WO2019165379A1 - Dosage forms and methods for enantiomerically enriched or pure bupropion - Google Patents

Dosage forms and methods for enantiomerically enriched or pure bupropion Download PDF

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Publication number
WO2019165379A1
WO2019165379A1 PCT/US2019/019445 US2019019445W WO2019165379A1 WO 2019165379 A1 WO2019165379 A1 WO 2019165379A1 US 2019019445 W US2019019445 W US 2019019445W WO 2019165379 A1 WO2019165379 A1 WO 2019165379A1
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WO
WIPO (PCT)
Prior art keywords
bupropion
dosage form
human
dextromethorphan
administered
Prior art date
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PCT/US2019/019445
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English (en)
French (fr)
Inventor
Herriot TABUTEAU
Original Assignee
Axsome Therapeutics, Inc.
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Publication date
Priority to BR112020017179-4A priority Critical patent/BR112020017179A2/pt
Priority to KR1020207027256A priority patent/KR20210003091A/ko
Priority to CR20200415A priority patent/CR20200415A/es
Priority to MX2020008704A priority patent/MX2020008704A/es
Priority to AU2019223187A priority patent/AU2019223187B2/en
Priority to KR1020237017449A priority patent/KR20230075531A/ko
Priority to KR1020247017593A priority patent/KR20240091043A/ko
Priority to IL276871A priority patent/IL276871B2/en
Priority to NZ767378A priority patent/NZ767378A/en
Application filed by Axsome Therapeutics, Inc. filed Critical Axsome Therapeutics, Inc.
Priority to PE2020001272A priority patent/PE20211752A1/es
Priority to MYPI2020004315A priority patent/MY202993A/en
Priority to CA3092076A priority patent/CA3092076A1/en
Priority to IL313368A priority patent/IL313368A/en
Priority to JP2020544420A priority patent/JP2021513998A/ja
Priority to SG11202008056SA priority patent/SG11202008056SA/en
Priority to EP19756920.5A priority patent/EP3755312A4/en
Priority to CN201980026874.5A priority patent/CN112087999A/zh
Priority to US16/364,005 priority patent/US20190216800A1/en
Priority to US16/364,463 priority patent/US20190216801A1/en
Publication of WO2019165379A1 publication Critical patent/WO2019165379A1/en
Priority to US17/183,645 priority patent/US20210196704A1/en
Priority to US17/187,454 priority patent/US20210177834A1/en
Priority to AU2022204521A priority patent/AU2022204521B2/en
Priority to JP2022124557A priority patent/JP2022153638A/ja
Priority to JP2024041381A priority patent/JP2024075655A/ja
Priority to AU2024205858A priority patent/AU2024205858A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • Described herein are dosage forms of enantiomerically enriched (S)-bupropion or enantiomerically enriched (/?)-bupropion.
  • the (S)-bupropion or the (/?)-bupropion may be deuterium enriched, or may have natural isotopic abundance.
  • These dosage forms may be administered, either fed or fasted, to treat a condition recited herein, to achieve a certain pharmacokinetic parameter of a bupropion or a metabolite of a bupropion, and/or to enhance dextromethorphan plasma levels.
  • Some embodiments include a method of delivering a bupropion or a metabolite thereof to plasma comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, at least once per day, to a human being.
  • Some embodiments include a method of providing a bupropion to the plasma of a human being, comprising: selecting a human patient in need of the bupropion with a pharmacokinetic profile provided by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve the same pharmacokinetic profile that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily; and wherein the second amount is about 40% to about 60% of the first amount.
  • Some embodiments include a method of treating a condition that is treatable with racemic bupropion, comprising: selecting a human patient having the condition that is treatable by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve the same therapeutic effect that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily; and wherein the second amount is about 40% to about 60% of the first amount.
  • Some embodiments include a method of enhancing the plasma levels of (S)-bupropion and dextromethorphan, comprising orally co-administering, at least once per day, dextromethorphan and at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with both (S)-bupropion and dextromethorphan, wherein the method achieves a C m ax of (S)-bupropion that is at least about 90 ng/mL in the human being, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 3-fold as compared to the C m ax of (/?)-bupropion that results from administering the same amount of (/?)-bupropion to the human being.
  • Some em bodiments include a method of enhancing the plasma levels of (/?,/?)- hydroxybupropion and dextromethorphan, comprising orally co-administering, at least once per day, dextromethorphan and at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with both (/?,/?)- hydroxybupropion and dextromethorphan, wherein the method achieves a Cmax of (/?,/?)- hydroxybupropion that is at least about 700 ng/mL in the human being, wherein the method is effective in increasing the Cmax of (/?,/?)-hydroxybupropion at least 3-fold as compared the Cm a x of (/?,/?)-hydroxybupropion that results from administering the same amount of (/?)- bupropion to the human being.
  • Some embodiments include a method of enhancing the plasma levels of (S)-bupropion comprising orally administering, at least once per day, at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment (5)- bupropion, wherein the method achieves a C m in of (S)-bupropion that is at least about 20 ng/mL, wherein the method is effective in increasing the C m m of (S)-bupropion at least 3-fold as compared to the C m m of (/?)-bupropion that results from administering a dosage form containing the same amount of (/?)-bupropion to the human being.
  • Some embodiments include a method of enhancing the plasma levels of (/?,/?)- hydroxybupropion comprising orally administering, at least once per day, at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (/?,/?)-hydroxybupropion, wherein the method achieves a C m m of (/?,/?)- hydroxybupropion that is at least about 700 ng/mL in the human being, wherein the method is effective in increasing the C m in of (/?,/?)-hydroxy bupropion at least 3-fold as compared to the Cmin of (/?,/?)-hydroxybupropion that results from administering the same amount of (/?)- bupropion to the human being.
  • Some embodiments include a method of treating a central nervous system (CNS) disorder in a human being comprising administering: a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, and dextromethorphan, to the human being.
  • CNS central nervous system
  • Some embodiments include a method of achieving an increased plasma level of (5)- bupropion while enhancing dextromethorphan plasma levels, comprising administering a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, and dextromethorphan, to a human being in need of treatment with bupropion.
  • Some embodiments include a dosage form comprising at least about 95% enantiomerically pure (/?)-bupropion and dextromethorphan, wherein orally administering the dosage form to a human being provides an increased enhancement to a plasma level of dextromethorphan in the human being as compared to orally administering a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include a method of increasing enhancement of dextromethorphan plasma level in a human being, comprising administrating a dosage form comprising at least about 95% enantiomerically pure (/?)-bupropion and dextromethorphan to the human being, wherein the dosage form provides an increased enhancement to a plasma level of dextromethorphan in the human being as compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include a method of treating a central nervous system (CNS) disorder in a human being comprising administering a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion to the human being to treat the CNS disorder, wherein the human being does not receive dextromethorphan.
  • CNS central nervous system
  • Some embodiments include a method of enhancing the plasma level of (S)-bupropion, comprising administering a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, wherein the dosage form is free of dextromethorphan, to a human being in need of treatment with bupropion.
  • Some embodiments include a method of enhancing the plasma levels of (5)- bupropion, comprising orally administering an oral dosage form containing at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (S)-bupropion and dextromethorphan, wherein the method achieves a C m ax of (S)-bupropion that is at least about 90 ng/mL in the human being, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 3-fold as compared to the C m ax of (/?)- bupropion that results from administering a dosage form containing the same amount of (/?)- bupropion to the human being, wherein the human being does not receive dextromethorphan.
  • Some embodiments include a method of enhancing the plasma levels of (/?,/?)- hydroxybupropion, comprising orally administering an oral dosage form containing at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (/?,/?)-hydroxybupropion and dextromethorphan, wherein the method achieves a Cmax of (/?,/?)-hydroxybupropion that is at least about 90 ng/mL, wherein the method is effective in increasing the Cmax of (/?,/?)-hydroxybupropion at least 3-fold as compared to the C m ax of (/?,/?)-hydroxybupropion that results from administering a dosage form containing the same amount of (/?)-bupropion to the human being, wherein the human being does not receive dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion in an enantiomeric excess of at least 95%, and dextromethorphan, wherein the dosage form provides an increased enhancement to a plasma level of dextromethorphan in a human being as compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion and dextromethorphan, wherein the dosage form can enhance plasma levels of dextromethorphan in a human being on day 1 or day 8 in a much greater extent than that of a reference oral dosage form when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic-bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 1 by at least 150% when orally administered to the human being daily for at least 8 consecutive days as compared to that of a reference oral dosage form on day 1 when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 8 by at least 25% when orally administered to the human being daily for at least 8 consecutive days as compared to that of a reference oral dosage form on day 8 when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion and dextromethorphan, wherein the dosage form increases a mean Cmax of dextromethorphan in a human being on day 8 by at least 20-fold as compared to that of a reference dosage form on day 1, when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic- bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (/?)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 1 by at least 60% as compared to that of a reference dosage form on day 1, when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic- bupropion and the same amount of dextromethorphan.
  • Some embodiments include an oral dosage form comprising (fl)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human on day 8 being by at least 20% as compared to that of a reference dosage form on day 8, when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic- bupropion and the same amount of dextromethorphan.
  • Some embodiments include a method of enhancing the plasma levels of dextromethorphan on day 1 or day 8, comprising orally administering a dosage form containing (fl)-bupropion and dextromethorphan, in a much greater extent than orally administering a reference dosage form, when orally administered to a human being daily for at least 8 consecutive days, wherein the reference dosage form contains the same amount of bupropion as a (S)-bupropion and the same amount of dextromethorphan.
  • Some embodiments include a method of treating a neuropsychiatric disorder, comprising administering a dosage form described in any preceding paragraph to a human being in need thereof.
  • Some embodiments include a method of treating cold or cough, comprising administering a dosage form described in any preceding paragraph to a human being in need thereof.
  • Some embodiments include a method of relieving pain, comprising administering a dosage form described in any preceding paragraph to a human being in need thereof.
  • Some embodiments include a method for treatment of addiction, comprising administering a dosage form described in any preceding paragraph to a human being in need thereof.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being having a condition that is treatable with (S)-bupropion, wherein the amount of (S)-bupropion administered is selected to be about 20% to about 70% of the amount of racemic bupropion that would be administered to treat the same human being for the same condition.
  • Some embodiments include a method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being, and wherein the method achieves a C m ax of (R,R)- hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to a human being in need of treatment with (S)-bupropion, wherein the (S)-bupropion is the sole active agent used to treat the human being.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion.
  • Some em bodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of (S)-bupropion that is at least about 60 ng/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)- hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being.
  • Some embodiments include a method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being.
  • Some embodiments include a method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)-hydroxybupropion, wherein the method achieves a C m ax of (R,R)- hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C ma x of (S)-bupropion that is at least about 70 ng/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0-12 of (S)-bupropion that is at least about 600 ng-h/mL.
  • Some em bodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C ma x of (R,R)-hydroxybupropion that is at least about 800 ng/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0 12 of (R,R)-hydroxybupropion that is at least about 8,000 ng- h/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a Cm a x of erythrohydroxybupropion that is at least about 90 ng/mL.
  • Some em bodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUCo i2 of erythrohydroxybupropion that is at least about 1,000 ng- h/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of threohydroxybupropion that is at least about 450 ng/mL.
  • Some embodiments include a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0-12 of threohydroxybupropion that is at least about 5,000 ng- h/mL.
  • Some embodiments include a dosage form comprising (S)-bupropion which is at least 95% enantiomerically pure.
  • Some embodiments include a method of enhancing the plasma level of (S)-bupropion or a metabolite thereof, comprising administering any dosage form described herein to a human being in need of treatment with bupropion or a metabolite thereof.
  • Some embodiments include a method of treating a neurological condition, comprising administering a dosage form described in any preceding paragraph to a human being in need thereof.
  • Some embodiments include a method of increasing the plasma levels of dextromethorphan comprising administering a combination of (/?)-bupropion and dextromethorphan to a human being in need of treatment by dextromethorphan, wherein the (/?)-bupropion is at least 95% enantiomerically pure.
  • Some embodiments include a method of delivering (S)-bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being.
  • Some embodiments include a method of delivering both (/?)-bupropion and (5)- bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being, wherein the C m ax of (/?)-bupropion is within 20% of the C m ax of (/?)-bupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Some embodiments include a method of delivering a bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being, wherein the AUC0 12 of (/?)-bupropion is within 20% of the AUC0 12 of (/?)-bupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Some embodiments include a method of delivering a bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being, wherein the C m ax of (/?,/?)- hydroxybupropion is within 20% of the C m ax of (/?,/?)-hydroxybupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Some dosage forms contain an enantiomeric excess of (S)-bupropion, or enantiomerically pure (S)-bupropion.
  • the (S)-bupropion may be at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure, up to (nearly) 100% enantiomeric purity.
  • (S)-bupropion that is 99.99% enantiomerically pure (or enantiomeric excess, or 99.99% ee) contains 99.99% (S)-bupropion and 0.005% [[0.01%]] (/?)-bupropion.
  • any of the above may be referred to as "(S)-bupropion.”
  • This type of dosage form may be useful in treating conditions where increased levels of (S)-bupropion and/or (/?,/?)-hydroxybupropion are therapeutically beneficial, or where a human being is in need of treatment with (S)-bupropion and/or (/?,/?)-hydroxybupropion.
  • increased levels of (S)-bupropion or (/?,/?)-hydroxybupropion may be useful to increase bioavailability or increase plasma levels of dextromethorphan, for example by co-administering the (5)- bupropion with dextromethorphan.
  • co-administration of an enantiomeric excess of (5)- bupropion, or enantiomerically pure (S)-bupropion, with dextromethorphan may be useful in treating conditions that respond to dextromethorphan alone, or a combination of (S)-bupropion and dextromethorphan.
  • use of dextromethorphan may not be desirable with (S)-bupropion or (/?,/?)-hydroxybupropion.
  • some dosage forms are substantially free of dextromethorphan, and some treatments involve administration of (5)- bupropion without co-administration of dextromethorphan.
  • Some embodiments include a method of providing a pharmacokinetic equivalent of racemic bupropion to the plasma of a human being, comprising: selecting a human patient in need of a pharmacokinetic profile provided by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve the same pharmacokinetic profile that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily; and wherein the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of the first amount.
  • the second amount is 60-90 mg.
  • 60-90 mg of (S)-bupropion would be administered once daily to achieve the same pharmacokinetic profile as would be achieved by administering 150 mg of racemic bupropion once daily; or 60- 90 mg of (S)-bupropion would be administered twice daily to achieve the same pharmacokinetic profile as would be achieved by administering 150 mg of racemic bupropion twice daily.
  • Some em bodiments include a method of treating a condition that is treatable with racemic bupropion, comprising: selecting a human patient having the condition that is treatable by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at the first dosing frequency to achieve the same therapeutic effect that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once daily or twice daily; and wherein the second amount is about 40- 60%, about 45-55%, or about 50% of the first amount.
  • the second amount is 60-90 mg.
  • 60-90 mg of (S)-bupropion would be administered once daily to treat a condition so that the same therapeutic effect is achieved as would be achieved by administering 150 mg of racemic bupropion once daily; or 60-90 mg of (S)-bupropion would be administered twice daily to treat a condition so that the same therapeutic effect is achieved as would be achieved by administering 150 mg of racemic bupropion twice daily.
  • the dosage form containing enantiomerically pure (S)-bupropion is recognized by the FDA as bioequivalent to a dosage form containing racemic bupropion, then the two dosage forms have the same pharmacokinetic profile.
  • Some dosage forms contain an enantiomeric excess of (R)-bupropion, or enantiomerically pure (fl)-bupropion.
  • the (R)-bupropion may be at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure, up to (nearly) 100% enantiomeric purity.
  • any of the a bove may be referred to as "(/?)- bupropion.”
  • This type of dosage forms may be useful to increase bioavailability or increase plasma levels of dextromethorphan, for example by co-administering the (R)-bupropion with dextromethorphan.
  • co-administration of an enantiomeric excess of (R)-bupropion, or enantiomerically pure (R)-bupropion, with dextromethorphan may be useful in treating conditions that respond to dextromethorphan.
  • the dosage forms and methods described above may be incorporated into methods for reducing an adverse event associated with treatment by bupropion, increasing a bupropion plasma level, such as increasing an (S)-bupropion plasma level, decreasing the dose amount or the number of doses of a bupropion that need to be administered without loss of efficacy, improving a therapeutic property of a bupropion, reducing a trough effect of a bupropion, or other methods.
  • the dosage forms and methods described above with respect to dextromethorpha n may be incorporated into methods for increasing dextromethorphan plasma levels, increasing the metabolic lifetime of dextromethorphan, reducing an adverse event associated with treatment by dextromethorphan, decreasing the dose amount or the number of doses of dextromethorphan that need to be administered without loss of efficacy, decreasing dextrorphan plasma levels, improving a therapeutic property of dextromethorphan, inhibiting the meta bolism of dextromethorpha n, correcting extensive metabolism of dextromethorphan, improving the antitussive properties of dextromethorphan, treating cough, reducing a trough effect of dextromethorphan, or other methods.
  • dosage forms and methods described above may be applied to neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, and related conditions.
  • enantiomerically enriched (S)-bupropion, or enantiomerically enriched (/?)-bupropion, and/or dextromethorphan may occur one or more times in a single day, e.g. by oral administration, or for multiple days, such as multiple consecutive days.
  • enantiomerically enriched (S)-bupropion, alone or in combination with dextromethorphan may be administered once or twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61- 89, 90, or more consecutive days.
  • enantiomerically enriched (/?)-bupropion alone or in combination with dextromethorphan, may be administered once or twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days.
  • the patient may be fasted prior to and/or after oral administration of a dosage form containing (S)-bupropion, or (/?)-bupropion, and/or dextromethorphan
  • a treatment described above may include administering the dosage form containing (/?)-bupropion or (S)-bupropion, alone or in combination with dextromethorphan, once a day for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice a day treatment.
  • the dosage form containing (/?)-bupropion or (S)-bupropion could be administered once a day on day 1, 2, and 3, and then twice a day starting on day 4, and continued twice a day for an extended period of time, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15- 20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period.
  • Starting with a once daily dose for a short period of time, followed by increasing the dose frequency to twice a day may be helpful in reducing seizure risk.
  • any reference to a compound herein, such as (5)- bupropion, (/?)-bupropion, or dextromethorphan, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, crystals, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, such as deuterium modified dextromethorphan; or a ny chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • a dosage form contains at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, about 4-90 mg, about 50-100 mg, about 50-150 mg, about 70-95 mg, about 50-70 mg, about 60-80 mg, about 60-90 mg, about 70-80 mg, about 70-74 mg, about 72-76 mg, about 74-76 mg, about 74-78 mg, about 70-90 mg, about 90-110 mg, about 90-120 mg, about 100-200 mg, about 100-140 mg, about 140- 160 mg, about 160-200 mg, about 104-106 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 145-155 mg, about 148-152 mg, about
  • Ranges of amounts of (5)-Bu obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for the amount of (S)-bupropion in the dosage form: about 50 mg, about 60 mg, about 75 mg, or about 90 mg, about 105 mg, or about 150 mg. These are values that are believed to potentially be of particular utility.
  • a dosage form containing an amount of (S)-bupropion listed above may be administered once, twice, or three times a day for a daily dose that is 1, 2, or 3 times that of any dose amount or any dose range listed above, e.g.
  • any daily dose obtained by combining any of the dose ranges or endpoints above and multiplying that result by 1, 2, or 3 are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values: about 150 mg, about 210 mg, or about 250 mg. These are values that are believed to potentially be of particular utility.
  • Some solid compositions may comprise at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, about 10-30%, about 30-50%, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% of (5)- bupropion by weight.
  • the dosage form may be free, or substantially free, of any active pharmaceutical agents, or drugs, other than the (S)-bupropion.
  • the dosage form may contain less than 10% by weight, less than 5% by weight, less than 1% by weight, or less than 0.1% by weight of any other active pharmaceutical agent, as compared to the weight of the (S)-bupropion.
  • the dosage form may contain less than 10% by weight, less than 5% by weight, less than 1% by weight, or less than 0.1% by weight of dextromethorphan, as compared to the weight of the (S)-bupropion, or may contain no dextromethorphan.
  • (S)-bupropion may be combined with another compound, such as dextromethorphan, in the dosage form.
  • Administering (S)-bupropion may be useful in increasing plasma levels of (5)- bupropion by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, about 5-20 fold, at least about 10- fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150- fold, at least about 200-fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130
  • the method is effective in increasing the AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0 12 of an individual, of (5)- bupropion by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 8-fold, , at least about 10-fold, about 10-fold, at least about 15-fold, at least about 20-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold,
  • the method achieves an AUC0 12, such as the average AUC0 12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of (S)-bupropion, or of ('Sj-bupropion and (7?J-bupropion combined, that is at least about 300 ng-hr/mL, at least about 400 ng-hr/mL, at least about 500 ng-hr/mL, at least about 600 ng-hr/mL, at least about 700 ng-hr/mL, at least about 750 ng-hr/mL, at least about 800 ng-hr/mL, at least about 850 ng-hr/mL, at least about 900 ng-hr/mL, at least about 950 ng-hr/mL, at least about 1,000 ng-hr/mL, at least about 1,100 ng-hr/mL, at least about 1,200 ng-hr/mL, up to about
  • Ranges of AUC0-12 obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for AUC0 12: 350 ng-hr/mL, 400 ng-hr/mL, 750 ng- hr/mL, 900 ng-hr/mL, 1,150 ng- hr/mL, or 1,400 ng-hr/mL. These are values that are believed to potentially be of particular utility.
  • the AUC ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • the method is effective in increasing the C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of (S)-bupropion by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4- fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8- fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 8-fold, about 5-20 fold, at least about 10-fold, about 10-fold, at least about 20-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30
  • the method achieves a Cmax, such as the average Cmax, the mean Cmax, the median Cmax, or the Cmax of an individual, of (S)-bupropion, or a combined Cmax of (S)-bupropion and (R)-bupropion, that is at least about 30 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 95 ng/mL, at least about 100 ng/mL, at least about 105 ng/mL, at least about 110 ng/mL, at least about 115 ng/mL, at least about 120 ng/mL, at least about 125 ng/mL, at least about 130 ng/mL, at least about 140 ng/mL, up to about 130 ng/mL, up to about 140 ng/mL, up to about 150 ng/mL
  • Ranges of C m ax obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for C ma x: 45 ng/mL, 90 ng/mL, 130 ng/mL, 160 ng/mL, or 190 ng/mL. These are values that are believed to potentially be of particular utility.
  • the C m ax ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • the method is effective in increasing the C m m, such as the average C m m, the mean C m m, the median C m in, or the C m in of an individual, of (S)-bupropion by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 8-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold,
  • the method achieves a C m m, such as the average C m m, the mean Cmin, the median C m in, or the C m m of an individual, of (S)-bupropion that is at least about 20 ng/mL, at least about 25 ng/mL, at least about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL, about 20-60 ng/mL, about 25-30 ng/mL, about 30-35 ng/mL, about 35-40 ng/mL, about 30-40 ng/mL, about 40-45 ng/mL, about 45-50 ng/mL, about 30-50 ng/mL, about 40-50 ng/mL, or about 50-60 ng/mL.
  • a C m m such as the average C m m, the mean Cmin, the median C m in, or the C m m of an individual, of (S)-bupropion that is at least about 20
  • Ranges of Cmin obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for C min : 20 ng/mL, 30 ng/mL, 40 ng/mL, or 50 ng/mL. These are values that are believed to potentially be of particular utility.
  • Administering (S)-bupropion may be useful in increasing plasma levels of (/?,/?)- hydroxybupropion, by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 5-10 fold, about 5-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, as compared to administering a dosage form containing the same amount of
  • Administering (S)-bupropion may be useful in increasing the AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of (/?,/?)-hydroxybupropion, by at least about 1.1-fold, at least about 1.5-fold, at least about 2- fold, at least about 3-fold, at least about 5-fold, about 6-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 5-10 fold, about 5-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold,
  • the method achieves an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of (/?,/?)- hydroxybupropion, or (5,5)-hydroxybupropion and (/?,/?)-hydroxybupropion combined, that is at least about 1,000 ng-hr/mL, at least about 3,000 ng-hr/mL, at least about 4,000 ng-hr/mL, at least about 6,000 ng-hr/mL, at least about 7,000 ng-hr/mL, at least about 7,500 ng-hr/mL, at least about 8,000 ng-hr/mL, at least about 8,500 ng-hr/mL, at least about 9,000 ng-hr/mL, at least about 9,500 ng-hr/mL, at least about 10,000 ng-hr/mL, at least about 12,000 ng-hr/mL, at least about 13,000 ng-hr
  • Ranges of AUC0-12 obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for AUC0-12: 4,000 ng- hr/mL, 5,000 ng/mL, 10,000 ng-hr/mL, 13,400 ng-hr/mL, 16,000 ng-hr/mL, or 22,000 ng- hr/mL. These are values that are believed to potentially be of particular utility.
  • the AUC ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • Administering (S)-bupropion may be useful in increasing the C m ax, such as the average Cmax, the mean C m ax, the median C m ax, or the C m ax of an individual, of (/?,/?)-hydroxybupropion, by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4- fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8- fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, about 6-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 5-10 fold, about 10-20 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold,
  • the method achieves a C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of (/?,/?)-hydroxybupropion or (5,5)- hydroxybupropion and (/?,/?)-hydroxybupropion combined, that is at least about 90 ng/mL, at least about 150 ng/mL, at least about 200 at least about 300 ng/mL, at least about 400 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 700 ng/mL, at least about 800 ng/mL, at least about 900 ng/mL, at least about 1,000 ng/mL, at least about 1,100 ng/mL, at least about 1,200 ng/mL, at least about 1,300 ng/mL, up to about 1,400 ng/mL, up to about 1,500 ng/m
  • Ranges of C m ax obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more of the following values for C ma x: 400 ng/mL, 950 ng/mL, 1,100 ng/mL, 1,250 ng/mL, 1,400 ng/mL, or 2,100 ng/mL. These are values that are believed to potentially be of particular utility.
  • the Cm a x ra nges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • Administering (S)-bupropion may be useful in increasing the C m m, such as the average Cmin, the mean Cmin, the median Cmin, or the Cmin of an individual, of (/?,/?)-hydroxybupropion, by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4- fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8- fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 60-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 1-5 fold, about 5-10 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 60-70 fold
  • the method achieves a C m m, such as the average C m m, the mean Cmin, the media n C m m, or the C m in of an individual, of (/?,/?)-hydroxybupropion that is at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 700 ng/mL, at least about 800 ng/mL, at least about 900 ng/mL, at least about 1,000 ng/mL, at least about 1,100 ng/mL, at least about 1,200 ng/mL, up to about 1,300 ng/mL, up to about 1,400 ng/mL, up to about 1,500 ng/mL, up to about 1,600 ng/mL, up to about 1,700 ng/mL, up to about 1,800 ng/mL,
  • Ranges of C m m obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more of the following values for C m m: 350 ng/mL, 600 ng/mL, 800 ng/mL, 1,000 ng/mL, 1,200 ng/mL, or 1,400 ng/mL. These are values that are believed to potentially be of particular utility.
  • Administering (S)-bupropion to a human being may result in (/?,/?)-hydroxybupropion being at least 90%, at least 95%, at least 97%, at least 97.2%, at least at least 97.4%, at least 97.6%, at least 97.8%, or at least 98% of the total of amount of (/?,/?)-hydroxybupropion and (5,5)-hydroxybupropion present in the plasma of the human being.
  • the method achieves an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of erythrohydroxybupropion that is at least about 500 ng- hr/mL, at least about 600 ng- hr/mL, at least about 800 ng-hr/mL, at least about 1,000 ng- hr/mL, at least about 1,200 ng-hr/mL, at least about 1,400 ng-hr/mL, at least about 1,500 ng- hr/mL, at least about 1,600 ng-hr/mL, at least about 1,800 ng-hr/mL, at least about 2,000 ng-hr/mL, up to about 1,400 ng- hr/mL, up to about 1,600 ng-hr/mL, up to about 1,800 ng-hr/mL, up to about 2,000 ng-hr/mL,
  • Ranges of AUC0-12 obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for AUC0-12: 500 ng-hr/mL, 1,300 ng- hr/mL, 1,500 ng- hr/mL, 1,800 ng- hr/mL, or 2,600 ng-hr/mL. These are values that are believed to potentially be of particular utility.
  • the AUC ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • the method achieves a C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of erythrohydroxybupropion that is at least about 40 ng/mL, at least about 60 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 120 ng/mL, at least about 140 ng/mL, at least about 160 ng/mL, at least about 180 ng/mL, at least about 200 ng/mL, up to about 160 ng/mL, up to about 180 ng/mL, up to about 200 ng/mL, up to about 220 ng/mL, up to about 240 ng/mL, up to about 260 ng/mL, up to about 280 ng/mL, about 40-60 ng/mL, about 60-
  • Ranges of Cmax obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for Cm a x: 60 ng/mL, 120 ng/mL, 130 ng/mL, 200 ng/mL, or 240 ng/mL. These are the values that are believed to potentially be of particular utility.
  • the C m ax ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • the method achieves an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of threohydroxybupropion that is at least 1,000 ng-hr/mL, at least about 2,000 ng-hr/mL, at least about 3,000 ng-hr/mL, at least about 4,000 ng-hr/mL, at least about 5,000 ng-hr/mL, at least about 6,000 ng- hr/mL, at least about 7,000 ng-hr/mL, at least about 8,000 ng-hr/mL, up to about 8,000 ng-hr/mL, up to about 9,000 ng- hr/mL, up to about 10,000 ng-hr/mL, up to about 11,000 ng- hr/mL, up to about 12,000 ng-hr/mL, up to about 13,000 ng-hr/mL, up to about 1
  • Ranges of AUCo -i2 obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for AUC0-12: 3,000 ng-hr/mL, 6,000 ng-hr/mL, 8,000 ng-hr/mL, or 12,000 ng-hr/mL. These are the values that are believed to potentially be of particular utility.
  • the AUC ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • the method achieves a C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of threohydroxybupropion that is at least about 200 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least about 450 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 700 ng/mL, at least about 800 ng/mL, up to about 800 ng/mL, up to about 900 ng/mL, up to about 1,000 ng/mL, up to about 1,100 ng/mL, up to about 1,200 ng/mL, up to about 1,300 ng/mL, up to about 1,400 ng/mL, about 200-300 ng/mL, about 300-400 ng/m L, about 400-500 ng/mL
  • Ranges of C m ax obtained by combining any of the ranges or endpoints above are also contemplated, especially if the range obtained encompasses, or is near, one or more the following values for C ma x: 300 ng/mL, 500 ng/mL, 600 ng/mL, 900 ng/mL, or 1,200 ng/mL. These are values that are believed to potentially be of particular utility.
  • the C m ax ranges targeted may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.
  • a dosage form contains at least about 80 mg, at least about 90 mg, at least a bout 100 mg, about 90-110 mg, about 100- 200 mg, about 100-150 mg, about 100-140 mg, about 140-160 mg, about 160-200 mg, about
  • Such a dosage form may be administered with dextromethorphan, wherein the dextromethorphan may be administered in a separate dosage form, or in the same dosage form as the (/?)-bupropion.
  • a dosage form containing an amount of (/?)-bupropion listed above may be administered once, twice, or three times a day for a daily dose amount that is 1, 2, or 3 times that of any dose amount or dose range listed above.
  • the dosage form may be free, or substantially free, of any active pharmaceutical agents, or drugs, other than the (/?)-bupropion and/or dextromethorphan.
  • the dosage form may contain less than 10% by weight, less than 5% by weight, less than 1% by weight, or less than 0.1% by weight of any other active pharmaceutical agent, as compared to the weight of the (/?)-bupropion plus dextromethorphan.
  • Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 60% (w/w) to about 70% (w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of (/?)- bupropion.
  • a dosage form containing an enantiomeric excess of (S)-bupropion or an enantiomeric excess of (/?)- bupropion may be administered with dextromethorphan, or may contain dextromethorphan.
  • Dextromethorphan has the structure shown below.
  • any reference to a compound herein, such as (5)- bupropion, (/?)-bupropion, and/or dextromethorphan, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, crystals, solvates, hydrates, etc.; tautomers; deuterium-modified compounds, such as deuterium modified dextromethorphan; or any chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • the dextromethorphan may be deuterium enriched, or may have natural isotopic abundance.
  • Dextromethorphan is used as a cough suppressant. According to the FDA's dextromethorphan product labeling requirement under the OTC Monograph [21CFR341.74], dextromethorphan should be dosed 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).
  • Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers.
  • Fluman beings can be: 1) extensive metabolizers of dextromethorphan— those who rapidly metabolize dextromethorphan; 2) poor metabolizers of dextromethorphan— those who only poorly metabolize dextromethorphan; or 3) intermediate metabolizers of dextromethorpha n — those whose metabolism of dextromethorphan is somewhere between that of an extensive metabolizer and a poor metabolizer.
  • Extensive metabolizers can also be ultra-rapid metabolizers.
  • Extensive metabolizers of dextromethorphan represent a significant portion of the human population.
  • Dextromethorphan can, for exam ple, be metabolized to dextrorphan (DX).
  • the DM/DX ratio can often be used to represent the extent of metabolism of dextromethorphan.
  • a lower DM/DX ratio represents higher extent of metabolism of dextromethorphan.
  • a person having a DM/DX ratio of ⁇ 0.3 is usually considered a phenotypically extensive metabolizer.
  • dextromethorphan When given the same oral dose of dextromethorphan, plasma levels of dextromethorphan are significantly higher in poor metabolizers or intermediate metabolizers as compared to extensive metabolizers of dextromethorphan.
  • the low plasma concentrations of dextromethorphan can limit its clinical utility as a single agent for extensive metabolizers and possibly intermediate metabolizers of dextromethorphan.
  • Some therapeutically active compounds including antidepressants such as (S)-bupropion or (/?)- bupropion, inhibit the metabolism of dextromethorphan, and raise the plasma concentration of dextromethorphan, and can thus improve its therapeutic efficacy.
  • (S)-bupropion or (/?)-bupropion may al low dextromethorphan to be given less often, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, without loss of therapeutic efficacy. Also (S)-bupropion or (/?)-bupropion may allow dextromethorphan to be given less amount of each dose or total dose or both.
  • a dosage form containing dextromethorphan used to this end may contain any suitable amount of dextromethorphan, such as about 1- 150 mg, about 10-100 mg, about 10-50 mg, about 20-50 mg, about 10-20, about 15-25, about 20-30, about 25-35, about 30-40, about 35-45, about 30-50 mg, about 40-50 mg, about 43-48 mg, about 44-46 mg, about 50-100 mg, about 50-80 mg, about 80-100 mg about 85-95 mg, about 88-92 mg, about 100-150 mg, about 30 mg, about 45 mg, or about 60 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by any of these values.
  • a dosage form containing an amount of dextromethorphan listed above may be administered once, twice, or three times a day for a daily dose that is
  • Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), about 60% (w/w) to about 70% (w/w), about 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.
  • (S)-Bupropion, (fl)-bupropion, and/or dextromethorphan may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005.
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005.
  • the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration, and standard pharmaceutical practice.
  • (S)-bupropion, (R)-bupropion, and/or dextromethorphan may be administered to a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally.
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal; ophthalmic; sublingual; and buccal, and topically including ophthalmic; dermal; ocular; rectal; and nasal.
  • (S)-bupropion, (R)-bupropion, and/or dextromethorphan may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the food of the diet.
  • the active compound may be incorporated with an excipient and used in the form of ingestible ta blets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Tablets, troches, pills, capsules and the like containing (S)-bupropion, (R)-bupropion, and/or dextromethorphan may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch, or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose, or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch, or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
  • a lubricant such as magnesium stea
  • the dosage form When the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coating, for instance, tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable for material in a dosage form or pharmaceutical composition to be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.
  • (S)-bupropion, (R)-bupropion, and/or dextromethorphan may be formulated for parental or intraperitoneal administration.
  • Solutions of the active compounds as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant.
  • a dispersion can also have an oil dispersed within, or dispersed in, glycerol, liquid polyethylene glycols, and mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • a dosage form or a composition that contains both (S)-Bupropion, or (/?)-bupropion, and dextromethorphan may be a blend or mixture of the bupropion a nd the dextromethorphan, either alone or within a vehicle.
  • (S)-Bupropion or (/?)- bupropion and dextromethorphan may be dispersed within each other or dispersed together within a vehicle.
  • a dispersion may include a mixture of solid materials wherein small individual particles are substantially one compound, but the small particles are dispersed within one another, such as might occur if two powders of two different drugs are blended with a solid vehicle material, and the blending is done in the solid form.
  • dextromethorphan and (S)-bupropion or (/?)-bupropion may be substantially uniformly dispersed within a composition or dosage form.
  • dextromethorphan and (S)-Bupropion or (/?)-bupropion may be in separate domains or phases within a composition or dosage form.
  • one drug may be in a coating and another drug may be in a core within the coating.
  • one drug may be formulated for sustained release and another drug may be formulated for immediate release.
  • Some embodiments include administration of a tablet that contains (S)-Bupropion or (/?)-bupropion in a form that provides sustained release, and dextromethorphan, if present, in a form that provides immediate release.
  • (S)-Bupropion or (/?)-bupropion is combined with hydroxypropyl methylcellulose.
  • particles of (S)-Bupropion or (/?)- bupropion could be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL ® ) to form an admixture of blended powders. This could then be combined with immediate release dextromethorphan in a single tablet.
  • Administering a combination of (/?)-bupropion and dextromethorphan to a human being in need of treatment by dextromethorphan may result in increased dextromethorpha n levels, as compared to administering a combination of the same amount of (S)-bupropion and the same amount dextromethorphan in the same amounts.
  • the C m ax such as the average C m ax, the mean C m ax, the media n C m ax, or the C m ax of an individual, or AUCo- i2, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, or AUCo- , such as the average AUCo- , the mean AUCo- , the median AUCo- , or the AUCo- of dextromethorphan is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 80%, at least about 100%, at least about 150%, or at least about 200%, as compared to administering the same amount of (S)-bupropion and the same amount of dextromethorphan. This increase may be observed on day 1, 2, 3, 4, 5, 6, 7, or 8 of the
  • the combination of (/?)-bupropion and dextromethorphan may achieve an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUCo 12 of an individual, of dextromethorphan, such as on days 1-60, that is about 30-150 ng- hr/mL, about 50-100 ng-hr/mL, about 80-100 ng- hr/mL, about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng- hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-h
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 5 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of dextromethorphan on day 6 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 7 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of dextromethorphan on day 8 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0-12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 9 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-5
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUC0-12 of an individual, of dextromethorphan on day 10 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an AUC0-12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 11 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-5
  • the combination of (/?)-bupropion and dextromethorphan may achieve a C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan, such as on days 1-60, that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 2-20 ng/mL, 5-10 ng/mL, about 10-15 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/m
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C max , such as the average C max , the mean C max , the median C max , or the C max of an individual, of dextromethorphan on day 5 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45- 50
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C max , such as the average C max , the mean C max , the median C max , or the C max of an individual, of dextromethorphan on day 6 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45- 50
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C max , such as the average C max , the mean C max , the median C max , or the C max of an individual, of dextromethorphan on day 7 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45- 50
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 8 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 9 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 10 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve a C max , such as the average C max , the mean C max , the median C max , or the C max of an individual, of dextromethorphan on day 11 that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 30 ng/mL, at least about 40 ng/mL, at least about 50 ng/mL, at least about 60 ng/mL, at least about 70 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45- 50
  • the dextromethorphan fluctuation index values Fl(%) can be determined by equation: 100.
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 8 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 8 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 9 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 9 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • the combination of (/?)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (/?)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 10 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 10 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • administering a combination of (/?)-bupropion and dextromethorphan to a human being in need of treatment by dextromethorphan may result in increased dextromethorphan levels, as compared to administering a combination of (S)-bupropion and dextromethorphan in the same amounts, administering a combination of (S)-bupropion and dextromethorphan can still result in an increase of dextromethorphan plasma levels as compared to administering dextromethorphan without administering a (S)-bupropion.
  • administering a combination of (/?)-bupropion and dextromethorphan to a human being in need of treatment by dextromethorphan may result in increased dextromethorphan levels, as compared to administering a combination of racemic-bupropion and dextromethorphan in the same amounts. In some embodiments, such an increase can be significant or substantial.
  • the combination of (S)-bupropion and dextromethorphan may achieve an AUC0-12, such as the average AUC0-12, the mean AUC0-12, the median AUC0-12, or the AUCo 12 of an individual, of dextromethorphan, such as on days 1-60, that is about 10-50 ng- hr/mL, about 20-40 ng- hr/mL, about 30-100 ng-hr/mL, about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng- hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 5 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 6 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 7 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 8 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 9 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 10 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an AUC0 12, such as the average AUC0 12, the mean AUC0 12, the median AUC0 12, or the AUC0 12 of an individual, of dextromethorphan on day 11 that is about 400-425 ng-hr/mL, about 425-450 ng-hr/mL, about 400-450 ng-hr/mL, about 450-475 ng-hr/mL, about 475-500 ng-hr/mL, about 450-500 ng-hr/mL, about 500-510 ng-hr/mL, about 510-520 ng-hr/mL, about 520-530 ng-hr/mL, about 530-540 ng-hr/mL, about 540-560
  • the combination of (S)-bupropion and dextromethorphan may achieve a C m ax, such as the average C m ax, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan, such as on days 1-60, that is about 1-10 ng/mL, about 2-5 ng/mL, about 5-10 ng/mL, about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50-55 ng/mL, about 55-58 ng/mL, about 58-60 ng/
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C max , such as the average Cmax, the mean Cmax, the median Cmax, or the Cmax of an individual, of dextromethorphan on day 5 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL, about 58-60 ng/mL, about 55-60 ng/mL
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 6 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL,
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 7 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL,
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 8 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL, about
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C max , such as the average C max , the mean C max , the median C max , or the C max of an individual, of dextromethorphan on day 9 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL, about 58-60 ng/mL, about 55-60 ng
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C max , such as the average Cmax, the mean Cmax, the median Cmax, or the Cmax of an individual, of dextromethorphan on day 10 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL, about 58-60 ng/mL, about 55-60 ng/mL
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve a C m ax, such as the average C ma x, the mean C m ax, the median C m ax, or the C m ax of an individual, of dextromethorphan on day 11 that is about 40-43 ng/mL, about 43-45 ng/mL, about 40-45 ng/mL, about 45-48 ng/mL, about 48-50 ng/mL, about 45-50 ng/mL, about 50-51 ng/mL, about 51-52 ng/mL, about 52-53 ng/mL, about 53-54 ng/mL, about 54-56 ng/mL, about 50- 55 ng/mL, about 55-58 ng/mL,
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 8 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 8 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 9 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 9 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • the combination of (S)-bupropion and dextromethorphan for example by twice daily administration of about 30-60 mg of dextromethorphan, and twice daily administration of about 50-150 mg of (S)-bupropion, may achieve an Fl(%) value, such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 10 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a range bounded by any of these values.
  • an Fl(%) value such as the average Fl(%) value, the mean Fl(%) value, the median Fl(%) value, or the Fl(%) value of an individual, of dextromethorphan on day 10 that is less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, or any Fl(%) value in a
  • Examples of neurological disorders or central nervous system disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxy bupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to: affective disorders, psychiatric disorders, cerebral function disorders, movement disorders, dementias, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.
  • Affective disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, depression, major depression, treatment resistant depression and treatment resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mood disorders, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDFI), and attention deficit/hyperactivity disorder (AD/FID), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, an addictive disorder, substance addiction or abuse, nicotine addiction, psycho-
  • Depression may be manifested by depressive symptoms. These symptoms may include psychological changes such as changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and/or self- deprecation. Physical symptoms of depression may include insomnia, anorexia, appetite loss, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, aches, pains, headaches, cramps, digestive issues, and/or abnormal hormonal circadian rhythms. Some patients, even after treatment with medications such as antidepressants, may have an inadequate or no response to the treatment.
  • Treatment resistant depression is a condition generally associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis for TRD is for the patient to have had an inadequate response to treatment with the antidepressants after an adequate dose and adequate course. TRD may be more difficult to treat due to the comorbidity of other medical or psychological illnesses, such as drug/alcohol abuse or eating disorders, or TRD being misdiagnosed. Some TRD patients have had an inadequate response to 1, 2, 3, or more adequate antidepressant treatment trials or have failed or had an inadequate response to 1, 2, 3, or more prior antidepressant treatments. In some embodiments, a patient being treated for treatment resistant depression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant therapies.
  • Measures of treatment effect that may be improved by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan, include, but are not limited to: Montgomery-Asberg Depression Rating Scale (MADRS), Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, Range of Impaired Functioning Tool, Sheehan Disability Scale, Patient Rated Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Quick Inventory of Depressive Symptomatology, Self-Report (QID(S)-SR), Clinical Global Impression (CGI) scale, Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item Quick Inventory of Depressive Symptomatology - Self Report (QID(5)
  • SDS Sheehan Disability Scale
  • QID(5)-SR16 16-item Quick Inventory of Depressive Symptomatology - Self Report
  • HAM-A Hamilton Anxiety Scale
  • CPFQ CPFQ - Cognitive subscales
  • Items 4 to 7 16-item Psychiatric Rating Scale (BPRS), etc.
  • BPRS Brief Psychiatric Rating Scale
  • DSST Digit Symbol Substitution Test
  • RAVLT Rey Auditory Verbal Learning Task
  • TMT Trail Making Test
  • STROOP Stroop Colour Naming Test
  • SRT Simple Reaction Time
  • CRT Choice Reaction Time
  • Patients who may benefit from the treatments described herein include pediatric patients, such as patients under about 18 years of age, about 0-5 years of age, about 5-10 years of age, about 10-12 years of age, or about 12-18 years of age, adult patients, such as patients having an age of about 18-65 years; about 18-30 years; about 30-50 years; about 50- 65 years, and elderly patients, such as patients over 65 years of age; about 65-75 years of age; about 75-90 years of age; or over 90 years of age.
  • Treatment of TRD using enhanced bioavailability or enhanced plasma levels of (5)- bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may result in a reduction of depressive symptoms of at least a bout 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%, up to about 100%, or any other reduction percentage in a range bounded by any of these values.
  • Psychiatric disorders that may be treated using enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, anxiety disorders, such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive- compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depressive illness, hypomania, unipolar depression, depression, stress disorders, somatoform disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.
  • anxiety disorders such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive- compulsive disorder, and post-traumatic stress disorder (PTSD);
  • Agitation associated with Alzheimer's disease occurs as the disease progresses. Agitation may present itself as inappropriate verbal, emotional, and/or physical behaviors. Inappropriate behaviors may include, but are not limited to, incoherent babbling, inappropriate emotional response, demands for attention, threats, irritability, frustration, screaming, repetitive questions, mood swings, cursing, abusive language, physical outbursts, emotional distress, restlessness, shredding, sleeping disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body motions, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and/or kicking.
  • treatment of agitation associated with Alzheimer's disease using enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxy bupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may result in a reduction of agitation-related symptoms of 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%, up to about 100%, or any other reduction percentage in a range bounded by any of these values.
  • Measures of treatment effect of agitation that may be improved by treatment enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, Neuropsychiatric Inventory-Clinician (NPI-C) rating scale, overall and all domains; Neuropsychiatric Inventory-Clinician (NPI-C) rating scale Agitation domain; Cohen-Mansfield Agitation Inventory (CMAI); Cornell Scale for Depression in Dementia (CSDD); Neuropsychiatric Inventory (NPI Agitation/Aggression Domain); Cocomitant Medications (Frequency of using concomitant medications); Alzheimer's Disease Cooperative Study - Activities of Daily Living Inventory (ADC(S)-ADL); Neuropsychiatric Inventory (NPI) Individual Domains and NPI Total Scores (range 0-144), including NPI-C Apathy domain
  • Substance addiction abuse that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytic and hypnotic drugs, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes nicotine addiction of all known forms, such as smoking cigarettes, cigars and/or pipes, electronic cigarettes, and addiction to chewing tobacco.
  • psychostimulants e.g., crack, cocaine, speed, meth
  • nicotine e.g., alcohol, opioids, anxiolytic and hypnotic drugs
  • cannabis marijuana
  • amphetamines e.g
  • Cerebral function disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia.
  • disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbances of consciousness, coma, lowering of attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia.
  • Cerebral function disorders also include disorders caused by cerebrovascular diseases including, but not limited to, stroke, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.
  • Movement disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and Wilson's disease.
  • akathisia akinesia
  • associated movements athetosis, ataxia, ball
  • Dementias that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, fronto-temporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke- Korsakoff Syndrome, and Pick's disease.
  • Motor neuron diseases that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach's disease, Sandoff disease, and hereditary spastic paraplegia.
  • Neurodegenerative diseases that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson's disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL
  • Seizure disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile seizures; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and epilepsia partialis continua; generalized seizures including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.
  • Types of headaches that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)- hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, but are not limited to, migraine, tension, and cluster headaches.
  • Other neurological disorders that may be treated by enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan include, Rett Syndrome, autism, tinnitus, disturbances of consciousness disorders, sexual dysfunction, intractable coughing, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasms, including, but not limited to, abductor spasmodic dysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, and vocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity, such as methotrexate neurotoxicity; incontinence including, but not limited, stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.
  • enhanced bioavailability or enhanced plasma levels of (5)- bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough (including chronic cough), etc.
  • ALS amyotrophic lateral sclerosis
  • enhanced bioavailability or enhanced plasma levels of (5)- bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may be used to treat treatment refractory depression.
  • Enhanced bioavailability or enhanced plasma levels of (S)-bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxy bupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may be used to treat, or provide relief to, any type of pain including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritis pain, complex regional pain syndrome, etc.
  • enhanced bioavailability or enhanced plasma levels of (5)- bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may be useful to relieve neuropathic pain.
  • neuropathic pain examples include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc.
  • Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV- associated neuropathy, and radio- or chemo-therapy associated neuropathy, etc.
  • enhanced bioavailability or enhanced plasma levels of (5)- bupropion, enhanced bioavailability or enhanced plasma levels of (/?,/?)-hydroxybupropion, and/or enhanced bioavailability or enhanced plasma levels of dextromethorphan may be administered to relieve fibromyalgia.
  • Adverse events associated with bupropion or dextromethorphan that may be avoided or reduced by a method described herein include a central nervous system adverse event, a gastrointestinal event, or another type of adverse event associated with any of these compounds.
  • Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, sleeplessness, light-headedness, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or excitement, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, lassitude, incoordination, fatigue, euphoria, nervousness, insomnia, sleeping disturbances, convulsive seizures, excitation, catatonic-like states, hysteria, hallucinations, delusions, paranoia, headaches and/or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle
  • Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, feeling of fullness in stomach, indigestion, bloating, hyperacidity, dry mouth, gastrointestinal disturbances, and gastric pain.
  • adverse events that may be reduced or avoided by a method described herein include abnormal sensation of rotation and movement, agitation, arm weakness, bloating, blurred vision, burning sensation in the eyes, buzzing sound in ear, changes in vital signs (including, but not limited to, heart rate, respiratory rate, body temperature, blood pressure), cold sensation, constipation, difficulty concentrating, difficulty sleeping, difficulty in falling asleep, difficulty urinating, difficulty with bowel movement, discomfort in the ear, discomfort in the eye, discomfort in the stomach, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feeling feverish, feeling heavy headed, feeling more agitated than usual, feeling more tired than usual, feeling tired, hand tremors, hand weakness, headache, heartburn, hot flashes, increased blood pressure, increased skin sensitivity, increased skin sensitivity at head and face, involuntary muscle contraction, involuntary muscle contractions at all over the body, knee pain, leg weakness, lightheadedness, loose stool, loss of appetite, low back pain, menstrual disorder, metallic taste
  • treating includes the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals, or any activity that otherwise affects the structure or any function of the body of man or other animals.
  • Patients who may benefit from the treatments described herein include pediatric patients, such as patients under about 18 years of age, about 0-5 years of age, about 5-10 years of age, about 10-12 years of age, or about 12-18 years of age; adult patients, such as patients having an age of about 18-65 years, about 18-30 years, about 30-50 years, about 50- 65 years; and elderly patients, such as patients over 65 years of age, about 65-75 years of age, about 75-90 years of age, or over 90 years of age.
  • Embodiment 1 A method of delivering a bupropion or a metabolite thereof to plasma comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, at least once per day, to a human being.
  • Embodiment 2 A method of providing a bupropion to the plasma of a human being, comprising:
  • the first dosing frequency is once daily or twice daily
  • the second amount is about 40% to about 60% of the first amount.
  • Embodiment 3 A method of treating a condition that is treatable with racemic bupropion, comprising:
  • first dosing frequency is once daily or twice daily; and wherein the second amount is about 40% to about 60% of the first amount.
  • Embodiment 4 The method of embodiment 1, wherein the human being is in need of treatment with (S)-bupropion.
  • Embodiment 5 The method of embodiment 1, 2, 3, or 4, wherein the method achieves a Cmax of (S)-bupropion that is at least about 60 ng/mL.
  • Embodiment 6 The method of embodiment 1, 2, 3, 4, or 5, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 5-fold as compared to the C m ax of (R)- bupropion that results from administering the same amount of (R)-bupropion to the huma n being.
  • Embodiment 7. The method of embodiment 1, 2, 3, 4, 5, or 6, wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Embodiment 8 The method of embodiment 1, 2, 3, 4, 5, 6, or 7 , wherein the method is effective in increasing the Cmin of (R,R)-hydroxybupropion at least 3-fold as compared to the Cmin of (R,R)-hydroxybupropion that results from administering the same amount of (R)- bupropion to the human being.
  • Embodiment 9 The method of embodiment 1, 2, 3, 4, 5, 6, 7 , or 8, wherein the dosage form is administered once daily.
  • Embodiment 10 The method of embodiment 1, 2, 3, 4, 5, 6, 7 , or 8, wherein the dosage form is administered twice daily.
  • Embodiment 11 The method of embodiment 1, 2, 3, 4, 5, 6, 1 , 8, 9, or 10, wherein (R,R)- hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)- hydroxybupropion present in the plasma of the human being.
  • Embodiment 12 The method of embodiment 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, or 11, which is effective in providing therapeutically effective plasma levels of (R,R)-hydroxybupropion.
  • Embodiment 13 The method of embodiment 1, 2, 3, 4, 5, 6, 1 , 8, 9, 10, 11, or 12, which is effective in providing therapeutically effective plasma levels of (S)-bupropion.
  • Embodiment 14 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the human being is in need of treatment with (R,R)-hydroxybupropion.
  • Embodiment 15. The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Embodiment 16 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or
  • Embodiment 15 wherein the dosage form is administered for at least 8 consecutive days.
  • Embodiment 17 The method of embodiment 16, wherein the dosage form is administered for at least 14 consecutive days.
  • Embodiment 18 The method of embodiment 16, wherein the dosage form is administered for at least 21 consecutive days.
  • Embodiment 19 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the dosage form contains about 60 mg to about 90 mg of (S)-bupropion.
  • Embodiment 20 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
  • the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 21 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is administered twice a day for at least the following 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 22 The method of embodiment 1, 2, 3, 4, 5, 6, 1 , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.
  • Embodiment 23 The method of embodiment 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 method achieves a C m ax of (S)-bupropion in the human being that is at least about 70 ng/mL.
  • Embodiment 24 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the method achieves an AUC0-12 of (S)-bupropion in the huma n being that is at least about 400 ng- hr/mL.
  • Embodiment 25 The method of embodiment 24, wherein the method achieves an AUC0 12 of (S)-bupropion in the human being that is about 500 ng-hr/mL to about 900 ng-hr/mL.
  • Embodiment 26 The method of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the dosage form provides sustained release of the (S)-bupropion.
  • Embodiment 27 The method of embodiment 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 dosage form further contains dextromethorphan.
  • Embodiment 28 The method of embodiment 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, or 27, wherein the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.
  • Embodiment 29 The method of embodiment 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, or 28, wherein the method achieves a Cm a x of (R,R)-hydroxybupropion in the human being that is at least about 600 ng/mL.
  • Embodiment 30 The method of embodiment 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, or 29, wherein the method achieves an AUCo-
  • Embodiment 31 The method of embodiment 30, wherein the method achieves an AUC0-12 of (R,R)-hydroxybupropion in the human being that is at least about 8000 ng-hr/mL.
  • Embodiment 32 A method of enhancing the plasma levels of (S)-bupropion and dextromethorphan, comprising orally co-administering, at least once per day, dextromethorphan and at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with both (S)-bupropion and dextromethorphan, wherein the method achieves a C m ax of (S)-bupropion that is at least about 90 ng/mL in the human being, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 3-fold as compared the C m ax of (R)-bupropion that results from administering the same of amount of (R)-bupropion to the human being.
  • Embodiment 33 The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.
  • Embodiment 34 The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 14 consecutive days.
  • Embodiment 35 The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.
  • Embodiment 36 The method of embodiment 33, 34, or 35, wherein the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 37 The method of embodiment 33, 34, or 35, wherein the dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is administered twice a day for at least the following 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 38 The method of embodiment 32, 33, 34, 35, 36, or 37, wherein (S)- bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.
  • Embodiment 39 The method of embodiment 32, 33, 34, 35, 36, 37, or 38, wherein the C ma x of (S)-bupropion in the human being that is at least about 110 ng/mL.
  • Embodiment 40 The method of embodiment 32, 33, 34, 35, 36, 37, 38, or 39, wherein the method achieves an AUC0-12 of (S)-bupropion in the human being is at least about 800 ng- hr/mL.
  • Embodiment 41 The method of embodiment 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)- bupropion.
  • Embodiment 42 A method of enhancing the plasma levels of (R,R)-hydroxybupropion and dextromethorphan, comprising orally co-administering, at least once per day, dextromethorphan and at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with both (R,R)- hydroxybupropion and dextromethorphan, wherein the method achieves a Cmax of (R,R)- hydroxybupropion that is at least about 700 ng/mL in the human being, wherein the method is effective in increasing the Cmax of (R,R)-hydroxybupropion at least 3-fold as compared the Cmax of (R,R)-hydroxybupropion that results from administering the same of amount of (R)- bupropion to the human being.
  • Embodiment 43 The method of embodiment 42, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.
  • Embodiment 44 The method of embodiment 42, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 21 consecutive days.
  • Embodiment 45 The method of embodiment 42, 43 or 44, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.
  • Embodiment 46 The method of embodiment 42, 43, 44, or 45, wherein the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 47 The method of embodiment 42, 43, 44, 45, or 46, wherein the dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is administered twice a day for at least the following 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 48 The method of embodiment 42, 43, 44, 45, 46, or 47, wherein (S)- bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.
  • Embodiment 49 The method of embodiment 42, 43, 44, 45, 46, 47, or 48, wherein the C ma x of (R,R)-hydroxybupropion in the human being is at least about 900 ng/mL.
  • Embodiment 50 The method of embodiment 42, 43, 44, 45, 46, 47, 48, or 49, wherein the method achieves an AUCo i2 of (R,R)-hydroxybupropion in the human being that is at least about 10,000 ng- hr/mL.
  • Embodiment 51 The method of embodiment 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)- bupropion.
  • Embodiment 52 A method of enhancing the plasma levels of (S)-bupropion comprising orally administering, at least once per day, at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment (S)-bupropion, wherein the method achieves a Cmin of (S)-bupropion that is at least about 20 ng/mL, wherein the method is effective in increasing the Cmin of (S)-bupropion at least 3-fold as compared the Cmin of (R)-bupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 53 The method of embodiment 52, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.
  • Embodiment 54 The method of embodiment 52, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 14 consecutive days.
  • Embodiment 55 The method of embodiment 52, 53, or 54, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.
  • Embodiment 56 The method of embodiment 52, 53, 54, or 55, wherein the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 57 The method of embodiment 52, 53, 54, 55, or 56, wherein the dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is administered twice a day for at least the following 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 58 The method of embodiment 52, 53, 54, 55, 56, or 57, wherein (S)- bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.
  • Embodiment 59 The method of embodiment 52, 53, 54, 55, 56, 57, or 58, wherein the method achieves a C m ax of (S)-bupropion in the human being that is at least about 110 ng/mL.
  • Embodiment 60 The method of embodiment 52, 53, 54, 55, 56, 57, 58, or 59, wherein the method achieves an AUC0-12 of (S)-bupropion in the human being is at least about 800 ng- hr/mL.
  • Embodiment 61 The method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, or 60, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)- bupropion.
  • Embodiment 62 A method of enhancing the plasma levels of (R,R)-hydroxybupropion comprising orally administering, at least once per day, at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)- hydroxybupropion, wherein the method achieves a Cmin of (R,R)-hydroxybupropion that is at least about 700 ng/mL in the huma n being, wherein the method is effective in increasing the Cmin of (R,R)-hydroxybupropion at least 3-fold as compared the Cmin of (R,R)- hydroxybupropion that results from administering the same of amount of (R)-bupropion to the human being.
  • Embodiment 63 The method of embodiment 62, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.
  • Embodiment 64 The method of embodiment 62, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 21 consecutive days.
  • Embodiment 65 The method of embodiment 62, 63, or 64, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.
  • Embodiment 66 The method of embodiment 62, 63, 64, or 65, wherein the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 67 The method of embodiment 62, 63, 64, 65, or 66, wherein the dosage form is administered once daily for 1 to 7 consecutive days, then the dosage form is administered twice a day for at least the following 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 68 The method of 62, 63, 64, 65, 66, or 67, wherein (S)-bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.
  • Embodiment 69 The method of embodiment 62, 63, 64, 65, 66, 66, 67, or 68, wherein the method achieves a Cmax of (R,R)-hydroxybupropion in the human being that is at least about 900 ng/mL.
  • Embodiment 70 The method of embodiment 62, 63, 64, 65, 66, 67, 68, or 69, wherein the method achieves an AUC0-12 of (R,R)-hydroxybupropion in the human being that is at least about 10,000 ng-hr/mL.
  • Embodiment 71 The method of embodiment 62, 63, 64, 65, 66, 67, 68, 69, or 70, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)- bupropion.
  • Embodiment 72 A method of treating a central nervous system (CNS) disorder in a human being comprising administering: a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, and dextromethorphan, to the human being to treat the CNS disorder.
  • CNS central nervous system
  • Embodiment 73 The method of embodiment 72, wherein the CNS disorder comprises depression.
  • Embodiment 74 The method of embodiment 72, wherein the CNS disorder comprises treatment-resistant depression.
  • Embodiment 75 The method of embodiment 72, wherein the CNS disorder comprises an addictive disorder.
  • Embodiment 76 The method of embodiment 72, wherein the CNS disorder comprises a nicotine addiction.
  • Embodiment 77 The method of embodiment 72, wherein the CNS disorder comprises an alcohol addiction.
  • Embodiment 78 The method of embodiment 72, wherein the CNS disorder comprises Alzheimer's disease.
  • Embodiment 79 The method of embodiment 72, 73, 74, 75, 76, 77, or 78, wherein the dosage form is in a form of tablet, capsule, or syrup.
  • Embodiment 80 The method of embodiment 72, 73, 74, 75, 76, 77, 78, or 79, wherein the dosage form is orally administered to the human being.
  • Embodiment 81 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, or 80, wherein the dosage form is orally administered to the human being daily.
  • Embodiment 82 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, or 81, wherein the dosage form is orally administered to the huma n being once daily.
  • Embodiment 83 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, or 82, wherein the dosage form is orally administered to the huma n being twice daily.
  • Embodiment 84 The method of embodiment 72, 73, 74, 75, 76, 77 , 78, 79, 80, 81, 82, or
  • the dosage form is orally administered to the human being under fasting conditions.
  • Embodiment 85 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, or 84, wherein the dosage form is orally administered to the human being daily for at least 8 consecutive days.
  • Embodiment 86 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,
  • Embodiment 87 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 86, wherein the dosage form contains about 104 mg to about 106 mg of the (S)- bupropion.
  • Embodiment 88 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, or 87, wherein the dosage form contains about 148 mg to about 152 mg of the (S)- bupropion.
  • Embodiment 89 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88, wherein the both the (S)-bupropion and the dextromethorphan are in the dosage form.
  • Embodiment 90 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89, wherein the dosage form contains about 10 mg to about 50 mg of the dextromethorphan.
  • Embodiment 91 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90, wherein the dosage form contains about 44 mg to about 46 mg of the dextromethorphan.
  • Embodiment 92 The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, or 91, wherein the dosage form is well tolerated.
  • Embodiment 93 Embodiment 93.
  • a method of achieving an increased plasma level of (S)-bupropion while enhancing dextromethorphan plasma levels comprising administering a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, and dextromethorphan, to a human being in need of treatment with bupropion.
  • Embodiment 94 The method of embodiment 93, wherein the method is effective in achieving an increased C m ax of (S)-bupropion as compared to administering the same amount racemic bupropion.
  • Embodiment 95 The method of embodiment 93 or 94, wherein the method is effective in achieving a C ma x of (S)-bupropion that is at least 3 times as high as the C ma x of (R)-bupropion that results from administering a dosage form containing the same amount of (R)-bupropion to the human being.
  • Embodiment 96 The method of embodiment 93, 94, or 95, wherein the method is effective in achieving an increased AUCo i2 of (S)-bupropion as compared to administering the same amount racemic bupropion.
  • Embodiment 97 The method of embodiment 96, wherein the method is effective in achieving an AUC0 12 of (S)-bupropion that is at least 3 times as high as the AUC0 12 of (R)- bupropion that results from administering a dosage form containing the same amount of (R)- bupropion to the human being.
  • Embodiment 98 The method of embodiment 95, 96, or 97, wherein the dosage form is administered at least once a day for at least 8 consecutive days.
  • Embodiment 99 The method of embodiment 95, 96, 97, or 98, wherein the dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 100 The dosage form of embodiment 95, 96, 97, 98, or 99, wherein the dosage form is well tolerated.
  • Embodiment 101 A dosage form comprising at least about 95% enantiomerically pure (R)- bupropion and dextromethorphan, wherein orally administering the dosage form to a human being provides an increased enhancement to a plasma level of dextromethorphan in the human being as compared to orally administering a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 102 The dosage form of embodiment 101, wherein the dosage form contains about 100 mg to about 200 mg of (R)-bupropion.
  • Embodiment 103 The dosage form of embodiment 102, wherein the dosage form contains about 104 mg to about 106 mg of (R)-bupropion.
  • Embodiment 104 The dosage form of embodiment 102, wherein the dosage form contains about 148 mg to about 152 mg of (R)-bupropion.
  • Embodiment 105 The dosage form of embodiment 101, 102, 103, or 104, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.
  • Embodiment 106 The dosage form of embodiment 105, wherein the dosage form contains about 44 mg to about 46 mg of dextromethorpha n.
  • Embodiment 107 The dosage form of embodiment 101, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.
  • Embodiment 108 The dosage form of embodiment 101, 102, 103, 104, 105, 106, or 107, wherein the dosage form is orally administered to the human being daily.
  • Embodiment 109 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, or 108, wherein the dosage form is orally administered to the huma n being once daily.
  • Embodiment 110 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, or 108, wherein the dosage form is orally administered to the huma n being twice daily.
  • Embodiment 111 The dosage form of embodiment 109 or 110, wherein the dosage form is orally administered to the human being daily for at least 8 consecutive days.
  • Embodiment 112. The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, or 111, wherein the dosage form is orally administered to the human being under fasting conditions.
  • Embodiment 113 The dosage form of embodiment 111, wherein the dosage form achieves a Cm a x of dextromethorphan of at least about 80 ng/mL in the human being on day 8 of oral administration of the dosage form daily for 8 consecutive days.
  • Embodiment 114 The dosage form of embodiment 113, wherein the dosage form is in a form of syrup, tablet, capsule, spray, or lozenge.
  • Embodiment 115 The dosage form of embodiment 113 or 114, wherein the dosage form is used for treating a neuropsychiatric disorder in the huma n being in need thereof.
  • Embodiment 116 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used for treating cold or cough in the human being in need thereof.
  • Embodiment 117 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used for relieving pain in the human being in need thereof.
  • Embodiment 118 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used for treatment of addiction in a human being in need thereof.
  • Embodiment 119 The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, or 118, wherein the dosage form is well tolerated when administered to the human being.
  • Embodiment 120 A method of increasing enhancement of dextromethorphan plasma level in a human being, comprising administrating a dosage form comprising at least about 95% enantiomerically pure (R)-bupropion and dextromethorphan to the human being, wherein the dosage form provides an increased enhancement to a plasma level of dextromethorphan in the human being as compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 121 The method of embodiment 120, wherein the dosage form contains about 100 mg to about 200 mg of (R)-bupropion.
  • Embodiment 122 The method of embodiment 120, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion.
  • Embodiment 123 The method of embodiment 120, wherein the dosage form contains about 148 mg to about 152 mg of (R)-bupropion.
  • Embodiment 124 The method of embodiment 120, 121, 122, or 123, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.
  • Embodiment 125 The method of embodiment 124, wherein the dosage form contains about 40 mg to about 50 mg of dextromethorphan.
  • Embodiment 126 The method of embodiment 125, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.
  • Embodiment 127 The method of embodiment 120, 121, 122, 123, 124, 125, or 126, wherein the dosage form is orally administered to the human being under fasting conditions.
  • Embodiment 128 The method of embodiment 120, 121, 122, 123, 124, 125, 126, or 127, wherein the dosage form is well tolerated.
  • Embodiment 129. A method of treating a central nervous system (CNS) disorder in a human being comprising administering a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion to the human being to treat the CNS disorder, wherein the human being does not receive dextromethorphan.
  • CNS central nervous system
  • Embodiment 130 The method of embodiment 129, wherein the CNS disorder comprises depression.
  • Embodiment 131. The method of embodiment 129 or 130, wherein the CNS disorder comprises treatment resistant depression.
  • Embodiment 132 The method of embodiment 129, 130, or 131 wherein the CNS disorder is an addictive disorder.
  • Embodiment 133. The method of embodiment 132, wherein the CNS disorder is nicotine addiction.
  • Embodiment 134 The method of embodiment 132, wherein the CNS disorder is alcohol addiction.
  • Embodiment 135. The method of embodiment 132, wherein the CNS disorder is Alzheimer's disease.
  • Embodiment 136 The method of embodiment 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form contains no active pharmaceutical agent other than (S)-bupropion.
  • Embodiment 137 The method of embodiment 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form contains less than 0.1% of any active pharmaceutical agent other than (S)- bupropion.
  • Embodiment 138 The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, or 137, wherein the dosage form is in a form of a tablet, capsule, or syrup.
  • Embodiment 139 The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, or 138, wherein the dosage form is orally administered to the human being daily.
  • Embodiment 140 The method of embodiment 139, wherein the dosage form is orally administered to the human being once daily.
  • Embodiment 141 The method of embodiment 139, wherein the dosage form is orally administered to the human being twice daily.
  • Embodiment 142 The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, or 141, wherein the dosage form is orally administered to the human being under fasting conditions.
  • Embodiment 143 The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, or 142 wherein the dosage form is orally administered to the human being daily for at least 8 consecutive days.
  • Embodiment 144 The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, or 143, wherein the dosage form contains about 100 mg to about
  • Embodiment 145 The method of embodiment 144, wherein the dosage form contains about 104 mg to about 106 mg of (S)-bupropion.
  • Embodiment 146 The method of embodiment 144, wherein the dosage form contains about 148 mg to about 152 mg of (S)-bupropion.
  • Embodiment 147 A method of enhancing the plasma level of (S)-bupropion, comprising administering comprising administering a dosage comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, wherein the dosage form is free of dextromethorphan, to a human being in need of treatment with bupropion.
  • Embodiment 149 The method of embodiment 147 or 148, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 3-fold as compared the C m ax of (R)-bupropion that results from administering a dosage form containing the same of amount of (R)- bupropion to the human being.
  • Embodiment 150 The method of embodiment 147, 148, or 149, wherein the method is effective in enhancing the AUC0-12 of (S)-bupropion.
  • Embodiment 151 The method of embodiment 147, 148, 149, or 150, wherein the method is effective in increasing the AUC0-12 of (S)-bupropion at least 3-fold as compared the AUC0-12 of (R)-bupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 152 The method of embodiment 147, 148, 149, 150, or 151, wherein the dosage form is administered at least once a day for at least 8 consecutive days.
  • Embodiment 153 The method of embodiment 152, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 154 The dosage form of embodiment 147, 148, 149, 150, 151, 152, or 153, wherein the dosage form is well tolerated.
  • Embodiment 155 A method of enhancing the plasma levels of (S)-bupropion, comprising orally administering an oral dosage form containing at least about 90 mg of (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (S)- bupropion and dextromethorphan, wherein the method achieves a C m ax of (S)-bupropion that is at least about 90 ng/mL in the human being, wherein the method is effective in increasing the Cmax of (S)-bupropion at least 3-fold as compared the C m ax of (R)-bupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being, wherein the human being does not receive dextromethorphan.
  • Embodiment 156 The method of embodiment 155, wherein the oral dosage form is administered for at least 8 consecutive days.
  • Embodiment 157 The method of embodiment 156, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 158 The method of embodiment 155, 156, or 157, wherein the dosage form contains about 100 mg to about 110 mg of (S)-bupropion.
  • Embodiment 159 The method of embodiment 155, 156, 157, or 158, wherein the Cm a x of (S)- bupropion in the human being is at least about 110 ng/mL.
  • Embodiment 160 A method of enhancing the plasma levels of (R,R)-hydroxybupropion, comprising orally administering an oral dosage form containing at least about 90 mg of (S)- bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)-hydroxybupropion and dextromethorphan, wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 90 ng/mL, wherein the method is effective in increasing the C m ax of (R,R)-hydroxybupropion at least 3-fold as compared the C m ax of (R,R)- hydroxybupropion that results from administering a dosage form containing the same of amount
  • Embodiment 161 The method of embodiment 160, wherein the oral dosage form is administered for at least 8 consecutive days.
  • Embodiment 162 The method of embodiment 161, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, then the dosage form is administered twice a day for at least the following 4 to 7 consecutive days, so that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.
  • Embodiment 163 The method of embodiment 160, 161, or 162, wherein the dosage form contains about 100 mg to about 110 mg of (S)-bupropion.
  • Embodiment 164 An oral dosage form comprising (R)-bupropion in an enantiomeric excess of at least 95%, and dextromethorphan, wherein the dosage form provides an increased enhancement to a plasma level of dextromethorphan in a human being as compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 165 An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form can enhance plasma levels of dextromethorphan in a human being on day 1 or day 8 in a much greater extent than that of a reference oral dosage form when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic-bupropion and the same amount of dextromethorphan.
  • Embodiment 166 Embodiment 166.
  • An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 1 by at least 150% when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 167 An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 8 by at least 25% when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 168 An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 8 by at least 20-fold as compared to that of a reference dosage form on day 1, when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic-bupropion and the same amount of dextromethorphan.
  • Embodiment 169 An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form increases a mean C m ax of dextromethorphan in a human being on day 1 by at least 60% when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic-bupropion and the same amount of dextromethorphan.
  • Embodiment 170 An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form increases a mean Cmax of dextromethorphan in a human on day 8 being by at least 20% when orally administered to the human being daily for at least 8 consecutive days, wherein the reference oral dosage form contains the same amount of bupropion as a racemic-bupropion and the same amount of dextromethorphan.
  • Embodiment 171 A method of enhancing the plasma levels of dextromethorphan on day 1 or day 8, comprising orally administering a dosage form containing (R)-bupropion and dextromethorphan, in a much greater extent than orally administering a reference dosage form, when orally administered to a human being daily for at least 8 consecutive days, wherein the reference dosage form contains the same amount of bupropion as a (S)- bupropion and the same amount of dextromethorphan.
  • Embodiment 172 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the (R)-bupropion in the dosage form is at least 95% enantiomerically pure.
  • Embodiment 173 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the (S)-bupropion in the reference dosage form is at least 95% enantiomerically pure.
  • Embodiment 174 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the dosage form contains about 100 mg to about 150 mg of (R)- bupropion.
  • Embodiment 175. The dosage form or method of embodiment 174, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion.
  • Embodiment 176 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.
  • Embodiment 177 The dosage form or method of embodiment 176, wherein the dosage form contains about 40 mg to about 50 mg of dextromethorphan.
  • Embodiment 178 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is orally administered once daily.
  • Embodiment 179 The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is orally administered twice a day.
  • Embodiment 180 The dosage form or method of embodiment 178 or 179, wherein the dosage form is orally administered for at least 8 consecutive days.
  • Embodiment 181. The dosage form or method of embodiment 180, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.
  • Embodiment 182 The dosage form or method of embodiment 180 or 181, wherein the oral dosage form achieves a mean Cm a x of dextromethorphan of at least about 80 ng/mL in the human being on day 8 of oral administration of the dosage form daily for 8 consecutive days.
  • Embodiment 183 The dosage form or method of embodiment 180, 181, or 182, wherein the dosage form is in a form of syrup, tablet, capsule, spray, or lozenge.
  • Embodiment 184 A method of treating a neuropsychiatric disorder, comprising administering a dosage form any preceding embodiment to a human being in need thereof.
  • Embodiment 185 A method of treating cold or cough, comprising administering a dosage form of any preceding embodiment to a human being in need thereof.
  • Embodiment 186 A method of relieving pain, comprising administering a dosage form of any preceding em bodiment to a human being in need thereof.
  • Embodiment 187 A method for treatment of addiction, comprising administering a dosage form of any preceding embodiment to a human being in need thereof.
  • Embodiment 188 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being having a condition that is treatable with (S)-bupropion, wherein the amount of (S)-bupropion administered is selected to be about 20% to about 70% of the amount of racemic bupropion that would be administered to treat the same huma n being for the same condition.
  • Embodiment 189 A method of providing therapeutically effective plasma levels of (R,R)- hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)- hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being, and wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Embodiment 190 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to a human being in need of treatment with (S)-bupropion, wherein the (S)-bupropion is the sole active agent used to treat the human being.
  • Embodiment 191 A method of treating a human being comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion.
  • Embodiment 192 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of (S)-bupropion that is at least about 60 ng/mL.
  • Embodiment 193 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of (S)-bupropion that is at least about 60 ng/mL.
  • a method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein (R,R)- hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)- hydroxybupropion present in the plasma of the human being.
  • (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day
  • a method of providing therapeutically effective plasma levels of (R,R)- hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)- hydroxybupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total of amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human being.
  • Embodiment 195 A method of providing therapeutically effective plasma levels of (R,R)- hydroxybupropion comprising orally administering, one or two times per day, (S)-bupropion that is at least 95% enantiomerically pure, to a human being in need of treatment with (R,R)- hydroxybupropion, wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 500 ng/mL in the human being.
  • Embodiment 196 The method of any preceding embodiment, such as embodiments 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, or 195, wherein dextromethorphan is not administered to the human being.
  • Embodiment 197 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C max of (S)-bupropion that is at least about 70 ng/mL.
  • Embodiment 198 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0 12 of (S)-bupropion that is at least about 600 ng-h/mL.
  • Embodiment 199 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of (R,R)-hydroxybupropion that is at least about 800 ng/mL.
  • Embodiment 200 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0-12 of (R,R)-hydroxybupropion that is at least about 8,000 ng-h/mL.
  • Embodiment 201 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of erythrohydroxybupropion that is at least about 90 ng/mL.
  • Embodiment 202 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUCo i2 of erythrohydroxybupropion that is at least about 1,000 ng- h/mL.
  • Embodiment 203 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves a C m ax of threohydroxybupropion that is at least about 450 ng/mL.
  • Embodiment 204 A method of treating a human being comprising orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure, one or two times per day, to a human being in need of treatment with (S)-bupropion, wherein the method achieves an AUC0 12 of threohydroxybupropion that is at least about 5,000 ng- h/mL.
  • Embodiment 205 A dosage form comprising (S)-bupropion which is at least 95% enantiomerically pure.
  • Embodiment 206 The dosage form of embodiment 205, which contains about 100 mg to about 200 mg of (S)-bupropion.
  • Embodiment 207 The dosage form of any preceding embodiment, wherein the dosage form contains less than 0.1% of any other active pharmaceutical agent.
  • Embodiment 208 The dosage form of any preceding embodiment, further comprising dextromethorphan.
  • Embodiment 209 The dosage form of embodiment 208, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorpha n.
  • Embodiment 210 A method of enhancing the plasma level of (S)-bupropion or a metabolite thereof, comprising administering a dosage form of embodiment 205, 206, 207, 208, or 209 to a human being in need of treatment with bupropion or a metabolite thereof.
  • Embodiment 211 The method of any preceding embodiment, wherein the method is effective in enhancing the C m ax of (S)-bupropion.
  • Embodiment 212 The method of any preceding embodiment, wherein the method is effective in increasing the C m ax of (S)-bupropion at least 3-fold as compared the C m ax of (R)- bupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 213. The method of any preceding embodiment, wherein the method is effective in enhancing the AUC0-12 of (S)-bupropion.
  • Embodiment 214 The method of any preceding embodiment, wherein the method is effective in increasing the AUC0-12 of (S)-bupropion at least 3-fold as compared the AUC0-12 of (R)-bupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 215. The method of any preceding embodiment, wherein the method is effective in enhancing the C m ax of (R,R)-hydroxybupropion.
  • Embodiment 216 The method of any preceding embodiment, wherein the method is effective in increasing the C m ax of (R,R)-hydroxybupropion at least 3-fold as compared the C m ax of (R,R)-hydroxybupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 217 The method of any preceding embodiment, wherein the method is effective in enhancing the AUC0 12 of (R,R)-hydroxybupropion.
  • Embodiment 218 The method of embodiment 13, wherein the method is effective in increasing the AUC0-12 of (R,R)-hydroxybupropion at least 3-fold as compared the AUC0-12 of (R,R)-hydroxybupropion that results from administering a dosage form containing the same of amount of (R)-bupropion to the human being.
  • Embodiment 219. The method of any preceding embodiment, wherein the dosage form is administered at least once a day for at least 8 consecutive days.
  • Embodiment 220. A method of treating a neurological condition, comprising administering a dosage form of any preceding embodiment to a human being in need thereof.
  • Embodiment 221. The method of embodiment 16, wherein the neurological condition is depression.
  • Embodiment 222 A method of increasing the plasma levels of dextromethorphan comprising administering a combination of (R)-bupropion and dextromethorphan to a human being in need of treatment by dextromethorphan, wherein the (R)-bupropion is at least 95% enantiomerically pure.
  • Embodiment 223. The method of embodiment 18, wherein the C m ax of dextromethorphan is increased by at least 20% as compared to administering the same amount of (S)-bupropion and the same amount of dextromethorphan.
  • Embodiment 224. A method of delivering (S)-bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being.
  • Embodiment 225 A method of delivering both (R)-bupropion and (S)-bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)- bupropion that is at least 95% enantiomerically pure to the human being, wherein the C m ax of (R)-bupropion is within 20% of the C m ax of (R)-bupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Embodiment 226 A method of delivering a bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being, wherein the AUCo-i2 of (R)-bupropion is within 20% of the AUCO-12 of (R)-bupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Embodiment 227 A method of delivering a bupropion to the plasma of a human being comprising: orally administering a dosage form containing (S)-bupropion that is at least 95% enantiomerically pure to the human being, wherein the C m ax of (R,R)-hydroxybupropion is within 20% of the C m ax of (R,R)-hydroxybupropion that would result from administering the same amount of racemic bupropion to the human being.
  • Embodiment 228 The method of embodiment 224, 225, 226, or 227 wherein the (S)- bupropion is administered for at least 8 consecutive days.
  • Embodiment 229. The method of embodiment 228, wherein the (S)-bupropion is administered for at least 14 consecutive days.
  • Embodiment 230. The method of embodiment 224, 225, 226, 227, 228, or 229, wherein the dosage form contains about 50 mg to about 150 mg of (S)-bupropion.
  • Embodiment 23 The method of embodiment 224, 225, 226, 227, 228, or 229, wherein the dosage form contains about 40 mg to about 90 mg of (S)-bupropion.
  • Embodiment 232 The method of any preceding embodiment, wherein administering the dosage form results in a combined C ma x of (S)-bupropion and (R)-bupropion, on day 8, that is at least about 100 ng/mL.
  • Embodiment 233 The method of any preceding embodiment, wherein administering the dosage form results in a combined AUC0-12 of (S)-bupropion and (R)-bupropion, on day 8, that is at least about 800 ng-hr/mL.
  • Embodiment 234. The method of any preceding embodiment, wherein administering the dosage form results in a combined C ma x of (S,S)-hydroxybupropion and (R,R)- hydroxybupropion, on day 8, that is at least about 1,000 ng/mL.
  • Embodiment 235 The method of any preceding embodiment, wherein administering the dosage form results in a combined AUC0-12 of (S,S)-hydroxybupropion and (R,R)- hydroxybupropion, on day 8, that is at least about 10,000 ng-hr/mL.
  • Embodiment 236 The method of any preceding embodiment, wherein administering the dosage form results in a Cm a x of erythrohydroxybupropion, on day 8, that is at least about 100 ng/mL.
  • Embodiment 237 The method of any preceding embodiment, wherein administering the dosage form results in a AUC0 12 of erythrohydroxybupropion, on day 8, that is at least about 1,500 ng- hr/mL.
  • Embodiment 238 The method of any preceding embodiment, wherein administering the dosage form results in a C m ax of threohydroxybupropion, on day 8, that is at least about 600 ng/mL.
  • Embodiment 239. The method of any preceding embodiment, wherein administering the dosage form results in a combined AUC0-12 of threohydroxybupropion, on day 8, that is at least about 5,000 ng-hr/mL.

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CA3092076A CA3092076A1 (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
CR20200415A CR20200415A (es) 2018-02-23 2019-02-25 Formas y mètodos de dosis para bupropión enantioméricamente enriquecido o puro
MX2020008704A MX2020008704A (es) 2018-02-23 2019-02-25 Formas y métodos de dosis para bupropión enantioméricamente enriquecido o puro.
AU2019223187A AU2019223187B2 (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
KR1020237017449A KR20230075531A (ko) 2018-02-23 2019-02-25 거울상이성질체적으로 농후한 또는 순수한 부프로피온을 위한 투여 형태 및 방법
KR1020247017593A KR20240091043A (ko) 2018-02-23 2019-02-25 거울상이성질체적으로 농후한 또는 순수한 부프로피온을 위한 투여 형태 및 방법
IL276871A IL276871B2 (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
NZ767378A NZ767378A (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
KR1020207027256A KR20210003091A (ko) 2018-02-23 2019-02-25 거울상이성질체적으로 농후한 또는 순수한 부프로피온을 위한 투여 형태 및 방법
PE2020001272A PE20211752A1 (es) 2018-02-23 2019-02-25 Formas y metodos de dosis para bupropion enantiomericamente enriquecido o puro
JP2020544420A JP2021513998A (ja) 2018-02-23 2019-02-25 鏡像異性体的に濃縮された、または鏡像異性体的に純粋なブプロピオンの剤形
BR112020017179-4A BR112020017179A2 (pt) 2018-02-23 2019-02-25 Formas de dosagem e métodos para bupropiona enriquecida enantiomericamente ou pura
IL313368A IL313368A (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
MYPI2020004315A MY202993A (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
SG11202008056SA SG11202008056SA (en) 2018-02-23 2019-02-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
EP19756920.5A EP3755312A4 (en) 2018-02-23 2019-02-25 DOSAGE FORMS AND PROCESSES FOR ENANTIOMER ENHANCED OR PURE BUPROPION
CN201980026874.5A CN112087999A (zh) 2018-02-23 2019-02-25 用于对映体富集的或纯的安非他酮的剂型和方法
US16/364,005 US20190216800A1 (en) 2013-11-05 2019-03-25 Dosage forms and methods for enantiomerically enriched or pure bupropion
US16/364,463 US20190216801A1 (en) 2013-11-05 2019-03-26 Dosage forms and methods for enantiomerically enriched or pure bupropion
US17/183,645 US20210196704A1 (en) 2013-11-05 2021-02-24 Dosage forms and methods for enantiomerically enriched or pure bupropion
US17/187,454 US20210177834A1 (en) 2013-11-05 2021-02-26 Dosage forms and methods for enantiomerically enriched or pure bupropion
AU2022204521A AU2022204521B2 (en) 2018-02-23 2022-06-27 Dosage forms and methods for enantiomerically enriched or pure bupropion
JP2022124557A JP2022153638A (ja) 2018-02-23 2022-08-04 鏡像異性体的に濃縮された、または鏡像異性体的に純粋なブプロピオンの剤形および方法
JP2024041381A JP2024075655A (ja) 2018-02-23 2024-03-15 鏡像異性体的に濃縮された、または鏡像異性体的に純粋なブプロピオンの剤形および方法
AU2024205858A AU2024205858A1 (en) 2018-02-23 2024-08-17 Dosage forms and methods for enantiomerically enriched or pure bupropion

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US11660273B2 (en) 2018-09-20 2023-05-30 Axsome Therapeutics, Inc. Dosage forms and methods for enantiomerically enriched or pure bupropion
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