). Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, attention

deficit/hyperactivity disorder (AD/HD). Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a manic

condition. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, an obsessive-compulsive disorder.

not have, and/or may be selected for not having, a bulimia. Some patients treated with

selected for not having, obesity or weight-gain. Some patients treated with reboxetine for

narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not

having, a chronic fatigue syndrome.

may not have, and/or may be selected for not having, a premenstrual syndrome. Some

have, and/or may be selected for not having, a substance addiction or abuse. Some patients

may be selected for not having, a nicotine addiction. Some patients treated with reboxetine

for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not

having, a psycho-sexual dysfunction. Some patients treated with reboxetine for narcolepsy

pseudobulbar affect. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, emotional

lability.

may not have, and/or may be selected for not having, an anxiety disorder. Some patients

may be selected for not having, a phobia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a generalized anxiety disorder. Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a social

anxiety disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, a panic disorder. Some

have, and/or may be selected for not having, an agoraphobia. Some patients treated with

selected for not having, an obsessive-compulsive disorder. Some patients treated with

selected for not having, post-traumatic stress disorder (PTSD). Some patients treated with

selected for not having, a mania.

may not have, and/or may be selected for not having, a manic depressive illness. Some

have, and/or may be selected for not having, a hypomania. Some patients treated with

selected for not having, a unipolar depression. Some patients treated with reboxetine for

having, a stress disorder. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a somatoform

disorder. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, a personality disorder. Some

have, and/or may be selected for not having, a psychosis.

may not have, and/or may be selected for not having, schizophrenia. Some patients treated

selected for not having, a delusional disorder. Some patients treated with reboxetine for

having, a schizoaffective disorder. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having, a

schizotypy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, aggression. Some patients treated

selected for not having, aggression in Alzheimer's disease. Some patients treated with

selected for not having, agitation. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having, agitation in

Alzheimer's disease.

may not have, and/or may be selected for not having, a drug dependence. Some patients

may be selected for not having, addiction to cocaine. Some patients treated with reboxetine

having, addiction to or dependence on a psychostimulant. Some patients treated with

selected for not having, addiction to or dependence on crack. Some patients treated with

selected for not having, addiction to or dependence on cocaine. Some patients treated with

selected for not having, addiction to or dependence on speed. Some patients treated with

selected for not having, addiction to or dependence on methamphetamine. Some patients

may be selected for not having, addiction to or dependence on nicotine.

may not have, and/or may be selected for not having, addiction to or dependence on alcohol.

not have, and/or may be selected for not having, addiction to or dependence on an opioid.

not have, and/or may be selected for not having, addiction to or dependence on an anxiolytic

and/or a hypnotic drug. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, addiction to or dependence on a cannabis (marijuana). Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having,

addiction to or dependence on an amphetamine. Some patients treated with reboxetine for

having, addiction to or dependence on a hallucinogen. Some patients treated with reboxetine

having, an addiction to or dependence on phencyclidine.

may not have, and/or may be selected for not having, addiction to or dependence on a volatile

solvent. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, addiction to or dependence on a

volatile nitrite. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, senile dementia. Some

have, and/or may be selected for not having, an Alzheimer's type dementia. Some patients

may be selected for not having, memory loss. Some patients treated with reboxetine for

having, an amnesia/amnestic syndrome. Some patients treated with reboxetine for

having, an apilepsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, disturbances of

consciousness.

may not have, and/or may be selected for not having, a coma. Some patients treated with

selected for not having, a lowering of attention. Some patients treated with reboxetine for

having, a speech disorder. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a voice spasm.

Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Parkinson's disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Lennox-Gastaut syndrome.

may not have, and/or may be selected for not having, autism. Some patients treated with

selected for not having, a hyperkinetic syndrome. Some patients treated with reboxetine for

having, schizophrenia. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, had a stroke.

not have, and/or may be selected for not having, a cerebral infarction. Some patients treated

selected for not having, a cerebral bleeding. Some patients treated with reboxetine for

having, a cerebral arteriosclerosis. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral

venous thrombosis. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a head injury.

may not have, and/or may be selected for not having, an akinesia. Some patients treated

selected for not having, an athetosis. Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, an

ataxia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS)

may not have, and/or may be selected for not having, a ballismus. Some patients treated

selected for not having, a hemiballismus. Some patients treated with reboxetine for

having, a bradykinesia. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral palsy.

may not have, and/or may be selected for not having, a chorea. Some patients treated with

selected for not having, Huntington's disease. Some patients treated with reboxetine for

having, a rheumatic chorea. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a Sydenham's

chorea. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, adyskinesia. Some patients

may be selected for not having, a tardive dyskinesia. Some patients treated with reboxetine

having, a dystonia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, a blepharospasm.

may not have, and/or may be selected for not having, a spasmodic torticollis. Some patients

may be selected for not having, a dopamine-responsive dystonia. Some patients treated with

selected for not having, restless legs syndrome (RLS). Some patients treated with reboxetine

having, a tremor. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, an essential tremor. Some

have, and/or may be selected for not having, Tourette's syndrome. Some patients treated

selected for not having, Wilson's disease.

may not have, and/or may be selected for not having, a vascular dementia. Some patients

may be selected for not having, a dementia with Lewy bodies. Some patients treated with

reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a mixed dementia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a fronto-temporal dementia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Creutzfeldt-Jakob disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a normal pressure hydrocephalus. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Wernicke Korsakoff Syndrome. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Pick's disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a progressive bulbar palsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a primary lateral sclerosis (PLS). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a progressive muscular atrophy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a post-polio syndrome (PPS). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal muscular atrophy (SMA). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal motor atrophy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Tay-Sach's disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Sandoff disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a hereditary spastic paraplegia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Alzheimer's disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a prion-related disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebellar ataxia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinocerebellar ataxia (SCA). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spinal muscular atrophy (SMA). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a bulbar muscular atrophy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a Friedrich's ataxia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for 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 for not having, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, multiple sclerosis (MS). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a multiple system atrophy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Shy-Drager syndrome. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a corticobasal degeneration. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a progressive supranuclear palsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Wilson's disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, Menkes disease. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, an adrenoleukodystrophy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

(CADASIL). Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, a muscular dystrophy.

may not have, and/or may be selected for not having, a Charcot-Marie-Tooth disease (CMT).

not have, and/or may be selected for not having, a familial spastic paraparesis. Some patients

may be selected for not having, a neurofibromatosis. Some patients treated with reboxetine

having, an olivopontine cerebellar atrophy or degeneration. Some patients treated with

selected for not having, a striatonigral degeneration. Some patients treated with reboxetine

having, Guillain-Barr-syndrome. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having, a spastic

paraplesia. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, epileptic seizures. Some patients

may be selected for not having, nonepileptic seizures. Some patients treated with reboxetine

having, epilepsy. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, febrile seizures. Some

have, and/or may be selected for not having, partial seizures. Some patients treated with

selected for not having, simple partial seizures. Some patients treated with reboxetine for

having, Jacksonian seizures. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, complex partial

seizures. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, an epilepsia partialis continua.

Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, generalized seizures. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, generalized tonic-clonic seizures. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, an absence seizure.

may not have, and/or may be selected for not having, atonic seizures. Some patients treated

selected for not having, myoclonic seizures. Some patients treated with reboxetine for

having, juvenile myoclonic seizures. Some patients treated with reboxetine for narcolepsy

infantile spasm. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy

and/or EDS) may not have, and/or may be selected for not having, status epilepticus. Some

have, and/or may be selected for not having, Rett Syndrome. Some patients treated with

selected for not having, a tinnitus. Some patients treated with reboxetine for narcolepsy (e.g.

with cataplexy and/or EDS) may not have, and/or may be selected for not having,

disturbances of consciousness disorders. Some patients treated with reboxetine for

having, a sexual dysfunction. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, a voice disorder

due to uncontrolled laryngeal muscle spasms. Some patients treated with reboxetine for

having, an abductor spasmodic dysphonia. Some patients treated with reboxetine for

having, an adductor spasmodic dysphonia. Some patients treated with reboxetine for

having, a muscular tension dysphonia. Some patients treated with reboxetine for narcolepsy

(e.g. with cataplexy and/or EDS) may not have, and/or may be selected for not having, a vocal

tremor. Some patients treated with reboxetine for narcolepsy (e.g. with cataplexy and/or

EDS) may not have, and/or may be selected for not having, a diabetic neuropathy. Some

have, and/or may be selected for not having, a chemotherapy-induced neurotoxicity. Some

have, and/or may be selected for not having, methotrexate neurotoxicity. Some patients

may be selected for not having, a stress urinary incontinence. Some patients treated with

selected for not having, urge urinary incontinence. Some patients treated with reboxetine

having, fecal incontinence. Some patients treated with reboxetine for narcolepsy (e.g. with

cataplexy and/or EDS) may not have, and/or may be selected for not having, erectile

dysfunction.

Cataplexy includes a sudden reduction or loss of muscle tone while a patient is awake,

which may affect specific parts of the body or the entire body, such as eyelids, head drop,

facial sagging and/or twitching, slurred speech, jaw weakness, weakness in arms, shoulders,

or hands, and/or buckling of knees. Cataplexy may be pathognomonic for narcolepsy.

Cataplexy may be triggered by strong emotions, such as laughter, elation, surprise, or anger.

Cataplexy may be partial or localized (in about 75% of cases) and is usually of short duration.

The frequency of cataplexy may vary widely. Narcolepsy with cataplexy may be socially

disabling and isolating.

Some patients being treated with reboxetine may have, and/or may be selected for

having, narcolepsy with cataplexy (Type 1) that is an autoimmune disorder resulting in a loss

of hypocretin (orexin)-producing neurons in the CNS. Hypocretins (orexins) are hypothalamic

specific peptides with neuroexcitatory activity. A patient being treated with reboxetine for

narcolepsy with cataplexy is, and may be selected for being, a predisposed individual with

specific genetic markers including human leukocyte antigen (HLA DQB1/06:02) and/or T-cell

receptor alpha variants. Some patients being treated with reboxetine may not have, and may

be selected for not having, narcolepsy associated with loss of hypocretin neurons. Some

patients being treated with reboxetine may have, or may be selected for having, narcolepsy

precipitated by seasonal Streptococcus infections, H1N1influenza, and/or H1N1vaccination

in genetically predisposed individuals.

Existing treatments for narcolepsy only address some of its symptoms, provide

variable efficacy, and have significant side effects. Additionally, all existing treatments are

controlled substances.

Accordingto the FDA, "there is a continued need foradditional effective and tolerable

treatment options for patients to improve their daily functioning." (The Voice of the Patient,

A series of reportsfrom the U.S. Food and Drug Administration's(FDA's) Patient-Focused Drug

Development Initiative, Narcolepsy, June 2014. p. 25)

In some embodiments, administering reboxetine may reduce daytime sleepiness by

at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about

30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least

about 80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about

30-40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about

90-100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to

baseline, placebo, or some other appropriate control (including an active control, such as a

stimulant (e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate,

a tricyclic antidepressant, a selective serotonin reuptake inhibitor (SSRI), or a selective

norepinephrine reuptake inhibitor (SNRI)).

In some embodiments, administering reboxetine may reduce cataplexy by at least

about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at

least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about

80%, at least about 90%, about 1-5%, about 1-10%, about 10-20%, about 20-30%, about 30

40%, about 40-50%, about 50-60%, about 60-70%, about 70-80%, about 80-90%, about 90

100%, about 1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to

a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce the number of cataplexy

attacks by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at

least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about

90%, at least about 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 per week, at least about 2 per week, at least about 3 per week, at least about 4 per week, at least about 5 per week, at least about 6 per week, at least about 7 per week, at least about 8 per week, at least about 9 per week, at least about 10 per week, at least about 12 per week, at least about 14 per week, at least about 16 per week, at least about 18 per week, at least about 20 per week, at least about 22 per week, at least about 24 per week, at least about 26 per week, at least about 28 per week, at least about 30 per week, at least about 40 per week, at least about 50 per week, about 1-2 per week, about 2-3 per week, about 3-4 per week, about 4-5 per week, about 5-6 per week, about 6-7 per week, about 7-8 per week, about 8-9 per week, about 9 10 per week, about 10-11 per week, about 11-12 per week, about 12-13 per week, about 13 14 per week, about 14-15 per week, about 15-16 per week, about 16-17 per week, about 17 18 per week, about 18-19 per week, about 19-20 per week, about 1-10 per week, about 10 20 per week, about 20-30 per week, about 30-40 per week, about 40-50 per week, about 50 60 per week, or more, e.g. as compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI). In some embodiments, administering reboxetine may reduce the ESS score by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, 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,atleastabout15,atleastabout16,atleastabout17,at leastabout18,at leastabout19, at least about 20, at least about 21, at least about 22, at least about 23, about 24, about 1-2, about2-3,about3-4,about4-5,about5-6,about6-7,about7-8,about8-9,about9-10,about 10-11,about11-12,about12-13,about13-14,about14-15,about15-16,about16-17,about 17-18,about18-19,about19-20,about20-21,about21-22,about22-23,about23-24,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 e.g. as compared to baseline, placebo, or some other appropriate control (including an active control, such as a stimulant (e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce the MWT score by at

least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about

50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, 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, e.g. as compared to baseline, placebo, or some

other appropriate control (including an active control, such as a stimulant (e.g.

methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce the cataplexy score on

the UNS by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at

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 about9, at least about10, about 11,about 2-3,about 3-4, about4-5,about

5-6,about6-7,about7-8,about8-9,about9-10,about2-4,about4-6,about6-8,about8-10,

about 10-11, about 2-6, or about 6-10, about 5-11, e.g. as compared to baseline, placebo, or

some other appropriate control (including an active control, such as a stimulant (e.g.

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may increase sleep latency on the

MSLT by at least about 30%, at least about 50%, at least about 60%, at least about 70%, at

least about 80%, at least about 90%, at least about 95%, about 50-60%, about 60-70%, about

70-80%, about 80-90%, about 90-100%, about 50-75%, or about 75-100%, 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

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce nightmares or

unpleasant dreams (such as frequent nightmares and frequent unpleasant dreams) by at least

about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at

1-25%, about 25-50%, about 50-75%, or about 75-100%, e.g. as compared to baseline,

placebo, or some other appropriate control (including an active control, such as a stimulant

(e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce hallucinations by at least

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce sleep paralysis by at

least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 40%,

at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about

antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce disturbed nocturnal

sleep by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least

about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at

least about 90%, at least about 95%, about 1-10%, about 10-20%, about 20-30%, about 30

a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce narcolepsy-related

accidents by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at

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%, e.g. as

compared to baseline, placebo, or some other appropriate control (including an active

control, such as a stimulant (e.g. methylphenidate, an amphetamine), modafanil, armodafanil, sodium oxybate, a tricyclic antidepressant, an SSRI, or an SNRI).

In some embodiments, administering reboxetine may reduce narcolepsy-related

injuries by at least about 1%, at least about 10%, at least about 20%, at least about 30%, at

In some embodiments, administering reboxetine may reduce narcolepsy-related fatal

Reboxetine (with the structure shown below) is a highly selective and potent

norepinephrine reuptake inhibitor that has the potential to address the key symptoms of

narcolepsy, such as cataplexy or EDS. Unlike existing treatments for narcolepsy, reboxetine

is not a controlled substance. Thus, the treatment with reboxetine would not be scheduled.

/0\

NH (reboxetine)

Unless otherwise indicated, any reference to a compound herein, such as reboxetine, by structure, name, or any other means, includes pharmaceutically acceptable salts; free acids or bases; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; enantiomers; deuterium modified compounds, such as deuterium modified reboxetine; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein. In some embodiments, reboxetine is in a salt form, a free base form, or may contain an excess (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (+)-reboxetine or an excess (e.g. at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97%, or at least 99%) of (-)-reboxetine. For treatment of narcolepsy, the reboxetine may be administered in a manner that results in 1) a first local maximum in reboxetine plasma concentration and 2) a second local maximum in reboxetine plasma concentration. There are many potential ways that reboxetine could be administered in a manner that results in a first local maximum in reboxetine plasma concentration and a second local maximum in reboxetine plasma concentration. A local maximum described herein is a maximum of a plasma concentration in a time period of interest in an individual patient, which is not necessarily the Cmax. The local maximum may be lower or the same as Cmax. One potential way to administer reboxetine in a manner that results in a first local maximum in reboxetine plasma concentration and a second local maximum in reboxetine plasma concentration is to administer a first dosage form containing reboxetine and, at a later time, a second dosage form containing reboxetine. The doses are administered at times that result in a first local maximum in reboxetine plasma concentration and a second local maximum in 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, after the

first dosage form, or any time period in a range bounded by any of these values.

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 in a day, the only dosage

form administered during the day, or the first of two or more dosage forms administered

during the day, is administered shortly after waking, such as within about 3 hours, within

about 2 hours, within about 1.5 hours, within about 1 hour, within about 30 minutes, orwithin

about 15 minutes of waking from an overnight sleep.

For a single dosage form comprising a first release component and a second release

component that is administered in a day, the first release component may release reboxetine,

may begin releasing reboxetine, or may result in a first local maximum in the plasma

concentration of reboxetine, about 0-30 minutes, about 30-60 minutes, about 60-90 minutes,

or about 90-120 minutes after the dosage form is orally administered, or any time period in a

range bounded by any of these values. The second release component may release

reboxetine after the first release component releases reboxetine, or may cause an increase

of reboxetine plasma concentration or a second local maximum in the plasma concentration

of reboxetine, that is 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 5-6 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 reboxetine is first released from the first release component, or afterthe first local

maximum in the plasma concentration of reboxetine, or at any time in a range bounded by

any of these values.

The first release component and the second release component may be incorporated

into one single dosage form (such as a pill, tablet, capsule, caplet, or cachou). In one

embodiment, the first release component would be located in one of the outer layers of the

dosage form and the second release component would be located in one of the inner layers of the same dosage form.

In another embodiment, 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 be in contact with one another.

In some embodiments, the two layers are stacked on top of one another and physically bound

in a bi-layer structure (e.g. where the largest surfaces of the two layers contact one another,

or the layers are thin compared to the other dimensions of the layers). In some embodiments,

the two layers are positioned next to one another and physically bound in a bi-layer structure

(e.g. where the layers are thicker than other dimensions of the layers).

In another embodiment, the first release component and the second release

component may be constructed separately in their own specific granules, particles, or the like,

wherein the first release component particles are formulated to release reboxetine before

the second release component particles release reboxetine and 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, cachou or the like, and the two

release components may or may not be physically bound to one another.

In some embodiments, the first local maximum plasma concentration of reboxetine

occurs about 1-30 minutes, about 30-60 minutes, about 1-2 hours, about 2-3 hours, or about

3-4 hours after the single dosage form or the first dosage form is administered, or at any time

in a range bounded by any of these values. Generally, the second local maximum plasma

concentration of reboxetine occurs 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 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, after the first local maximum plasma

concentration of reboxetine, or any time period in a range bounded by any of these values.

For dosage forms containing a first release component and a second release

component, the first release component is associated with the first local maximum in

reboxetine plasma concentration in that the first release component releases the reboxetine

that contributes to the first local maximum in reboxetine plasma concentration. For example,

the first release component could release reboxetine faster or sooner than the second release

component, so that most of the reboxetine contributing to the first local maximum plasma concentration of reboxetine that was released from the first release component. For dosage forms containing a first release component and a second release component, the second release component is associated with the second local maximum in reboxetine plasma concentration in that the second release component releases the reboxetine that contributes to the second local maximum in reboxetine plasma concentration. For example, the second release component could delay release of its reboxetine so that at a time when the reboxetine plasma concentration is decreasing after the first local maximum, the second release component releases a sufficient amount of reboxetine to again increase the plasma concentration of reboxetine so that the second local maximum in reboxetine plasma concentration is achieved. For dosage forms containing a first release component and a second release component, any suitable amount of reboxetine may be present in the first release component, 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, a bout 1-3 mg, a bout 2-4 mg, a bout 3-5 mg, a bout 4-6 mg, a bout 5-7 mg, a bout 7-10 mg, a bout 4 mg, about 5 mg, about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range bounded by any of these values. For dosage forms containing a first release component and a second release component, any suitable amount of reboxetine may be present in the second release component, 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 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range bounded by any ofthese values. The dose of reboxetine may gradually increase over time, such as for 1, 2, 3, 4, 5, 6, or 7 days, to a maintenance dose, which is a total dose given each day (e.g. a 10 mg maintenance dose could be a once daily 10 mg dose, or 5 mg given twice a day for a total of 10 mg per day). In some embodiments, the maintenance dose may be 2-3 mg, about 3-4 mg, about 4-5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 10-11 mg, about 11-12 mg, about 12-13 mg, about 13-14 mg, about 14-15 mg, about 15-16 mg, about 16-17 mg, about 2-5 mg, about 5-8 mg, about 8-11 mg, about 11-14 mg, about 14-17 mg, about 17-20 mg, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, 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 may be administered for at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least 4 months, at least 5 months, at least 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 immediate release of reboxetine. In some embodiments, the first release component provides delayed release of reboxetine. In some embodiments, the first release component provides sustained release 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 methods wherein the reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any suitable amount of reboxetine may be present in the first dosage form, such as about 1-10 mg, about 0.1-1 mg, about 0.1-2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about 4 mg, about 5 mg, about 0.0003 0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015-0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024 0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range bounded by any of these values. With respect to methods wherein the reboxetine is administered in a first dosage form containing reboxetine and a second dosage form containing reboxetine, any suitable amount of reboxetine may be present in the second dosage form, such as about 0.1-1 mg, about 0.1 2 mg, about 0.5-1.5 mg, about 1-3 mg, about 1-2 mg, about 1.5-2.5 mg, about 2-3 mg, about 2.5-3.5 mg, about 3-4 mg, about 3.5-4.5 mg, about 4-5 mg, about 4.5-5.5 mg, about 5-6 mg, about 6-7 mg, about 7-8 mg, about 8-9 mg, about 9-10 mg, about 2-4 mg, about 3-5 mg, about 4-6 mg, about 5-7 mg, about 7-10 mg, about4mg,aboutmg,about 0.0003-0.006 mmol, about 0.006-0.009 mmol, about 0.009-0.012 mmol, about 0.012-0.015 mmol, about 0.015 0.018 mmol, about 0.018-0.021 mmol, about 0.021-0.024 mmol, about 0.024-0.027 mmol, about 0.027-0.03 mmol, about 0.03-0.033 mmol, or any amount in a range bounded by any of these values. 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 single dosage forms containing both a first release component and a second release component, in some embodiments, the single dosage is administered within two hours of waking from an overnight sleep. For some embodiments wherein more than one dosage form is given, the first dosage form may be administered within two hours of waking from an overnight sleep. There are many factors that can affect the overall time required for a drug substance such as reboxetine to be fully absorbed and/or reach a maximum plasma concentration in a human being. Some of these factors include a human patient's age, weight, gender, level of stress, stomach contents, stomach pH level, and the presence of other medications. The time required to reach a maximum plasma concentration of the drug such as reboxetine may also be affected by the time of the day taken the drug such as reboxetine and the level of physical activity of the human patient. Another factor that can affect the time required to reach a maximum plasma concentration of the drug such as reboxetine is the presence or absence of a controlled release coating on the drug such as reboxetine. Controlled release includes: immediate release of drug substance such as reboxetine at a certain time or in a certain area of the body; delayed release of a drug substance; sustained release of drug substance at a certain time or place in the body; or an extended release of a drug substance such as reboxetine. Reboxetine is normally rapidly absorbed in human patients, reaching a maximum plasma concentration in about 2-4 hours. To achieve a delay in the time required to reach a maximum plasma concentration, a controlled release coating or mixture may be employed. Delayed release is a general drug delivery term that describes the form of an oral medication that does not immediately discharge its active drug component in the mouth or in the stomach of a patient. While there may be many ways to achieve delayed release, delayed release of reboxetine may be achieved by completely or partially surrounding the reboxetine, e.g. in the second release component, with a coating or layer (e.g. an inner controlled release coating) that does not immediately dissolve when swallowed. For example, the material of the coating or layer may slowly dissolve in the stomach, and/or slowly disintegrate by chemical reaction, such as by hydrolysis, in the stomach until the layer can no longer prevent the reboxetine from coming into contact with the gastric fluid. In some embodiments, the delayed release coating ensures delivery through the stomach and into the intestines. Once in the duodenum, the coating may begin to break down and begin to release reboxetine. In some cases, the reboxetine may be completely released in the duodenum. In some embodiments, the reboxetine may be partially released in the duodenum, and partially released in the jejunum. In some cases, the reboxetine may be completely released in the jejunum. In some cases, the reboxetine may be partially released in the jejunum and partially released in the ilium. In some cases, the reboxetine may be completely released in the ilium. In some cases, the reboxetine may be partially released in the duodenum, the jejunum, and the ilium. In some embodiments, the reboxetine may be partially released in the ilium, and partially released in the colon. In some cases, the reboxetine may be completely released in the colon.

The time of the delayed release, e.g. between release of the first reboxetine

component and the second reboxetine component, can be adjusted by using a material that

dissolves or disintegrates more or less slowly in the digestive system, adjusting the thickness

of the coating layer or the coating material (e.g. a thicker layer would provide a longer time),

and/or by using materials whose properties are sensitive to pH. For example, materials that

are less stable to, or more soluble in, acidic pHs, may dissolve or disintegrate more quickly in

the stomach because the stomach pH is lower than the pH in the intestines. Conversely,

materials that are stable at low pH, but less stable at higher pH may dissolve or disintegrate

later because of the time it takes the dosage form to travel through the gastrointestinal tract.

A controlled release formulation containing reboxetine can be coated with one or

more functional or non-functional coatings. Examples of functional coatings include

controlled release polymeric coatings (i.e. controlled release coats), moisture barrier

coatings, enteric polymeric coatings, and the like.

A controlled release polymer may be used for both sustained release or for delayed

release, depending upon the structure of the dosage form. For example, interspersing the

reboxetine throughout a controlled release polymer can provide sustained release, since the

drug will be released for as long as the polymer is present in the GI tract. Delayed release

may be achieved by creating a barrier, such as a coating, which is intended to lastfor a shorter

time (e.g. less than 12 hours, less than 10 hours, less than 6 hours, less than 3 hours, etc.), so

that when the barrier is penetrated, the reboxetine is freely released. The thickness of the

barrier can be used to control the delay time.

Any suitable controlled release polymer may be used, such as acrylic acid and

methacrylic acid copolymers and various esters thereof, e.g. methyl methacrylate

copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

Other suitable controlled release polymers include polymerizable quaternary

ammonium compounds, e.g. quaternized aminoalkyl esters and aminoalkyl amides of acrylic

acid and methacrylic acid, for example S-methacryloxyethyltrimethylammonium methosulfate, S-acryloxypropyltrimethylammonium chloride, and

trimethylaminomethylmethacrylamide methosulfate. The quaternary ammonium atom can

also be part of a heterocycle, as in methacryloxyethylmethylmorpholinium chloride or the

corresponding piperidinium salt, or it can be joined to an acrylic acid group or a methacrylic

acid group by way of a group containing hetero atoms, such as a polyglycol ether group.

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, diethylmethylammoniumethyl

acrylate and -methacrylate methosulfate, N-trimethylammoniumpropylmethacrylamide

chloride,andN-trimethylammonium-2,2-dimethylpropyl-1-methacrylatechloride.

Delayed release may also be achieved by using a controlled release polymer that

targets a particular pH, with the understanding that, with proper fasting or feeding, the

particular pH could correspond to a particular time after administration.

For some controlled release polymers, an acrylic or methacrylic polymer comprises

one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers (such

as those sold by Evonik under the trademark EUDRAGIT© RS and RL) are fully polymerized

copolymers of acrylic and methacrylic acid esters with a low content of quaternary

ammonium groups. The ammonium groups are appended to the ester portion of the

methacrylate (as 2-trimethylammonium-ethyl esters). The charged ammonium groups in

these polymers make them insoluble and highly permeable with pH-independent swelling.

These properties make these polymers useful for customized, time-controlled release of the

coated drug. In order to obtain a desirable dissolution profile for a given therapeutically

active agent, such as reboxetine, two or more ammonio methacrylate copolymers having

differing physical properties can be incorporated. For example, it is known that by changing the molar ratio of the pre-polymerized materials containing quaternary ammonium groups to pre-polymerized materials containing the uncharged, neutral methacrylic or acrylic esters, the permeability properties of the resultant coating can be modified.

In other embodiments, the control releasing coat further includes a polymer whose

permeability is pH dependent, such as anionic polymers synthesized from methacrylic acid

and methacrylic acid methyl ester. Such polymers are commercially available, e.g., from

Evonik, under the tradename EUDRAGIT© L and EUDRAGIT© S. The ratio of free carboxyl

groups to the esters is known to be 1:1 in EUDRAGIT© L and 1:2 in EUDRAGIT© S. EUDRAGIT©

L is insoluble in acids and pure water but becomes increasingly permeable above pH 5.0. This

makes EUDRAGIT L appropriate for targeting release of the coated drug substance such as

coated reboxetine in the duodenum and the jejunum of the small intestine. Thus, a

EUDRAGIT L coated drug substance may achieve a delay in maximum plasma concentration,

relative to an uncoated or immediate release drug substance (e.g. reboxetine in a first release

component), of about 30 min to about 1 hour, about 1-1.5 hours, about 1.5-2 hours, about 2

2.5 hours, about 2.5-3 hours, or about 3.5-4 hours.

EUDRAGIT S is similar to EUDRAGIT L, except that it becomes increasingly

permeable above pH 7. This makes EUDRAGIT S appropriate for targeting release of the

coated drug substance such as coated reboxetine in the ileum of the small intestine and also

the colon. Thus, a EUDRAGIT S coated drug substance may achieve a delay in maximum

plasma concentration, relative to an uncoated or immediate release drug substance (e.g.

reboxetine in a first release component), of about 1-2 hours, about 2-3 hours, about 3-4 hours

about4-5 hours,about5-6 hours,about6-7 hours,about7-8 hours,about8-9 hours,orabout

9-10 hours.

A hydrophobic acrylic polymer coating can also include a polymer which is based on

dimethylaminoethyl methacrylate and neutral methacrylic acid esters (such as EUDRAGIT E, commercially available from Evonik). EUDRAGIT E is not soluble in saliva (making it useful

for taste and odor masking) but is soluble in gastric fluid with pH 5 or less, which provides an

immediate release of drug product in the stomach. Reboxetine surrounded with a

EUDRAGIT E coating may release reboxetine, may begin releasing reboxetine, or may reach

a first local maximum in the plasma concentration of reboxetine, at a time of about 0-30

minutes, 30-60 minutes, 60-90 minutes, or 90-120 minutes after the dosage form is orally

administered, or any time period in a range bounded by any of these values.

A hydrophobic acrylic polymer coating can include a neutral copolymer based on a

poly methacrylate, such as EUDRAGIT© NE (NE=neutral ester), commercially available from

Evonik. EUDRAGIT© NE 30D lacquer films are insoluble in water and digestive fluids, but

permeable and swellable, providing another option for time-controlled release. EUDRAGIT©

NE has a pH-independent sustained release effect that can release a drug substance such as

reboxetine over a period of time, or may delay release for a period of time, wherein the time

of release or delay 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).

KOLLICOAT© EMM 30 D has a pH-independent sustained release effect that can release a drug

substance such as reboxetine over a period of time, or may delay release for a period of time,

wherein the time of release or delay 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 polyvinyl acetate

stabilized with polyvinylpyrrolidone and sodium lauryl sulfate such as KOLLICOAT SR30D

(BASF). The dissolution profile can be altered by changing the relative amounts of different

acrylic resin lacquers included in the coating. Also, by changing the molar ratio of

polymerizable permeability-enhancing agent (e.g., the quaternary ammonium compounds)

to the neutral methacrylic esters, the permeability properties (which affect the dissolution

profile) of the resultant coating can be modified. KOLLICOAT® SR30D is another coating with

a pH-independent sustained release effect that can release a drug substance such as

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 a dry polymer (such as ETHOCELTM, Dow Chemical Company) solubilized in organic

solvent prior to use, or as an aqueous dispersion. One suitable commercially-available

aqueous dispersion of ethylcellulose is Aquacoat* (Danisco). Aquacoat* ECD (ethylcellulose

aqueous dispersion), Aquacoat* ARC (alcohol-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.). This product can be prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (e.g. dibutyl sebacate), and stabilizer (e.g. oleic acid) may be mixed and prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates. These coatings have a pH-independent sustained release effect that can release a drug substance such as reboxetine over a period of time, or may delay release for a period of time, wherein the time of release or delay 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 the control-releasing coat include

cellulose acetate phthalate, cellulose acetate trimaleate, hydroxypropyl methylcellulose

phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl alcohol phthalate,

shellac, hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate,

sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol,

hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose based

cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption

of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl

methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin,

pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable

hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000 k),

polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionic and cationic hydrogels, zein,

polyamides, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and

carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene

or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, acacia,

acrylic acid polymer, sodium salt), diesters of polyglucan, crosslinked polyvinyl alcohol and

poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose,

sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl

cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers,

methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate,

cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthan, scleroglucan and mixtures and blends thereof.

In some embodiments, the dosage forms of reboxetine are coated with polymers in

order to facilitate mucoadhesion within the gastrointestinal tract. Non-limiting examples of

polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic

acid, Carbopol T M (Lubrizol), polycarbophil, gelatin and other natural or synthetic polymers.

The polymeric coatings of the present disclosure may be any one of the described

coatings or may be a combination of two or more of the described coatings to achieve the

desired release profiles of the release of reboxetine.

In addition to the modified release dosage forms described herein, other modified

release technologies known to those skilled in the art can be used in order to achieve the

modified release formulations of the present disclosure, i.e., formulations which provide a

mean Tmax of the drug and/or other pharmacokinetic parameters described herein when

administered e.g., orally or by other mode of administration to human patients. Such

formulations can be manufactured as a modified release oral formulation in a suitable tablet

or multiparticulate formulation known to those skilled in the art. In either case, the modified

release dosage form can optionally include a controlled release carrier which is incorporated

into a matrix along with the drug, or which is applied as a controlled release coating.

Any dosage form comprising an effective amount of reboxetine may further comprise

a binder, a lubricant, and other conventional inert excipients.

A binder (also sometimes called adhesive) can be added to a drug-filler mixture to

increase the mechanical strength of the granules and tablets during formation. Binders can

be added to the formulation in different ways: (1) as a dry powder, which is mixed with other

ingredients before wet agglomeration, (2) as a solution, which is used as agglomeration liquid

during wet agglomeration, and is referred to as a solution binder, and (3) as a dry powder,

which is mixed with the other ingredients before compaction. In this form the binder is

referred to as a dry binder. Solution binders are a common way of incorporating a binder into

granules. In certain embodiments, the binder used in the tablets is in the form of a solution

binder. Non-limiting examples of binders useful include hydrogenated vegetable oil, castor

oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers having hydrocarbon backbones, and mixtures thereof. Specific examples of water-soluble polymer binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (e.g. hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC)), polyvinyl alcohol and mixtures thereof. Any suitable amount of binder may be present, such as about 0.5-5%, about 5-10%, about 10-15%, about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or about 3% by weight of the tablet dry weight. In some embodiments, the binder is polyvinyl alcohol.

Lubricants can be added to pharmaceutical formulations to decrease any friction that

occurs between the solid and the die wall during tablet manufacturing. High friction during

tableting can cause a series of problems, including inadequate tablet quality (capping or even

fragmentation of tablets during ejection, and vertical scratches on tablet edges) and may even

stop production. Accordingly, lubricants may be added to tablet formulations. Non-limiting

examples of lubricants useful include glyceryl behenate, stearic acid, hydrogenated vegetable

leucine, polyethylene glycol (MW 1450, suitably 4000, and higher), magnesium stearate,

glyceryl monostearate, stearic acid, polyethylene glycol, ethylene oxide polymers (for

Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium

stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof and others as known in the art.

Any suitable amount of binder may be present, such as about 0.5-5%, about 5-10%, about 10

15%, about 15-20%, about 20-25%, about 0.5-25%, about 0.5-15%, about 1-6%, or about 3%

by weight of the tablet dry weight.

In some embodiments, reboxetine is administered once a day or twice a day 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, at least about 15 years, about 15-20 years, at least about 20 years, or longer.

An example, not as an attempt to limit the scope of the disclosure, of a useful composition for a dosage form containing about 5-10 mg of reboxetine is shown in Table 1 below:

Table 1. Example of dosage form of reboxetine

Component Amount (wt/wt) reboxetine 30-70% lubricant 1-10% diluent 20-70% disintegrant 1-10%

Treatment of narcolepsy with cataplexy with reboxetine in the dosage forms described herein may not have significant side effects as the existing treatment options. Treatment of narcolepsy with cataplexy with reboxetine in the dosage forms described herein may be well tolerated in mammals such as human beings. Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a dosage form (e.g. about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage form), wherein a unit of the dosage form comprises about 0.1-5 mg of reboxetine and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being. Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a dosage form (e.g. about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage form), wherein a unit of the dosage form comprises about 5-10 mg of reboxetine and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being. Some embodiments include a kit comprising a pharmaceutical composition comprising one or more units of a dosage form (e.g. about 1-30, about 30-60, about 60-90, about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage form), wherein a unit of the dosage form comprises about 10-15 mg of reboxetine and instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

Some embodiments include a kit comprising a pharmaceutical composition

comprising one or more units of a dosage form (e.g. about 1-30, about 30-60, about 60-90,

about 90-120, about 120-180, about 180-360, or about 360-720 units of a dosage form),

wherein a unit of the dosage form comprises about 15-20 mg of reboxetine and instructions

to use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

Some embodiments include a kit comprising a pharmaceutical composition

wherein a unit of the dosage form comprises about 5-20 mg of reboxetine and instructions to

use the pharmaceutical composition to treat narcolepsy with cataplexy in a human being.

EXAMPLES

Example 1

A 40 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

given reboxetine and instructed to take 5 mg of reboxetine at 8 am and 5 mg of reboxetine at

1 pm for three weeks. The patient is evaluated prior to treatment, and weekly to determine

the number of cataplexy attacks, the ESS score, and the MWT score. After one week of

treatment, the number of cataplexy attacks have decreased by 10-30%.

Example 2

A 20 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the number of cataplexy attacks have decreased by 30-60%.

Example 3

A 60 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

1 pm for three weeks. The patient is evaluated prior to treatment, and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After one week of treatment, the number of cataplexy attacks have decreased by 60-100%.

Example 4

A 50 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the ESS score has decreased by 10-30%.

Example 5

A 25 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

treatment, the ESS score has decreased by 30-60%.

Example 6

A 47 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the ESS score has decreased by 60-100%.

Example 7

A 19 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

treatment, the MWT score has decreased by 10-30%.

Example 8

A 42 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the MWT score has decreased by 30-60%.

Example 9

A 33 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

treatment, the MWT score has decreased by 60-100%.

Example 10

A 54 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of

treatment, the number of cataplexy attacks have decreased by 10-30%.

Example 11

A 27 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the number of cataplexy attacks have decreased by 30-60%.

Example 12

A 52 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

1 pm for three weeks. The patient is evaluated prior to treatment, and weekly to determine the number of cataplexy attacks, the ESS score, and the MWT score. After three weeks of treatment, the number of cataplexy attacks have decreased by 60-100%.

Example 13

A 66 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the ESS score has decreased by 10-30%.

Example 14

A 34 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

treatment, the ESS score has decreased by 30-60%.

Example 15

A 35 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the ESS score has decreased by 60-100%.

Example 16

treatment, the MWT score has decreased by 10-30%.

Example 17

A 70 year old female is diagnosed as suffering from narcolepsy with cataplexy. She is

treatment, the MWT score has decreased by 30-60%.

Example 18

A 57 year old male is diagnosed as suffering from narcolepsy with cataplexy. He is

treatment, the MWT score has decreased by 60-100%.

Unless otherwise indicated, all numbers expressing quantities of ingredients,

properties such as amounts, percentage, and so forth used in the specification and claims are

to be understood in all instances as indicating both the exact values as shown and as being

modified by the term "about." Accordingly, unless indicated to the contrary, the numerical

parameters set forth in the specification and attached claims are approximations that may

vary depending upon the desired properties sought to be obtained. At the very least, and not

as an attempt to limit the application of the doctrine of equivalents to the scope of the claims,

each numerical parameter should at least be construed in light of the number of reported

significant digits and by applying ordinary rounding techniques.

The terms "a," "an," "the" and similar referents used in the context of describing the

embodiments (especially in the context of the following claims) are to be construed to cover

both the singular and the plural, unless otherwise indicated herein or clearly contradicted by

context. All methods described herein can be performed in any suitable order unless

otherwise indicated herein or otherwise clearly contradicted by context. The use of any and

all examples, or exemplary language (e.g., "such as") provided herein is intended merely to

better illuminate the embodiments and does not pose a limitation on the scope of any claim.

No language in the specification should be construed as indicating any non-claimed element

essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein are not to be

construed as limitations. Each group member may be referred to and claimed individually or

in any combination with other members of the group or other elements found herein. It is

anticipated that one or more members of a group may be included in, or deleted from, a

group for reasons of convenience and/or to expedite prosecution. When any such inclusion

or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling

the written description of all Markush groups if 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, variations on these described

embodiments will become apparent to those of ordinary skill in the art upon reading the

foregoing description. The inventor expects skilled artisans to employ such variations as

appropriate, and the inventors intend for the claimed embodimentsto be practiced otherwise

than specifically described herein. Accordingly, the claims include all modifications and

equivalents of the subject matter recited in the claims as permitted by applicable law.

Moreover, any combination of the above-described elements in all possible variations thereof

is contemplated unless otherwise indicated herein or otherwise clearly contradicted by

context.

In closing, it is to be understood that the embodiments disclosed herein are illustrative

of the principles of the claims. Other modifications that may be employed are within the

scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments

may be utilized in accordance with the teachings herein. Accordingly, the claims are not

limited to embodiments precisely as shown and described.

Claims

1. A method of treating narcolepsy with cataplexy, comprising administering reboxetine

to a human being in need thereof, wherein reboxetine is administered at least once daily for

at least three weeks, wherein, two weeks from the beginning of treatment, the human being

experiences a reduction in the number of cataplexy attacks in a week, a reduction in the

Epworth Sleepiness Scale score, a decrease in the cataplexy subscore on the Ullanlinna

Narcolepsy Scale (NUS), or a reduction in the Maintenance of Wakefulness Test score as a

result of the treatment.

2. Use of reboxetine in the manufacture of a medicament for the treatment of

narcolepsy with cataplexy, wherein reboxetine is administered at least once daily for at least

three weeks.

3. A kit comprising a pharmaceutical composition comprising reboxetine and

instructions to use the pharmaceutical composition to treat narcolepsy with cataplexy in a

human being, wherein reboxetine is administered at least once daily for at least three weeks.

4. The method, the use, or the kit of claim 1, 2, or 3, wherein reboxetine is administered

twice daily, wherein a first dosage form is administered in the morning and a second dosage

form is administered about 2 hours to about 6 hours later.

5. The method, the use, or the kit of claim 4, wherein the second dosage form is

administered about 2 hours to about 3 hours after the first dosage form.

6. The method, the use, or the kit of claim 4, wherein the second dose is administered

about 3 hours to about 4 hours after the first dosage form.

7. The method, the use, or the kit of claim 4, wherein the second dosage form is

administered about 4 hours to about 5 hours after the first dosage form.

8. The method, the use, or the kit of claim 4, wherein the second dosage form is

administered about 5 hours to about 6 hours after the first dosage form.

9. The method, the use, or the kit of claim 1, wherein a single dosage form is

administered daily, wherein the single dosage form contains a first release component

comprising reboxetine and a second release component comprising reboxetine, wherein the

first release component provides a first local maximum in the plasma concentration of

reboxetine and the second release component provides a second local maximum in the

plasma concentration of reboxetine, wherein the first local maximum in the plasma concentration of reboxetine occurs about 2 to about 6 hours before the second local maximum in the plasma concentration of reboxetine.

10. The method, the use, or the kit of claim 9, wherein the second local maximum in the plasma concentration of reboxetine occurs about 2 to about 3 hours after the first local maximum in the plasma concentration of reboxetine.

11. The method, the use, or the kit of claim 9, wherein the second local maximum in the plasma concentration of reboxetine occurs about 3 to about 4 hours after the first local maximum in the plasma concentration of reboxetine.

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

13. The method, the use, or the kit of claim 9, wherein the second local maximum in the plasma concentration of reboxetine occurs about 5 to about 6 hours after the first local maximum in the plasma concentration of reboxetine.

14. The method, the use, or the kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, 12, or 13, wherein the human being is selected for not suffering from depression.

15. The method, the use, or the kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, the dose amount 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 0.01 mmol.

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

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

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

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

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

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

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

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

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

25. The method, the use, or the kit of claim 23, wherein the dosage form is administered once daily or twice daily for at least three weeks.

26. The method, the use, or the kit of claim 24, wherein the dosage form is administered once daily or twice daily for at least three weeks.

27. The method, the use, or the kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the human being experiences an increase in sleep latency on the multiple sleep latency test (MSLT).

28. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 10% in sleep latency on the MSLT.

29. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 20% in sleep latency on the MSLT.

30. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 30% in sleep latency on the MSLT.

31. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 40% in sleep latency on the MSLT.

32. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 50% in sleep latency on the MSLT.

33. The method, the use, or the kit of claim 27, wherein the human being experiences an increase of at least 60% in sleep latency on the MSLT.

34. The method, the use, or the kit of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33, wherein the human being experiences a decrease of at least 15% in the cataplexy subscore on the UNS.

35. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 20% in the cataplexy subscore on the UNS.

36. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 30% in the cataplexy subscore on the UNS.

37. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 40% in the cataplexy subscore on the UNS.

38. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 50% in the cataplexy subscore on the UNS.

39. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 60% in the cataplexy subscore on the UNS.

40. The method, the use, or the kit of claim 34, wherein the human being experiences a decrease of at least 70% in the cataplexy subscore on the UNS.

41. The method, the use, or the kit of claim 34, wherein the human being has a cataplexy subscore ofabout 0.