WO2015069809A1 - Compositions and methods comprising bupropion or related compounds and dextromethorphan - Google Patents

Compositions and methods comprising bupropion or related compounds and dextromethorphan Download PDF

Info

Publication number
WO2015069809A1
WO2015069809A1 PCT/US2014/064184 US2014064184W WO2015069809A1 WO 2015069809 A1 WO2015069809 A1 WO 2015069809A1 US 2014064184 W US2014064184 W US 2014064184W WO 2015069809 A1 WO2015069809 A1 WO 2015069809A1
Authority
WO
WIPO (PCT)
Prior art keywords
dextromethorphan
prodrug
administering
bupropion
day
Prior art date
Application number
PCT/US2014/064184
Other languages
French (fr)
Inventor
Herriot TABUTEAU
Original Assignee
Antecip Bioventures Ii Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Antecip Bioventures Ii Llc filed Critical Antecip Bioventures Ii Llc
Priority to CA2929415A priority Critical patent/CA2929415C/en
Priority to KR1020217016618A priority patent/KR20210068157A/en
Priority to EP14859589.5A priority patent/EP3065742A4/en
Priority to IL298972A priority patent/IL298972A/en
Priority to EP21191390.0A priority patent/EP3981403A1/en
Priority to SG11201603391XA priority patent/SG11201603391XA/en
Priority to KR1020227013910A priority patent/KR102603013B1/en
Priority to MX2016005867A priority patent/MX2016005867A/en
Priority to EP21191393.4A priority patent/EP3981404A1/en
Priority to KR1020237034772A priority patent/KR20230148385A/en
Priority to JP2016552474A priority patent/JP6605485B2/en
Priority to AU2014346807A priority patent/AU2014346807B2/en
Priority to CN201480072191.0A priority patent/CN106163522A/en
Priority to NZ719892A priority patent/NZ719892A/en
Priority to KR1020167013970A priority patent/KR102264179B1/en
Priority to MX2020004075A priority patent/MX2020004075A/en
Priority to US14/550,618 priority patent/US9198905B2/en
Priority to US14/555,085 priority patent/US9238032B2/en
Priority to US14/554,988 priority patent/US9205083B2/en
Priority to US14/554,947 priority patent/US20150126542A1/en
Priority to US14/602,177 priority patent/US9402843B2/en
Priority to US14/604,397 priority patent/US9168234B2/en
Priority to US14/617,624 priority patent/US9486450B2/en
Priority to US14/628,062 priority patent/US9402844B2/en
Publication of WO2015069809A1 publication Critical patent/WO2015069809A1/en
Priority to US14/863,284 priority patent/US9278095B2/en
Priority to US14/879,002 priority patent/US9375429B2/en
Priority to US14/878,998 priority patent/US9314462B2/en
Priority to US14/978,976 priority patent/US9370513B2/en
Priority to US14/997,316 priority patent/US9457025B2/en
Priority to US15/057,983 priority patent/US9408815B2/en
Priority to US15/130,807 priority patent/US9421176B1/en
Priority to IL245504A priority patent/IL245504B/en
Priority to US15/164,746 priority patent/US9457023B1/en
Priority to US15/164,767 priority patent/US9700528B2/en
Priority to US15/182,253 priority patent/US9474731B1/en
Priority to US15/206,057 priority patent/US9861595B2/en
Priority to US15/213,283 priority patent/US20160324807A1/en
Priority to US15/216,545 priority patent/US20160339017A1/en
Priority to US15/224,233 priority patent/US20160375008A1/en
Priority to US15/236,290 priority patent/US9763932B2/en
Priority to US15/238,182 priority patent/US20160361305A1/en
Priority to US15/263,138 priority patent/US9700553B2/en
Priority to US15/275,177 priority patent/US20170007558A1/en
Priority to US15/280,938 priority patent/US9707191B2/en
Priority to US15/599,163 priority patent/US9968568B2/en
Priority to US15/621,882 priority patent/US10105361B2/en
Priority to US15/645,939 priority patent/US9867819B2/en
Priority to US15/647,069 priority patent/US10105327B2/en
Priority to US15/647,852 priority patent/US10080727B2/en
Priority to US15/688,660 priority patent/US10058518B2/en
Priority to US15/691,532 priority patent/US10092560B2/en
Priority to US15/691,549 priority patent/US10064857B2/en
Priority to US15/695,995 priority patent/US10092561B2/en
Priority to US15/821,563 priority patent/US10512643B2/en
Priority to US15/842,599 priority patent/US20180116980A1/en
Priority to US15/933,075 priority patent/US10251879B2/en
Priority to US15/977,276 priority patent/US10463634B2/en
Priority to AU2018203638A priority patent/AU2018203638C1/en
Priority to US16/107,472 priority patent/US10806710B2/en
Priority to US16/114,886 priority patent/US20190000835A1/en
Priority to US16/116,393 priority patent/US10786496B2/en
Priority to US16/119,852 priority patent/US10780066B2/en
Priority to US16/127,832 priority patent/US10548857B2/en
Priority to US16/129,531 priority patent/US10881624B2/en
Priority to US16/130,898 priority patent/US20190008805A1/en
Priority to US16/133,553 priority patent/US10596167B2/en
Priority to US16/246,347 priority patent/US11273133B2/en
Priority to US16/290,653 priority patent/US20190192507A1/en
Priority to US16/359,958 priority patent/US10881657B2/en
Priority to US16/364,005 priority patent/US20190216800A1/en
Priority to US16/364,463 priority patent/US20190216801A1/en
Priority to AU2019236614A priority patent/AU2019236614C1/en
Priority to US16/588,399 priority patent/US20200022929A1/en
Priority to US16/681,317 priority patent/US10786469B2/en
Priority to AU2019275593A priority patent/AU2019275593B2/en
Priority to US16/736,752 priority patent/US10799497B2/en
Priority to US16/745,105 priority patent/US20200147008A1/en
Priority to US16/821,462 priority patent/US10874663B2/en
Priority to US16/821,330 priority patent/US10894046B2/en
Priority to US16/822,697 priority patent/US11090300B2/en
Priority to US16/822,564 priority patent/US10966974B2/en
Priority to US16/823,807 priority patent/US10874665B2/en
Priority to US16/823,724 priority patent/US10874664B2/en
Priority to US16/825,228 priority patent/US10864209B2/en
Priority to US16/825,195 priority patent/US10894047B2/en
Priority to US16/826,580 priority patent/US11007189B2/en
Priority to US16/826,598 priority patent/US20200237751A1/en
Priority to US16/828,237 priority patent/US20200237752A1/en
Priority to US16/838,829 priority patent/US10772850B2/en
Priority to US16/894,713 priority patent/US10898453B2/en
Priority to US16/983,873 priority patent/US10945973B2/en
Priority to US17/002,017 priority patent/US11541021B2/en
Priority to US17/003,777 priority patent/US10933034B2/en
Priority to US17/030,129 priority patent/US11065248B2/en
Priority to US17/039,551 priority patent/US10966941B2/en
Priority to US17/061,047 priority patent/US11020389B2/en
Priority to US17/063,364 priority patent/US11123343B2/en
Priority to US17/066,310 priority patent/US11229640B2/en
Priority to US17/068,309 priority patent/US10980800B2/en
Priority to US17/070,706 priority patent/US11129826B2/en
Priority to US17/071,925 priority patent/US11123344B2/en
Priority to US17/075,189 priority patent/US11096937B2/en
Priority to US17/087,890 priority patent/US11141416B2/en
Priority to US17/092,968 priority patent/US11234946B2/en
Priority to US17/095,256 priority patent/US11298351B2/en
Priority to US17/097,486 priority patent/US11213521B2/en
Priority to US17/099,226 priority patent/US11058648B2/en
Priority to US16/950,838 priority patent/US11311534B2/en
Priority to US16/952,759 priority patent/US11185515B2/en
Priority to US17/100,456 priority patent/US11273134B2/en
Priority to US17/103,819 priority patent/US11141388B2/en
Priority to US17/115,073 priority patent/US11207281B2/en
Priority to US17/183,645 priority patent/US20210196704A1/en
Priority to US17/187,454 priority patent/US20210177834A1/en
Priority to US17/191,014 priority patent/US11285146B2/en
Priority to US17/192,192 priority patent/US11191739B2/en
Priority to US17/192,563 priority patent/US11197839B2/en
Priority to US17/193,340 priority patent/US11253491B2/en
Priority to US17/193,306 priority patent/US20210205240A1/en
Priority to US17/194,739 priority patent/US11147808B2/en
Priority to US17/196,338 priority patent/US11253492B2/en
Priority to US17/197,971 priority patent/US11291638B2/en
Priority to US17/199,112 priority patent/US20210196705A1/en
Priority to US17/201,820 priority patent/US11298352B2/en
Priority to US17/207,256 priority patent/US11291665B2/en
Priority to US17/217,311 priority patent/US11357744B2/en
Priority to AU2021202497A priority patent/AU2021202497B2/en
Priority to US17/314,647 priority patent/US20210267967A1/en
Priority to US17/316,194 priority patent/US11344544B2/en
Priority to IL283760A priority patent/IL283760B2/en
Priority to US17/373,299 priority patent/US11426370B2/en
Priority to US17/380,751 priority patent/US11571417B2/en
Priority to US17/395,222 priority patent/US11426401B2/en
Priority to US17/405,429 priority patent/US11439636B1/en
Priority to US17/468,149 priority patent/US11364233B2/en
Priority to US17/470,831 priority patent/US11576909B2/en
Priority to US17/471,983 priority patent/US11617747B2/en
Priority to US17/473,860 priority patent/US11590124B2/en
Priority to US17/482,241 priority patent/US11285118B2/en
Priority to US17/498,507 priority patent/US20220233518A1/en
Priority to US17/525,339 priority patent/US11517543B2/en
Priority to US17/526,676 priority patent/US11534414B2/en
Priority to US17/456,146 priority patent/US11419867B2/en
Priority to US17/456,459 priority patent/US11382874B2/en
Priority to US17/541,461 priority patent/US20220233470A1/en
Priority to US17/547,050 priority patent/US11433067B2/en
Priority to US17/571,110 priority patent/US20220241221A1/en
Priority to US17/574,378 priority patent/US11571399B2/en
Priority to US17/581,292 priority patent/US11576877B2/en
Priority to US17/693,711 priority patent/US11617728B2/en
Priority to US17/705,930 priority patent/US11478468B2/en
Priority to US17/707,221 priority patent/US11517544B2/en
Priority to US17/657,832 priority patent/US11497721B2/en
Priority to US17/712,970 priority patent/US11510918B2/en
Priority to US17/716,796 priority patent/US11541048B2/en
Priority to US17/717,516 priority patent/US11524007B2/en
Priority to US17/721,827 priority patent/US11517542B2/en
Priority to US17/735,470 priority patent/US11524008B2/en
Priority to US17/748,475 priority patent/US11596627B2/en
Priority to US17/836,560 priority patent/US11628149B2/en
Priority to US17/841,274 priority patent/US11969421B2/en
Priority to US17/821,342 priority patent/US12109178B2/en
Priority to US17/929,147 priority patent/US11779579B2/en
Priority to US17/930,829 priority patent/US20230100913A1/en
Priority to US18/056,804 priority patent/US20230096437A1/en
Priority to US18/056,848 priority patent/US20230142244A1/en
Priority to US18/061,091 priority patent/US20230277478A1/en
Priority to US18/062,236 priority patent/US20230100008A1/en
Priority to US18/062,273 priority patent/US20230270740A1/en
Priority to US18/063,261 priority patent/US20230114111A1/en
Priority to US18/066,739 priority patent/US20230131854A1/en
Priority to US18/179,196 priority patent/US20230218550A1/en
Priority to AU2023203438A priority patent/AU2023203438A1/en
Priority to US18/475,841 priority patent/US20240024309A1/en

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Dextromethorphan is widely used as a cough suppressant.
  • Bupropion is an antidepressant approved for the treatment of depression and smoking cessation.
  • Antidepressant compounds such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be used to improve the therapeutic properties, such as in the treatment of neurological disorders, of dextromethorphan.
  • Bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds regardless of stereochemistry, can be effective in inhibiting or reducing the metabolism of dextromethorphan in some human beings.
  • This may be accomplished by co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan.
  • Some embodiments include a method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.
  • Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering bupropion with dextromethorphan to the human being.
  • Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
  • Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
  • Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering bupropion to a human being in need thereof.
  • Some embodiments include a method of improving the antitussive properties of dextromethorphan comprising administering bupropion in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Some embodiments include a method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human being in need thereof.
  • Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Some embodiments include a method of treating a neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 15 mg/day to about 60 mg/day of dextromethorphan to a human being in need thereof.
  • Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
  • Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
  • Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
  • Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
  • Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
  • Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
  • Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
  • Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
  • Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
  • Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of co-administration of bupropion with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for five consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for six consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.
  • Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for eight consecutive days.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.
  • Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.
  • Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering bupropion with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
  • Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
  • Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
  • Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
  • Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
  • Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
  • Some embodiments include a method of reducing an adverse event associated with treatment by bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with bupropion.
  • Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need thereof.
  • Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
  • Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
  • Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering bupropion in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering hydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering erythrohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering threohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Some embodiments include a method of treating cough comprising administering a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
  • Some embodiments include a method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
  • Some embodiments include a method of treating cough comprising administering a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
  • Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Some embodiments include a method of treating a neurological disorder comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Some embodiments include a method of treating a neurological disorder comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Some embodiments include a method of treating a neurological disorder comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Some embodiments include an oral sustained release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, dextromethorphan, and a water soluble vehicle.
  • Some embodiments include a method of decreasing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, to a human being in need of treatment with dextromethorphan.
  • Some embodiments include a pharmaceutical composition, dosage form, or medicament comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and a pharmaceutically acceptable excipient.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • FIG. 1 is a plot of the mean plasma concentrations of dextromethorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 2 depicts mean AUCo-12 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 3 depicts mean AUCo-2 4 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 4 depicts mean AUCo-inf of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 for subjects administered dextromethorphan alone as compared to dextromethorphan and bupropion.
  • FIG. 6 depicts mean AUCo-12 of dextromethorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 7 depicts mean dextromethorphan trough plasma concentrations for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 8 depicts mean dextromethorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 9 is a plot of the mean plasma concentrations of dextrorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • FIG. 1 1 depicts mean AUCo-12 of dextrorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
  • Some embodiments include a method of treating neurological disorders comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to a person in need thereof.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • Some embodiments include a method of enhancing the therapeutic properties of dextromethorphan in treating neurological disorders, comprising coadministering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • Some embodiments include a method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound, such as bupropion, and dextromethorphan to the human being.
  • an antidepressant compound such as bupropion
  • Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant.
  • an antidepressant compound such as bupropion
  • Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
  • an antidepressant compound such as bupropion
  • Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being in need thereof, such as a human being in need of treatment for pain.
  • an antidepressant compound such as bupropion
  • Some embodiments include a method of improving the therapeutic properties of dextromethorphan in treating neurological disorders comprising administering an antidepressant compound, such as bupropion, in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological disorder.
  • an antidepressant compound such as bupropion
  • Some embodiments include a method of treating neurological disorders comprising administering a combination of an antidepressant compound, such as bupropion, and dextromethorphan to a human being in need thereof.
  • an antidepressant compound such as bupropion
  • Dextromethorphan has the structure shown below.
  • Dextromethorphan is used as a cough suppressant. According to the FDA's dextromethorphan product labeling requirement under the OTC Monograph [21 CFR341 .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.
  • Human 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 dextromethorphan — 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 are a significant portion of the human population. Dextromethorphan can, for example, be metabolized to dextrorphan.
  • 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 antidepressants, such as bupropion inhibit the metabolism of dextromethorphan, and can thus improve its therapeutic efficacy.
  • antidepressants may allow 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.
  • Pain or other neurological disorders may be treated by a method comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to a person in need thereof.
  • an antidepressant compound such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • Examples of neurological disorders that may be treated, or that may be treated with increased efficacy, by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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 a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxy
  • Depression may be manifested by changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation.
  • Physical symptoms of depression may include insomnia, anorexia, weight loss, decreased energy and libido, and abnormal hormonal circadian rhythms.
  • Psychiatric disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, anxiety disorders, including but not limited to, 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolit
  • Substance addiction abuse that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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, and addiction to chewing tobacco.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • psychostimulants e.g.
  • Cerebral function disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer's type dementia, memory loss, amnesia/amnes
  • 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 a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion
  • Dementias that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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 a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
  • ALS amyotrophic lateral sclerosis
  • PPS primary lateral sclerosis
  • PPS primary lateral sclerosis
  • SMA spinal muscular atrophy
  • spinal motor atrophies Tay-Sach's disease
  • Sandoff disease Sandoff disease
  • hereditary spastic paraplegia hereditary spastic paraplegia.
  • Neurodegenerative diseases that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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 leukoencephal
  • Seizure disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, epileptic seizures, nonepil
  • Types of headaches that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, migraine, tension, and cluster headaches.
  • Other neurological disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
  • an antidepressant such as bupropion, hydroxy
  • a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may be used to treat pain, 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.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat dermatitis.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat dermatitis.
  • Pain relieving properties of dextromethorphan may be enhanced by a method comprising co-administering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, with dextromethorphan.
  • an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds
  • Pain relieving properties of bupropion may be enhanced by a method comprising co-administering dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • These methods 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, etc.
  • Examples of musculoskeletal pain include low back pain (i.e. lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondylarthritis including ankylosing spondylitis, etc.
  • low back pain i.e. lumbosacral pain
  • primary dysmenorrhea i.e. lumbosacral pain
  • arthritic pain such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondylarthritis including ankylosing spondylitis, etc.
  • a combination of dextromethorphan and an antidepressant such as bupropion is used to treat chronic musculoskeletal 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.
  • 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.
  • Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan.
  • Dextromethorphan and the antidepressant compound may be administered in separate compositions or dosage forms, or may be administered in a single composition or dosage form comprising both.
  • Antidepressant compounds that can be co-administered with dextromethorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tes
  • Bupropion has the structure shown below (bupropion hydrochloride form shown).
  • Combining bupropion with dextromethorphan may provide greater efficacy, such as greater pain relief, than would otherwise be achieved by administering either component alone.
  • dextromethorphan can be rapidly and extensively metabolized, yielding low systemic exposure even at high doses.
  • Bupropion besides possessing anti-depressant and analgesic properties, is an inhibitor of dextromethorphan metabolism.
  • Metabolites of bupropion which include hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threodihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythrodihydrobupropion), are also inhibitors of dextromethorphan metabolism.
  • bupropion is a prodrug of hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.
  • this inhibition may augment dextromethorphan plasma levels, resulting in additive or synergistic efficacy such as relief of neurological disorders including pain, depression, smoking cessation, etc.
  • co-administration of dextromethorphan with bupropion may thereby enhance the efficacy of bupropion for many individuals.
  • Coadministration of dextromethorphan with bupropion may enhance the analgesic properties of bupropion for many individuals.
  • Co-administration of dextromethorphan with bupropion may also enhance the antidepressant properties of bupropion for many individuals, including faster onset of action.
  • Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful to reduce the potential for an adverse event, such as somnolence, associated with treatment by dextromethorphan. This may be useful, for example, in human patients at risk of experiencing the adverse event as a result being treated with dextromethorphan.
  • Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful to reduce the potential for an adverse event, such as seizure, associated with treatment by bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • This may be useful, for example, in human patients at risk of experiencing the adverse event as a result being treated with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • co-administration may reduce 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, lightheadedness, 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 tone, ataxia, and tongue protrusion.
  • CNS Central nervous system
  • 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.
  • Co-administering dextromethorphan and an antidepressant does not necessarily require that the two compounds be administered in the same dosage form.
  • the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Additionally, the two compounds may be administered at the same time, but this is not required.
  • the compounds can be given at different times as long as both are in a human body at the same time for at least a portion of the time that treatment by co-administration is being carried out.
  • co-administration of a combination of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan results in both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan contributing to the pain relieving properties of the combination.
  • the combination may have improved pain relieving properties as compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, alone or compared to dextromethorphan alone, including potentially faster onset of action.
  • the combination may have improved pain relieving properties of at least about 0.5%, at least about 1 %, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 1 10%, about 1 10% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to bupropion, hydroxybupropion, erythrohydroxybupropion,
  • the combination may have improved pain relieving properties of at least about 0.5%, at least about 1 %, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 1 10%, about 1 10% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to as compared to dextromethorphan alone.
  • any reference to a compound herein such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, 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.
  • deuterium modified dextromethorphan examples include, but are not limited to, those shown below.
  • a dosage form or a composition may be a blend or mixture of dextromethorphan and a compound that inhibits the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, either alone or within a vehicle.
  • dextromethorphan and bupropion 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 bupropion may be substantially uniformly dispersed within a composition or dosage form.
  • dextromethorphan and 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 bupropion in a form that provides sustained release and dextromethorphan in a form that provides immediate release. While there are many ways that sustained release of bupropion may be achieved, in some embodiments bupropion is combined with hydroxypropyl methylcellulose. For example, particles of bupropion hydrochloride 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.
  • METHOCEL® hydroxypropyl methylcellulose
  • Dextromethorphan and/or an antidepressant such as bupropion, hydroxybupropion, threohydrobupropion and erythrohydrobupropion, or a non- bupropion antidepressant (all of which are referred to collectively herein as "therapeutic compounds" for convenience) 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.
  • 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.
  • Therapeutic compounds may be administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient.
  • the compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents.
  • they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
  • Therapeutic compounds 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; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.
  • the ratio of dextromethorphan to bupropion may vary.
  • the weight ratio of dextromethorphan to bupropion may be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1 , about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1 , about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
  • a ratio of 0.1 indicates that the weight of dextromethorphan is 1/10 that of bupropion.
  • a ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.
  • the amount of dextromethorphan in a therapeutic composition may vary.
  • some liquid compositions may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 0.001 % (w/v) to about 1 % (w/v), about 0.1 % (w/v) to about 0.5% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v), or about
  • Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 1 10 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.
  • 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 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.
  • Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 1 10 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.
  • the amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, in a therapeutic composition may vary. If increasing the plasma level of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, should be administered in an amount that increases the plasma level of dextromethorphan.
  • bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times, the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may administered to a human being in an amount that results in a 12 hour area under the curve from the time of dosing (AUCo- 12 ), or average plasma concentration in the human being for the 12 hours following dosing (C av g) of dextromethorphan, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may administered to a human being in an amount that results in a maximum plasma concentration (C ma x) of dextromethorphan in the human being, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • C ma x maximum plasma concentration
  • an increase in the dextromethorphan plasma level can occur on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered, as compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite of prodrug of any of these compounds.
  • the dextromethorphan plasma level on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least about 1 .5 times, at least about at least 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • the dextromethorphan AUC on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the AUC that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • the dextromethorphan C m ax on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the C ma x that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • the dextromethorphan trough level (e.g. plasmal level 12 hours after administration) on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the trough level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
  • the dextrorphan plasma level on the first day may be reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds are co-administered for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite of prodrug of any of these compounds, for five consecutive days.
  • the dextromethorphan plasma level on the fifth day may be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for five consecutive days.
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for six consecutive days.
  • the dextromethorphan plasma level on the sixth day may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for six consecutive days.
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered for at least seven consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the seventh day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for seven consecutive days.
  • the dextromethorphan plasma level on the seventh day may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for seven consecutive days.
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering bupropion with dextromethorphan that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1 ,000 times, the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or
  • bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for eight consecutive days.
  • the dextrorphan plasma level on the eighth day may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for eight consecutive days.
  • bupropion may be administered to a human being in an amount that results in an AUCo-12 of bupropion in the human being, on day 8, that is at least about 100 ng » hr/ml_, at least about 200 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 800 ng » hr/ml_, at least about 900 ng » hr/ml_, at least about 1 ,000 ng » hr/ml_, at least about 1 ,200 ng » hr/ml_, at least 1 ,600 ng » hr/ml_, or up to about 15,000 ng » hr/ml_.
  • bupropion may be administered to a human being in an amount that results in a C av g of bupropion in the human being, on day 8, that is at least about 10 ng/mL, at least about 20 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, at least about 100 ng/mL, at least 120 ng/mL, or up to about 1 ,500 ng/mL.
  • bupropion may be administered to a human being in an amount that results in a C ma x of bupropion in the human being, on day 8, that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 50 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 1 10 ng/mL, at least about 120 ng/mL, at least about 130 ng/mL, at least about 140 ng/mL, at least 200 ng/mL, or up to about 1 ,500 ng/mL.
  • Some liquid compositions may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
  • Some liquid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 1 10 mg to about 140 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
  • 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 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
  • Some solid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 1 10 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
  • bupropion is administered at a dose that results in a bupropion plasma level of about 0.1 ⁇ to about 10 ⁇ , about 0.1 ⁇ to about 5 ⁇ , about 0.2 ⁇ to about 3 ⁇ , 0.1 ⁇ to about 1 ⁇ , about 0.2 ⁇ to about 2 ⁇ , 1 ⁇ to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , about 2 ⁇ to about 3 ⁇ , or about 2.8 ⁇ to about 3 ⁇ , about 1 .5 ⁇ to about 2 ⁇ , about 4.5 ⁇ to about 5 ⁇ , about 2.5 ⁇ to about 3 ⁇ , about 1 .8 ⁇ , about 4.8 ⁇ , about 2.9 ⁇ , about 2.8 ⁇ , or any plasma level in a range bounded by, or between, any of these values.
  • bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered at a dose that results in a hydroxybupropion plasma level of about 0.1 ⁇ to about 10 ⁇ , about 0.1 ⁇ to about 5 ⁇ , about 0.2 ⁇ to about 3 ⁇ , 0.1 ⁇ to about 1 ⁇ , about 0.2 ⁇ to about 2 ⁇ , 1 ⁇ to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , about 2 ⁇ to about 3 ⁇ , or about 2.8 ⁇ to about 3 ⁇ , about 1 .5 ⁇ to about 2 ⁇ , about 4.5 ⁇ to about 5 ⁇ , about 2.5 ⁇ to about 3 ⁇ , about 1 .8 ⁇ , about 4.8 ⁇ , about 2.9 ⁇ , about 2.8 ⁇ , or any plasma level in a range bounded by, or between, any of these values.
  • bupropion, hydroxybupropion, or a prodrug of hydroxybupropion may be administered to a human being in an amount that results in an AUCo-12 of hydroxybupropion in the human being, on day 8, that is at least about 3,000 ng » hr/mL, at least about 7,000 ng » hr/mL, at least about 10,000 ng » hr/ml_, at least about 15,000 ng » hr/ml_, at least about 20,000 ng » hr/ml_, at least about 30,000 ng » hr/mL, up to about 50,000 ng » hr/mL, up to about 150,000 ng » hr/mL, or any AUC in a range bounded by, or between, any of these values.
  • bupropion, hydroxybupropion, or a prodrug of hydroxybupropion may be administered to a human being in an amount that results in a Cmax of hydroxybupropion in the human being, on day 8, that is at least about 300 ng/mL, at least about 700 ng/mL, at least about 1 ,000 ng/mL, at least about 1 ,500 ng/mL, at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any C ma x in a range bounded by, or between, any of these values.
  • bupropion, hydroxybupropion, or a prodrug of hydroxybupropion may be administered to a human being in an amount that results in a C av g of hydroxybupropion in the human being, on day 8, that is at least about 200 ng/mL, at least about 300 ng/mL, at least about 700 ng/mL, at least about 1 ,000 ng/mL, at least about 1 ,500 ng/mL, at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any C avg in a range bounded by, or between, any of these values.
  • bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is administered at a dose that results in a threohydroxybupropion plasma level of about 0.1 ⁇ to about 10 ⁇ , about 0.1 ⁇ to about 5 ⁇ , about 0.2 ⁇ to about 3 ⁇ , 0.1 ⁇ to about 1 ⁇ , about 0.2 ⁇ to about 2 ⁇ , 1 ⁇ to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , about 2 ⁇ to about 3 ⁇ , or about 2.8 ⁇ to about 3 ⁇ , about 1 .5 ⁇ to about 2 ⁇ , about 4.5 ⁇ to about 5 ⁇ , about 2.5 ⁇ to about 3 ⁇ , about 1 .8 ⁇ , about 4.8 ⁇ , about 2.9 ⁇ , about 2.8 ⁇ , or any plasma level in a range bounded by, or between, any of these values.
  • bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion may be administered to a human being in an amount that results in an AUCo-12 of threohydroxybupropion in the human being, on day 8, that is at least about 1 ,000 ng » hr/mL, at least about 2,000 ng » hr/mL, at least about 4,000 ng » hr/mL, at least about 5,000 ng » hr/mL, at least about 8,000 ng » hr/mL, up to about 10,000 ng » hr/mL, up to about 40,000 ng » hr/mL, or any AUC in a range bounded by, or between, any of these values.
  • bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion may be administered to a human being in an amount that results in a C ma x of threohydroxybupropion in the human being, on day 8, that is at least about 100 ng/mL, at least about 200 ng/mL, at least about 400 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any C ma x in a range bounded by, or between, any of these values.
  • bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion may be administered to a human being in an amount that results in a C av g of threohydroxybupropion in the human being, on day 8, that is at least about 100 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least about 600 ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any C avg in a range bounded by, or between, any of these values.
  • bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion is administered at a dose that results in an erythrohydroxybupropion plasma level of about 0.1 ⁇ to about 10 ⁇ , about 0.1 ⁇ to about 5 ⁇ , about 0.2 ⁇ to about 3 ⁇ , 0.1 ⁇ to about 1 ⁇ , about 0.2 ⁇ to about 2 ⁇ , 1 ⁇ to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , about 2 ⁇ to about 3 ⁇ , or about 2.8 ⁇ to about 3 ⁇ , about 1 .5 ⁇ to about 2 ⁇ , about 4.5 ⁇ to about 5 ⁇ , about 2.5 ⁇ to about 3 ⁇ , about 1 .8 ⁇ , about 4.8 ⁇ , about 2.9 ⁇ , about 2.8 ⁇ , or any plasma level in a range bounded by, or between, any of these values.
  • bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion may be administered to a human being in an amount that results in an AUCo-12 of erythrohydroxybupropion in the human being, on day 8, that is at least about 200 ng » hr/ml_, at least about 400 ng » hr/ml_, at least about 700 ng » hr/ml_, at least about 1 ,000 ng » hr/ml_, at least about 1 ,500 ng » hr/ml_, at least about 3,000 ng » hr/ml_, up to about 5,000 ng » hr/ml_, up to about 30,000 ng » hr/ml_, or any plasma level in a range bounded by, or between, any of these values.
  • bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion may be administered to a human being in an amount that results in a C m ax of erythrohydroxybupropion in the human being, on day 8, that is at least about 30 ng/mL, at least about 60 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1 ,000 ng/mL, or any C ma x in a range bounded by, or between, any of these values.
  • bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion may be administered to a human being in an amount that results in a C av g of erythrohydroxybupropion in the human being, on day 8, that is at least about 20 ng/mL, at least about 30 ng/mL, at least about 50 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1 ,000 ng/mL, up to about 5,000 ng/mL, or any C avg in a range bounded by, or between, any of these values.
  • compositions comprising both dextromethorphan and bupropion
  • some liquids may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphan and bupropion combined, or any amount in
  • 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 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) of dextromethorphan and bupropion combined, or any amount in a range bounded by, or between, any of these values.
  • the weight ratio of dextromethorphan to bupropion in a single composition or dosage form may be about 0.1 to about 2, about 0.2 to about 1 , about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1 , about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
  • a therapeutically effective amount of a therapeutic compound may vary depending upon the circumstances.
  • a daily dose of dextromethorphan may in some instances range from about 0.1 mg to about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg, about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg,
  • a daily dose of bupropion may in some instances range from about 10 mg to about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about 2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or any daily dose in a range bounded by, or between, any of these values.
  • Bupropion may be administered once daily; or twice daily or every 12 hours, or three times daily in an amount that is about half or one third, respectively, of the
  • [00175] in some embodiments: 1 ) about 50 mg/day to about 100 mg/day, about 100 mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about 150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day, about 250 mg/day to about 300 mg/day of bupropion, or about 300 mg/day to about 500 mg/day of bupropion; and/or 2) about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 1 10 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan, are administered to a human being in need thereof.
  • about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan.
  • about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.
  • about 75 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan.
  • about 75 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan.
  • An antidepressant compound such as bupropion
  • an antidepressant compound, such as bupropion, and dextromethorphan are administered at least once a day, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.
  • Therapeutic compounds 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 tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Tablets, troches, pills, capsules and the like 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 stearate
  • a sweetening agent such as sucrose, lactose, or saccharin
  • 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.
  • Therapeutic compounds 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, such as hydroxypropylcellulose.
  • 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.
  • Embodiment 1 A method of treating pain or a neurological disorder comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound, to a person in need thereof.
  • Embodiment 2 A method of treating pain comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
  • Embodiment 3 A method of enhancing the pain relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound.
  • Embodiment 4 A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound to the human being receiving a treatment that includes administration of dextromethorphan.
  • Embodiment 5 A method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
  • Embodiment 6 A method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
  • Embodiment 7 A method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being in need thereof.
  • Embodiment 8 A method of improving pain relieving properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for pain.
  • Embodiment 9 A method of improving antitussive properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
  • Embodiment 10 A method of treating cough comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
  • Embodiment 11 A method of improving a therapeutic property of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological disorder.
  • Embodiment 12 A method of treating a neurological disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
  • Embodiment 13 A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.
  • Embodiment 14 The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms.
  • Embodiment 15 A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient.
  • Embodiment 16 An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound to inhibit the metabolism of dextromethorphan in a human being that is an extensive metabolizer of dextromethorphan.
  • Embodiment 17 The oral dosage form of embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form.
  • Embodiment 18 The oral dosage form of embodiment 16 or 17, wherein about 100 mg to about 400 mg of bupropion is present in the dosage form.
  • Embodiment 19 The oral dosage form of any of embodiments 16, 17, or 18, comprising an amount of bupropion that results in a bupropion plasma level of about 0.1 ⁇ to about 10 ⁇ when the oral dosage form is administered to a human being.
  • Embodiment 20 The oral dosage form of embodiment 19, comprising an amount of bupropion that results in a bupropion plasma level of about 0.1 ⁇ to about 2 ⁇ when the oral dosage form is administered to a human being.
  • Embodiment 21 The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 ,
  • bupropion is administered at a dose that results in a bupropion plasma level of about 0.1 ⁇ to about 10 ⁇ .
  • Embodiment 22 The method of embodiment 21 , wherein bupropion is administered at a dose that results in a bupropion plasma level of about 0.3 ⁇ to about 1 ⁇ .
  • Embodiment 23 The method, composition, or dosage form of any of embodiments 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion or a metabolite thereof.
  • Embodiment 24 The method, composition, or dosage form of any of embodiments 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion.
  • Embodiment 25 The method, composition, or dosage form of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, or a pharmaceutically acceptable salt thereof
  • Embodiment 26 The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 1 1 , 12,
  • Embodiment 27 A method of treating a neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 30 mg/day to about 120 mg/day of dextromethorphan to a human being in need thereof.
  • Embodiment 28 A method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
  • Embodiment 29 The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, or 27, wherein bupropion is administered to the human being at least daily for at least 8 days.
  • Embodiment 30 The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, 27, or 28, wherein dexromethorphan is administered to the human being at least daily for at least 8 days.
  • Embodiment 31 The method of embodiment 28, 29, or 30, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without bupropion.
  • Embodiment 32 The method of embodiment 28, 29, 30, or 31 , wherein bupropion is administered in an amount that results in an AUCo-12 of hydroxybupropion, on day 8, that is at least about 3000 ng-hr/mL.
  • Embodiment 33 The method of embodiment 28, 29, 30, 31 , or 32, wherein bupropion is administered in an amount that results in an AUCo-12 of erythrohydroxybupropion, on day 8, that is at least about 400 ng-hr/mL.
  • Embodiment 34 The method of embodiment 28, 29, 30, 31 , 32, or 33, wherein bupropion is administered in an amount that results in an AUCo-12 of threohydroxybupropion, on day 8, that is at least about 2000 ng-hr/mL.
  • Embodiment 35 The method, composition, or dosage form of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the weight ratio of dextromethorphan to bupropion is about 0.1 to about 0.5.
  • Embodiment 36 The method of embodiment 27, 28, 29, 30, 31 , 32, 33, 34, or 35, wherein the human being is an extensive metabolizer of dextromethorphan.
  • Embodiment 37 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
  • Embodiment 38 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
  • Embodiment 39 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
  • Embodiment 40 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan.
  • Embodiment 41 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
  • Embodiment 42 The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.
  • Embodiment 43 The method of embodiment 4, 5, 6, 7, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , or 42, wherein dextromethorphan is administered to the human being for the treatment of pain.
  • Embodiment 44 The method of embodiment 43, wherein the pain comprises postoperative pain, cancer pain, arthritic pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain.
  • Embodiment 45 The method of embodiment 43, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.
  • Embodiment 46 The method of embodiment 43, wherein the pain comprises postoperative pain.
  • Embodiment 47 The method of embodiment 43, wherein the pain comprises cancer pain.
  • Embodiment 48 The method of embodiment 43, wherein the pain comprises arthritic pain.
  • Embodiment 49 The method of embodiment 43, wherein the pain comprises lumbosacral pain.
  • Embodiment 50 The method of embodiment 43, wherein the pain comprises musculoskeletal pain.
  • Embodiment 51 The method of embodiment 43, wherein the pain comprises neuropathic pain.
  • Embodiment 52 The method of embodiment 43, wherein the pain comprises nociceptive pain.
  • Embodiment 53 The method of embodiment 43, wherein the pain comprises chronic musculoskeletal pain.
  • Embodiment 54 The method of embodiment 43, wherein the pain is associated with rheumatoid arthritis.
  • Embodiment 55 The method of embodiment 43, wherein the pain is associated with juvenile rheumatoid arthritis.
  • Embodiment 56 The method of embodiment 43, wherein the pain is associated with osteoarthritis.
  • Embodiment 57 The method of embodiment 43, wherein the pain is associated with an axial spondyloarthritis.
  • Embodiment 58 The method of embodiment 43, wherein the pain is associated with ankylosing spondylitis.
  • Embodiment 59 The method of embodiment 43, wherein the pain is associated with diabetic peripheral neuropathy.
  • Embodiment 60 The method of embodiment 43, wherein the pain is associated with post-herpetic neuralgia.
  • Embodiment 61 The method of embodiment 43, wherein the pain is associated with trigeminal neuralgia.
  • Embodiment 62 The method of embodiment 43, wherein the pain is associated with monoradiculopathies.
  • Embodiment 63 The method of embodiment 43, wherein the pain is associated with phantom limb pain.
  • Embodiment 64 The method of embodiment 43, wherein the pain is associated with central pain.
  • Embodiment 65 The method of embodiment 43, wherein the pain comprises cancer-related pain.
  • Embodiment 66 The method of embodiment 43, wherein the pain is associated with lumbar nerve root compression.
  • Embodiment 67 The method of embodiment 43, wherein the pain is associated with spinal cord injury.
  • Embodiment 68 The method of embodiment 43, wherein the pain is associated with post-stroke pain.
  • Embodiment 69 The method of embodiment 43, wherein the pain is associated with central multiple sclerosis pain.
  • Embodiment 70 The method of embodiment 43, wherein the pain is associated with HIV-associated neuropathy.
  • Embodiment 71 The method of embodiment 43, wherein the pain is associated with radio-therapy associated neuropathy.
  • Embodiment 72 The method of embodiment 43, wherein the pain is associated with chemo-therapy associated neuropathy.
  • Embodiment 73 The method of embodiment 43, wherein the pain comprises dental pain.
  • Embodiment 74 The method of embodiment 43, wherein the pain is associated with primary dysmenorrhea.
  • Embodiment 75 The method of embodiment 4, 5, 6, 7, 9, 10, 1 1 , 12, 13,
  • Embodiment 76 The method of embodiment 75, wherein 45 mg of dextromethorphan is administered twice a day to the human being.
  • Embodiment 77 The method of embodiment 75 or 76, wherein 150 mg/day of bupropion is administered to the human being.
  • Embodiment 78 The method of embodiment 75 or 76, wherein 180 mg/day of bupropion is administered to the human being.
  • Embodiment 79 The method of embodiment 75 or 76, wherein 200 mg/day of bupropion is administered to the human being.
  • Embodiment 80 The method of claim 123 or 124, wherein 300 mg/day of bupropion is administered to the human being.
  • United States Provisional Application No. 61/900,354 is incorporated by reference herein in its entirety.
  • Dextromethorphan was dosed at 12-hour intervals on Days 1 -8, with a final morning dose on Day 8.
  • Bupropion was dosed once daily on Days 1 -3, and at 12-hour intervals thereafter, with a final morning dose on Day 8.
  • Plasma samples were collected for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8. Plasma samples for determination of trough concentrations of dextromethorphan were obtained approximately 12 hours after dosing on days 1 , 5, 6, and 8.
  • the AUC of dextromethorphan was significantly increased with administration of bupropion as show in Figs. 2-4.
  • administration of bupropion with dextromethorphan resulted in an approximately 60-fold, 80-fold, and 175-fold increase in mean dextromethorphan AUCo-12, AUC 0 -2 4 , and AUCo-inf, respectively on Day 8 as compared to administration of dextromethorphan alone.
  • the increase in dextromethorphan AUC occurred as early as Day 1 (an approximate 3-fold increase in AUC 0 -12)-
  • Trough plasma concentrations of dextromethorphan were significantly increased with administration of bupropion as illustrated in Fig. 7 and Table 3.
  • Administration of bupropion with dextromethorphan resulted in an approximately 105-fold increase in mean trough plasma concentration of dextromethorphan on Day 8 as compared to administration of dextromethorphan alone.
  • T max and elimination half life (Ti/ 2 e i) of dextromethorphan were significantly increased with administration of bupropion on Day 8.
  • Administration of bupropion with dextromethorphan resulted in a mean T max of 3.6 hours, compared to 2.3 hours for dextromethorphan alone.
  • Administration of bupropion with dextromethorphan resulted in a mean Ti/ 2 e i of 27.7 hours, compared to 6.6 hours for dextromethorphan alone.
  • Plasma concentrations of dextrorphan were significantly decreased with bupropion administration, as illustrated in Fig. 9 and Table 4.
  • average plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were at least 10 ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropion administration.
  • fold change or “fold increase” refers to the ratio of a value for bupropion with dextromethorphan to the same value for dextromethorphan alone (i.e. the value for bupropion with dextromethorphan divided by the same value for dextromethorphan alone).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

This disclosure relates to a method of treating a neurological disorder by administering an antidepressant compound and dextromethorphan to a human being in need thereof. This method may be useful for human beings that are extensive metabolizers of dextromethorphan. Compositions, medicaments, and dosage forms comprising antidepressant compounds and dextromethorphan are also described.

Description

COMPOSITIONS AND METHODS COMPRISING BUPROPION OR RELATED COMPOUNDS AND DEXTROMETHORPHAN
Inventor: Herriot Tabuteau
BACKGROUND
[0001] Dextromethorphan is widely used as a cough suppressant. Bupropion is an antidepressant approved for the treatment of depression and smoking cessation.
SUMMARY
[0002] Antidepressant compounds, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, can be used to improve the therapeutic properties, such as in the treatment of neurological disorders, of dextromethorphan. Bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, regardless of stereochemistry, can be effective in inhibiting or reducing the metabolism of dextromethorphan in some human beings. This may be accomplished by co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan.
[0003] Some embodiments include a method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.
[0004] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering bupropion with dextromethorphan to the human being.
[0005] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion. [0006] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
[0007] Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering bupropion to a human being in need thereof.
[0008] Some embodiments include a method of improving the antitussive properties of dextromethorphan comprising administering bupropion in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
[0009] Some embodiments include a method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human being in need thereof.
[0010] Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
[0011] Some embodiments include a method of treating a neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 15 mg/day to about 60 mg/day of dextromethorphan to a human being in need thereof.
[0012] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
[0013] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
[0014] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
[0015] Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
[0016] Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
[0017] Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
[0018] Some embodiments include a method of inhibiting metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
[0019] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
[0020] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
[0021] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
[0022] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of co-administration of bupropion with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
[0023] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof. [0024] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
[0025] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
[0026] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for five consecutive days.
[0027] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.
[0028] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.
[0029] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.
[0030] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.
[0031] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for six consecutive days.
[0032] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.
[0033] Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.
[0034] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
[0035] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.
[0036] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
[0037] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
[0038] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.
[0039] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for eight consecutive days.
[0040] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.
[0041] Some embodiments include a method of decreasing dextrorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.
[0042] Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering bupropion with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
[0043] Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
[0044] Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
[0045] Some embodiments include a method of reducing a trough effect of dextromethorphan comprising, co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after coadministering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
[0046] Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
[0047] Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
[0048] Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
[0049] Some embodiments include a method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
[0050] Some embodiments include a method of reducing an adverse event associated with treatment by bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with bupropion.
[0051] Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need thereof.
[0052] Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
[0053] Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
[0054] Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering bupropion in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
[0055] Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering hydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
[0056] Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering erythrohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
[0057] Some embodiments include a method of improving antitussive properties of dextromethorphan comprising administering threohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
[0058] Some embodiments include a method of treating cough comprising administering a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
[0059] Some embodiments include a method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
[0060] Some embodiments include a method of treating cough comprising administering a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
[0061] Some embodiments include a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
[0062] Some embodiments include a method of treating a neurological disorder comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
[0063] Some embodiments include a method of treating a neurological disorder comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
[0064] Some embodiments include a method of treating a neurological disorder comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
[0065] Some embodiments include an oral sustained release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, dextromethorphan, and a water soluble vehicle. [0066] Some embodiments include a method of decreasing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, to a human being in need of treatment with dextromethorphan.
[0067] Some embodiments include a pharmaceutical composition, dosage form, or medicament comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and a pharmaceutically acceptable excipient.
BRIEF DESCRIPTION OF THE DRAWINGS
[0068] FIG. 1 is a plot of the mean plasma concentrations of dextromethorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0069] FIG. 2 depicts mean AUCo-12 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0070] FIG. 3 depicts mean AUCo-24 of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0071] FIG. 4 depicts mean AUCo-inf of dextromethorphan on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0072] FIG. 5 depicts the fold changes in AUCs of dextromethorphan on Day 8 for subjects administered dextromethorphan alone as compared to dextromethorphan and bupropion.
[0073] FIG. 6 depicts mean AUCo-12 of dextromethorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0074] FIG. 7 depicts mean dextromethorphan trough plasma concentrations for subjects administered dextromethorphan alone or dextromethorphan and bupropion. [0075] FIG. 8 depicts mean dextromethorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0076] FIG. 9 is a plot of the mean plasma concentrations of dextrorphan over time after dosing on Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0077] FIG. 10 depicts mean dextrorphan maximum plasma concentrations on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
[0078] FIG. 1 1 depicts mean AUCo-12 of dextrorphan on Day 1 and Day 8 for subjects administered dextromethorphan alone or dextromethorphan and bupropion.
DETAILED DESCRIPTION
[0079] Some embodiments include a method of treating neurological disorders comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to a person in need thereof.
[0080] Some embodiments include a method of enhancing the therapeutic properties of dextromethorphan in treating neurological disorders, comprising coadministering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[0081] Some embodiments include a method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound, such as bupropion, and dextromethorphan to the human being.
[0082] Some embodiments include a method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant. [0083] Some embodiments include a method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
[0084] Some embodiments include a method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human being in need thereof, such as a human being in need of treatment for pain.
[0085] Some embodiments include a method of improving the therapeutic properties of dextromethorphan in treating neurological disorders comprising administering an antidepressant compound, such as bupropion, in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological disorder.
[0086] Some embodiments include a method of treating neurological disorders comprising administering a combination of an antidepressant compound, such as bupropion, and dextromethorphan to a human being in need thereof.
[0087] Dextromethorphan has the structure shown below.
Figure imgf000017_0001
[0088] Dextromethorphan is used as a cough suppressant. According to the FDA's dextromethorphan product labeling requirement under the OTC Monograph [21 CFR341 .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).
[0089] Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are extensive metabolizers. Human 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 dextromethorphan — 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 are a significant portion of the human population. Dextromethorphan can, for example, be metabolized to dextrorphan.
[0090] 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 antidepressants, such as bupropion, inhibit the metabolism of dextromethorphan, and can thus improve its therapeutic efficacy. Similarly, antidepressants may allow 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.
[0091] Pain or other neurological disorders may be treated by a method comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to a person in need thereof.
[0092] Examples of neurological disorders that may be treated, or that may be treated with increased efficacy, by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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. [0093] Affective disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorders including cyclothymia, seasonal affective disorder, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), and attention deficit/hyperactivity disorder (AD/HD), bipolar and manic conditions, obsessive-compulsive disorder, bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.
[0094] Depression may be manifested by changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical symptoms of depression may include insomnia, anorexia, weight loss, decreased energy and libido, and abnormal hormonal circadian rhythms.
[0095] Psychiatric disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, include, but are not limited to, anxiety disorders, including but not limited to, 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.
[0096] Substance addiction abuse that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, 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, and addiction to chewing tobacco.
[0097] Cerebral function disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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. 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.
[0098] Movement disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
[0099] Dementias that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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. [00100] Motor neuron diseases that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
[00101] Neurodegenerative diseases that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraparesis, neurofibromatosis, olivopontine cerebellar atrophy or degeneration, striatonigral degeneration, Guillain- Barre syndrome, and spastic paraplesia.
[00102] Seizure disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
[00103] Types of headaches that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, migraine, tension, and cluster headaches.
[00104] Other neurological disorders that may be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds 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.
[00105] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may be used to treat pain, 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.
[00106] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may be used to treat dermatitis.
[00107] Pain relieving properties of dextromethorphan may be enhanced by a method comprising co-administering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, with dextromethorphan.
[00108] Pain relieving properties of bupropion may be enhanced by a method comprising co-administering dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00109] These methods 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, etc.
[00110] Examples of musculoskeletal pain include low back pain (i.e. lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondylarthritis including ankylosing spondylitis, etc.
[00111] In some embodiments, a combination of dextromethorphan and an antidepressant, such as bupropion, is used to treat chronic musculoskeletal pain.
[00112] Examples of neuropathic pain 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.
[00113] The term "treating" or "treatment" 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.
[00114] Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. Dextromethorphan and the antidepressant compound may be administered in separate compositions or dosage forms, or may be administered in a single composition or dosage form comprising both.
[00115] Antidepressant compounds that can be co-administered with dextromethorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid, iproclozide, toloxatone, butriptyline, dosulepin, dibenzepin, iphndole, lofepramine, opipramol, norfluoxetine, dapoxetine, etc., or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds.
[00116] Bupropion has the structure shown below (bupropion hydrochloride form shown).
Figure imgf000024_0001
[00117] Combining bupropion with dextromethorphan may provide greater efficacy, such as greater pain relief, than would otherwise be achieved by administering either component alone. In extensive metabolizers, dextromethorphan can be rapidly and extensively metabolized, yielding low systemic exposure even at high doses. Bupropion, besides possessing anti-depressant and analgesic properties, is an inhibitor of dextromethorphan metabolism. Metabolites of bupropion, which include hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threodihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythrodihydrobupropion), are also inhibitors of dextromethorphan metabolism. Thus, bupropion is a prodrug of hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.
[00118] As explained above, this inhibition may augment dextromethorphan plasma levels, resulting in additive or synergistic efficacy such as relief of neurological disorders including pain, depression, smoking cessation, etc. Thus, while inhibition of dextromethorphan metabolism is only one of many potential benefits of the combination, co-administration of dextromethorphan with bupropion may thereby enhance the efficacy of bupropion for many individuals. Coadministration of dextromethorphan with bupropion may enhance the analgesic properties of bupropion for many individuals. Co-administration of dextromethorphan with bupropion may also enhance the antidepressant properties of bupropion for many individuals, including faster onset of action.
[00119] Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful to reduce the potential for an adverse event, such as somnolence, associated with treatment by dextromethorphan. This may be useful, for example, in human patients at risk of experiencing the adverse event as a result being treated with dextromethorphan.
[00120] Another potential benefit of co-administration of dextromethorphan and bupropion is that it may be useful to reduce the potential for an adverse event, such as seizure, associated with treatment by bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. This may be useful, for example, in human patients at risk of experiencing the adverse event as a result being treated with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00121] With respect to dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, co-administration may reduce 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, lightheadedness, 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 tone, ataxia, and tongue protrusion.
[00122] 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.
[00123] Co-administering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. Additionally, the two compounds may be administered at the same time, but this is not required. The compounds can be given at different times as long as both are in a human body at the same time for at least a portion of the time that treatment by co-administration is being carried out.
[00124] In some embodiments, co-administration of a combination of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan results in both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan contributing to the pain relieving properties of the combination. For example, the combination may have improved pain relieving properties as compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, alone or compared to dextromethorphan alone, including potentially faster onset of action.
[00125] In some embodiments, the combination may have improved pain relieving properties of at least about 0.5%, at least about 1 %, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 1 10%, about 1 10% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, alone.
[00126] In some embodiments, the combination may have improved pain relieving properties of at least about 0.5%, at least about 1 %, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 1 10%, about 1 10% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief in a range bounded by, or between, any of these values, as compared to as compared to dextromethorphan alone.
[00127] Unless otherwise indicated, any reference to a compound herein, such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, by structure, name, or any other means, includes pharmaceutically acceptable salts; alternate solid forms, such as polymorphs, 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.
[00128] Examples of deuterium modified dextromethorphan include, but are not limited to, those shown below.
Figure imgf000028_0001
[00129] A dosage form or a composition may be a blend or mixture of dextromethorphan and a compound that inhibits the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, either alone or within a vehicle. For example, dextromethorphan and bupropion 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. In some embodiments, dextromethorphan and bupropion may be substantially uniformly dispersed within a composition or dosage form. Alternatively, dextromethorphan and bupropion may be in separate domains or phases within a composition or dosage form. For example, one drug may be in a coating and another drug may be in a core within the coating. For example, one drug may be formulated for sustained release and another drug may be formulated for immediate release. [00130] Some embodiments include administration of a tablet that contains bupropion in a form that provides sustained release and dextromethorphan in a form that provides immediate release. While there are many ways that sustained release of bupropion may be achieved, in some embodiments bupropion is combined with hydroxypropyl methylcellulose. For example, particles of bupropion hydrochloride 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.
[00131] Dextromethorphan and/or an antidepressant, such as bupropion, hydroxybupropion, threohydrobupropion and erythrohydrobupropion, or a non- bupropion antidepressant (all of which are referred to collectively herein as "therapeutic compounds" for convenience) 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. 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.
[00132] Therapeutic compounds may be administered by any means that may result in the contact of the active agent(s) with the desired site or site(s) of action in the body of a patient. The compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. For example, they may be administered as the sole active agents in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.
[00133] Therapeutic compounds 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; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic. [00134] The ratio of dextromethorphan to bupropion may vary. In some embodiments, the weight ratio of dextromethorphan to bupropion may be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1 , about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1 , about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values. A ratio of 0.1 indicates that the weight of dextromethorphan is 1/10 that of bupropion. A ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.
[00135] The amount of dextromethorphan in a therapeutic composition may vary. For example, some liquid compositions may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 0.001 % (w/v) to about 1 % (w/v), about 0.1 % (w/v) to about 0.5% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of dextromethorphan.
[00136] Some liquid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 80 mg to about 100 mg, about 1 10 mg to about 130 mg, about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.
[00137] 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 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of dextromethorphan.
[00138] Some solid dosage forms may contain about 10 mg to about 500 mg, about 30 mg to about 350 mg, about 20 mg to about 50 mg, about 30 mg to about 60 mg, about 40 mg to about 50 mg, about 40 mg to about 42 mg, about 42 mg to about 44 mg, about 44 mg to about 46 mg, about 46 mg to about 48 mg, about 48 mg to about 50 mg, about 50 mg to about 200 mg, about 50 mg to about 70 mg, about 80 mg to about 100 mg, about 1 10 mg to about 130 mg, about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by, or between, any of these values.
[00139] The amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, in a therapeutic composition may vary. If increasing the plasma level of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, should be administered in an amount that increases the plasma level of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may be administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times, the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00140] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may administered to a human being in an amount that results in a 12 hour area under the curve from the time of dosing (AUCo-12), or average plasma concentration in the human being for the 12 hours following dosing (Cavg) of dextromethorphan, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00141] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, may administered to a human being in an amount that results in a maximum plasma concentration (Cmax) of dextromethorphan in the human being, on day 8, that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00142] For co-administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, an increase in the dextromethorphan plasma level can occur on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered, as compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite of prodrug of any of these compounds. For example, the dextromethorphan plasma level on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least about 1 .5 times, at least about at least 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. [00143] In some embodiments, the dextromethorphan AUC on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the AUC that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00144] In some embodiments, the dextromethorphan Cmax on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the Cmax that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00145] In some embodiments, the dextromethorphan trough level (e.g. plasmal level 12 hours after administration) on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered may be at least twice the trough level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.
[00146] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextrorphan plasma level on the first day may be reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion. [00147] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, are co-administered for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite of prodrug of any of these compounds, for five consecutive days. For example, the dextromethorphan plasma level on the fifth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for five consecutive days.
[00148] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan, are co-administered for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for six consecutive days. For example, the dextromethorphan plasma level on the sixth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 75 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for six consecutive days. [00149] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan, are co-administered for at least seven consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the seventh day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for seven consecutive days. For example, the dextromethorphan plasma level on the seventh day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 70 times, at least 80 times, at least 90 times, or up to about 500 times, the level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for seven consecutive days.
[00150] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan, are co-administered for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level, for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours, after co-administering bupropion with dextromethorphan that is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1 ,000 times, the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for eight consecutive days.
[00151] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, and dextromethorphan are co-administered for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for eight consecutive days. For example, the dextrorphan plasma level on the eighth day (for example at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) may be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%, as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, for eight consecutive days.
[00152] In some embodiments, bupropion may be administered to a human being in an amount that results in an AUCo-12 of bupropion in the human being, on day 8, that is at least about 100 ng»hr/ml_, at least about 200 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 800 ng»hr/ml_, at least about 900 ng»hr/ml_, at least about 1 ,000 ng»hr/ml_, at least about 1 ,200 ng»hr/ml_, at least 1 ,600 ng»hr/ml_, or up to about 15,000 ng»hr/ml_.
[00153] In some embodiments, bupropion may be administered to a human being in an amount that results in a Cavg of bupropion in the human being, on day 8, that is at least about 10 ng/mL, at least about 20 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, at least about 100 ng/mL, at least 120 ng/mL, or up to about 1 ,500 ng/mL.
[00154] In some embodiments, bupropion may be administered to a human being in an amount that results in a Cmax of bupropion in the human being, on day 8, that is at least about 10 ng/mL, at least about 20 ng/mL, at least about 50 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 1 10 ng/mL, at least about 120 ng/mL, at least about 130 ng/mL, at least about 140 ng/mL, at least 200 ng/mL, or up to about 1 ,500 ng/mL.
[00155] Some liquid compositions may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
[00156] Some liquid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 1 10 mg to about 140 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
[00157] 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 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
[00158] Some solid dosage forms may contain about 10 mg to about 1000 mg, about 50 mg to about 1000 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg, about 40 mg to about 90 mg, about 200 mg to about 300 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 1 10 mg to about 140 mg, about 50 mg to about 150 mg, about 180 mg to about 220 mg, about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by, or between, any of these values.
[00159] In some embodiments, bupropion is administered at a dose that results in a bupropion plasma level of about 0.1 μΜ to about 10 μΜ, about 0.1 μΜ to about 5 μΜ, about 0.2 μΜ to about 3 μΜ, 0.1 μΜ to about 1 μΜ, about 0.2 μΜ to about 2 μΜ, 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 2 μΜ to about 3 μΜ, or about 2.8 μΜ to about 3 μΜ, about 1 .5 μΜ to about 2 μΜ, about 4.5 μΜ to about 5 μΜ, about 2.5 μΜ to about 3 μΜ, about 1 .8 μΜ, about 4.8 μΜ, about 2.9 μΜ, about 2.8 μΜ, or any plasma level in a range bounded by, or between, any of these values.
[00160] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion, is administered at a dose that results in a hydroxybupropion plasma level of about 0.1 μΜ to about 10 μΜ, about 0.1 μΜ to about 5 μΜ, about 0.2 μΜ to about 3 μΜ, 0.1 μΜ to about 1 μΜ, about 0.2 μΜ to about 2 μΜ, 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 2 μΜ to about 3 μΜ, or about 2.8 μΜ to about 3 μΜ, about 1 .5 μΜ to about 2 μΜ, about 4.5 μΜ to about 5 μΜ, about 2.5 μΜ to about 3 μΜ, about 1 .8 μΜ, about 4.8 μΜ, about 2.9 μΜ, about 2.8 μΜ, or any plasma level in a range bounded by, or between, any of these values.
[00161] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion, may be administered to a human being in an amount that results in an AUCo-12 of hydroxybupropion in the human being, on day 8, that is at least about 3,000 ng»hr/mL, at least about 7,000 ng»hr/mL, at least about 10,000 ng»hr/ml_, at least about 15,000 ng»hr/ml_, at least about 20,000 ng»hr/ml_, at least about 30,000 ng»hr/mL, up to about 50,000 ng»hr/mL, up to about 150,000 ng»hr/mL, or any AUC in a range bounded by, or between, any of these values.
[00162] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion, may be administered to a human being in an amount that results in a Cmax of hydroxybupropion in the human being, on day 8, that is at least about 300 ng/mL, at least about 700 ng/mL, at least about 1 ,000 ng/mL, at least about 1 ,500 ng/mL, at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any Cmax in a range bounded by, or between, any of these values.
[00163] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion, may be administered to a human being in an amount that results in a Cavg of hydroxybupropion in the human being, on day 8, that is at least about 200 ng/mL, at least about 300 ng/mL, at least about 700 ng/mL, at least about 1 ,000 ng/mL, at least about 1 ,500 ng/mL, at least about 2,000 ng/mL, at least about 4,000 ng/mL, up to about 10,000 ng/mL, up to about 50,000 ng/mL, or any Cavg in a range bounded by, or between, any of these values.
[00164] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion, is administered at a dose that results in a threohydroxybupropion plasma level of about 0.1 μΜ to about 10 μΜ, about 0.1 μΜ to about 5 μΜ, about 0.2 μΜ to about 3 μΜ, 0.1 μΜ to about 1 μΜ, about 0.2 μΜ to about 2 μΜ, 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 2 μΜ to about 3 μΜ, or about 2.8 μΜ to about 3 μΜ, about 1 .5 μΜ to about 2 μΜ, about 4.5 μΜ to about 5 μΜ, about 2.5 μΜ to about 3 μΜ, about 1 .8 μΜ, about 4.8 μΜ, about 2.9 μΜ, about 2.8 μΜ, or any plasma level in a range bounded by, or between, any of these values.
[00165] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion, may be administered to a human being in an amount that results in an AUCo-12 of threohydroxybupropion in the human being, on day 8, that is at least about 1 ,000 ng»hr/mL, at least about 2,000 ng»hr/mL, at least about 4,000 ng»hr/mL, at least about 5,000 ng»hr/mL, at least about 8,000 ng»hr/mL, up to about 10,000 ng»hr/mL, up to about 40,000 ng»hr/mL, or any AUC in a range bounded by, or between, any of these values.
[00166] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion, may be administered to a human being in an amount that results in a Cmax of threohydroxybupropion in the human being, on day 8, that is at least about 100 ng/mL, at least about 200 ng/mL, at least about 400 ng/mL, at least about 500 ng/mL, at least about 600 ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any Cmax in a range bounded by, or between, any of these values.
[00167] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion, may be administered to a human being in an amount that results in a Cavg of threohydroxybupropion in the human being, on day 8, that is at least about 100 ng/mL, at least about 300 ng/mL, at least about 400 ng/mL, at least about 600 ng/mL, at least about 800 ng/mL, up to about 2,000 ng/mL, up to about 10,000 ng/mL, or any Cavg in a range bounded by, or between, any of these values. [00168] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, is administered at a dose that results in an erythrohydroxybupropion plasma level of about 0.1 μΜ to about 10 μΜ, about 0.1 μΜ to about 5 μΜ, about 0.2 μΜ to about 3 μΜ, 0.1 μΜ to about 1 μΜ, about 0.2 μΜ to about 2 μΜ, 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 2 μΜ to about 3 μΜ, or about 2.8 μΜ to about 3 μΜ, about 1 .5 μΜ to about 2 μΜ, about 4.5 μΜ to about 5 μΜ, about 2.5 μΜ to about 3 μΜ, about 1 .8 μΜ, about 4.8 μΜ, about 2.9 μΜ, about 2.8 μΜ, or any plasma level in a range bounded by, or between, any of these values.
[00169] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, may be administered to a human being in an amount that results in an AUCo-12 of erythrohydroxybupropion in the human being, on day 8, that is at least about 200 ng»hr/ml_, at least about 400 ng»hr/ml_, at least about 700 ng»hr/ml_, at least about 1 ,000 ng»hr/ml_, at least about 1 ,500 ng»hr/ml_, at least about 3,000 ng»hr/ml_, up to about 5,000 ng»hr/ml_, up to about 30,000 ng»hr/ml_, or any plasma level in a range bounded by, or between, any of these values.
[00170] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, may be administered to a human being in an amount that results in a Cmax of erythrohydroxybupropion in the human being, on day 8, that is at least about 30 ng/mL, at least about 60 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1 ,000 ng/mL, or any Cmax in a range bounded by, or between, any of these values.
[00171] In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, may be administered to a human being in an amount that results in a Cavg of erythrohydroxybupropion in the human being, on day 8, that is at least about 20 ng/mL, at least about 30 ng/mL, at least about 50 ng/mL, at least about 80 ng/mL, at least about 90 ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least about 200 ng/mL, at least about 300 ng/mL, up to about 1 ,000 ng/mL, up to about 5,000 ng/mL, or any Cavg in a range bounded by, or between, any of these values. [00172] For compositions comprising both dextromethorphan and bupropion, some liquids may comprise about 0.0001 % (w/v) to about 50% (w/v), about 0.01 % (w/v) to about 20% (w/v), about 0.01 % to about 10% (w/v), about 1 % (w/v) to about 3% (w/v), about 3% (w/v) to about 5% (w/v), about 5% (w/v) to about 7% (w/v), about 5% (w/v) to about 15% (w/v), about 7% (w/v) to about 10% (w/v), about 10% (w/v) to about 15% (w/v), about 15% (w/v) to about 20% (w/v), about 20% (w/v) to about 30% (w/v), about 30% (w/v) to about 40% (w/v), about 40% (w/v) to about 50% (w/v) of dextromethorphan and bupropion combined, or any amount in a range bounded by, or between, any of these values. 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 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) of dextromethorphan and bupropion combined, or any amount in a range bounded by, or between, any of these values. In some embodiments, the weight ratio of dextromethorphan to bupropion in a single composition or dosage form may be about 0.1 to about 2, about 0.2 to about 1 , about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1 , about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio in a range bounded by, or between, any of these values.
[00173] A therapeutically effective amount of a therapeutic compound may vary depending upon the circumstances. For example, a daily dose of dextromethorphan may in some instances range from about 0.1 mg to about 1000 mg, about 40 mg to about 1000 mg, about 20 mg to about 600 mg, about 60 mg to about 700 mg, about 100 mg to about 400 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 20 mg to about 60 mg, about 60 mg to about 100 mg, about 100 mg to about 200 mg, about 100 mg to about 140 mg, about 160 mg to about 200 mg, about 200 mg to about 300 mg, about 220 mg to about 260 mg, about 300 mg to about 400 mg, about 340 mg to about 380 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or any daily dose in a range bounded by, or between, any of these values. Dextromethorphan may be administered once daily; or twice daily or every 12 hours, three times daily, four times daily, or six times daily in an amount that is about half, one third, one quarter, or one sixth, respectively, of the daily dose.
[00174] A daily dose of bupropion, may in some instances range from about 10 mg to about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about 2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or any daily dose in a range bounded by, or between, any of these values. Bupropion may be administered once daily; or twice daily or every 12 hours, or three times daily in an amount that is about half or one third, respectively, of the daily dose.
[00175] In some embodiments: 1 ) about 50 mg/day to about 100 mg/day, about 100 mg/day to about 150 mg/day, about 150 mg/day to about 300 mg/day, about 150 mg/day to about 200 mg/day, about 200 mg/day to about 250 mg/day, about 250 mg/day to about 300 mg/day of bupropion, or about 300 mg/day to about 500 mg/day of bupropion; and/or 2) about 15 mg/day to about 60 mg/day, about 15 mg/day to about 30 mg/day, about 30 mg/day to about 45 mg/day, about 45 mg/day to about 60 mg/day, about 60 mg/day to about 100 mg/day, about 80 mg/day to about 1 10 mg/day, about 100 mg/day to about 150 mg/day, or about 100 mg/day to about 300 mg/day of dextromethorphan, are administered to a human being in need thereof.
[00176] In some embodiments, about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 90 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 120 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 90 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 120 mg/day of dextromethorphan, about 300 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 300 mg/day of bupropion and about 60 mg/day of dextromethorphan, about 300 mg/day of bupropion and about 90 mg/day of dextromethorphan, or about 300 mg/day of bupropion and about 120 mg/day of dextromethorphan is administered to the human being.
[00177] In some embodiments, about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan. In some embodiments, about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.
[00178] In some embodiments, about 75 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan. In some embodiments, about 75 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for 1 , 2, or 3 days, followed by about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan.
[00179] An antidepressant compound, such as bupropion, may be administered for as long as needed to treat a neurological condition, such as pain, depression or cough. In some embodiments, an antidepressant compound, such as bupropion, and dextromethorphan are administered at least once a day, such as once daily or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.
[00180] Therapeutic compounds 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. For oral therapeutic administration, the active compound may be incorporated with an excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
[00181] Tablets, troches, pills, capsules and the like 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. When the dosage unit 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.
[00182] Some compositions or dosage forms may be a liquid, or may comprise a solid phase dispersed in a liquid.
[00183] Therapeutic compounds 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, such as hydroxypropylcellulose. 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.
Specifically Contemplated Embodiments
[00184] The following are examples of embodiments that are specifically contemplated by the inventor:
Embodiment 1. A method of treating pain or a neurological disorder comprising administering a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound, to a person in need thereof.
Embodiment 2. A method of treating pain comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
Embodiment 3. A method of enhancing the pain relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound.
Embodiment 4. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan, comprising co-administering an antidepressant compound to the human being receiving a treatment that includes administration of dextromethorphan.
Embodiment 5. A method of inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
Embodiment 6. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering an antidepressant compound to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as the antidepressant compound.
Embodiment 7. A method of correcting extensive metabolism of dextromethorphan, comprising administering an antidepressant compound to a human being in need thereof.
Embodiment 8. A method of improving pain relieving properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for pain.
Embodiment 9. A method of improving antitussive properties of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
Embodiment 10. A method of treating cough comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
Embodiment 11. A method of improving a therapeutic property of dextromethorphan comprising administering an antidepressant compound in conjunction with administration of dextromethorphan to a human being in need of treatment for a neurological disorder.
Embodiment 12. A method of treating a neurological disorder comprising administering a combination of an antidepressant compound and dextromethorphan to a human being in need thereof.
Embodiment 13. A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.
Embodiment 14. The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms.
Embodiment 15. A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient.
Embodiment 16. An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound to inhibit the metabolism of dextromethorphan in a human being that is an extensive metabolizer of dextromethorphan.
Embodiment 17. The oral dosage form of embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form.
Embodiment 18. The oral dosage form of embodiment 16 or 17, wherein about 100 mg to about 400 mg of bupropion is present in the dosage form. Embodiment 19. The oral dosage form of any of embodiments 16, 17, or 18, comprising an amount of bupropion that results in a bupropion plasma level of about 0.1 μΜ to about 10 μΜ when the oral dosage form is administered to a human being.
Embodiment 20. The oral dosage form of embodiment 19, comprising an amount of bupropion that results in a bupropion plasma level of about 0.1 μΜ to about 2 μΜ when the oral dosage form is administered to a human being.
Embodiment 21. The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 ,
12, or 13, wherein bupropion is administered at a dose that results in a bupropion plasma level of about 0.1 μΜ to about 10 μΜ.
Embodiment 22. The method of embodiment 21 , wherein bupropion is administered at a dose that results in a bupropion plasma level of about 0.3 μΜ to about 1 μΜ.
Embodiment 23. The method, composition, or dosage form of any of embodiments 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion or a metabolite thereof.
Embodiment 24. The method, composition, or dosage form of any of embodiments 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion.
Embodiment 25. The method, composition, or dosage form of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxy indanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, or a pharmaceutically acceptable salt thereof
Embodiment 26. The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 1 1 , 12,
13, 14, 21 , 22, 23, 24, or 25, wherein dextromethorphan is administered to the human being for the treatment of cough. Embodiment 27. A method of treating a neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 30 mg/day to about 120 mg/day of dextromethorphan to a human being in need thereof.
Embodiment 28. A method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
Embodiment 29. The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, or 27, wherein bupropion is administered to the human being at least daily for at least 8 days.
Embodiment 30. The method of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, 27, or 28, wherein dexromethorphan is administered to the human being at least daily for at least 8 days.
Embodiment 31. The method of embodiment 28, 29, or 30, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without bupropion.
Embodiment 32. The method of embodiment 28, 29, 30, or 31 , wherein bupropion is administered in an amount that results in an AUCo-12 of hydroxybupropion, on day 8, that is at least about 3000 ng-hr/mL.
Embodiment 33. The method of embodiment 28, 29, 30, 31 , or 32, wherein bupropion is administered in an amount that results in an AUCo-12 of erythrohydroxybupropion, on day 8, that is at least about 400 ng-hr/mL.
Embodiment 34. The method of embodiment 28, 29, 30, 31 , 32, or 33, wherein bupropion is administered in an amount that results in an AUCo-12 of threohydroxybupropion, on day 8, that is at least about 2000 ng-hr/mL.
Embodiment 35. The method, composition, or dosage form of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or 34, wherein the weight ratio of dextromethorphan to bupropion is about 0.1 to about 0.5.
Embodiment 36. The method of embodiment 27, 28, 29, 30, 31 , 32, 33, 34, or 35, wherein the human being is an extensive metabolizer of dextromethorphan.
Embodiment 37. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
Embodiment 38. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
Embodiment 39. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
Embodiment 40. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan.
Embodiment 41. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
Embodiment 42. The method of embodiment 1,2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.
Embodiment 43. The method of embodiment 4, 5, 6, 7, 9, 10, 1 1 , 12, 13, 14, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , or 42, wherein dextromethorphan is administered to the human being for the treatment of pain.
Embodiment 44. The method of embodiment 43, wherein the pain comprises postoperative pain, cancer pain, arthritic pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain.
Embodiment 45. The method of embodiment 43, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.
Embodiment 46. The method of embodiment 43, wherein the pain comprises postoperative pain.
Embodiment 47. The method of embodiment 43, wherein the pain comprises cancer pain.
Embodiment 48. The method of embodiment 43, wherein the pain comprises arthritic pain.
Embodiment 49. The method of embodiment 43, wherein the pain comprises lumbosacral pain.
Embodiment 50. The method of embodiment 43, wherein the pain comprises musculoskeletal pain.
Embodiment 51. The method of embodiment 43, wherein the pain comprises neuropathic pain.
Embodiment 52. The method of embodiment 43, wherein the pain comprises nociceptive pain.
Embodiment 53. The method of embodiment 43, wherein the pain comprises chronic musculoskeletal pain. Embodiment 54. The method of embodiment 43, wherein the pain is associated with rheumatoid arthritis.
Embodiment 55. The method of embodiment 43, wherein the pain is associated with juvenile rheumatoid arthritis.
Embodiment 56. The method of embodiment 43, wherein the pain is associated with osteoarthritis.
Embodiment 57. The method of embodiment 43, wherein the pain is associated with an axial spondyloarthritis.
Embodiment 58. The method of embodiment 43, wherein the pain is associated with ankylosing spondylitis.
Embodiment 59. The method of embodiment 43, wherein the pain is associated with diabetic peripheral neuropathy.
Embodiment 60. The method of embodiment 43, wherein the pain is associated with post-herpetic neuralgia.
Embodiment 61. The method of embodiment 43, wherein the pain is associated with trigeminal neuralgia.
Embodiment 62. The method of embodiment 43, wherein the pain is associated with monoradiculopathies.
Embodiment 63. The method of embodiment 43, wherein the pain is associated with phantom limb pain.
Embodiment 64. The method of embodiment 43, wherein the pain is associated with central pain.
Embodiment 65. The method of embodiment 43, wherein the pain comprises cancer-related pain.
Embodiment 66. The method of embodiment 43, wherein the pain is associated with lumbar nerve root compression.
Embodiment 67. The method of embodiment 43, wherein the pain is associated with spinal cord injury. Embodiment 68. The method of embodiment 43, wherein the pain is associated with post-stroke pain.
Embodiment 69. The method of embodiment 43, wherein the pain is associated with central multiple sclerosis pain.
Embodiment 70. The method of embodiment 43, wherein the pain is associated with HIV-associated neuropathy.
Embodiment 71. The method of embodiment 43, wherein the pain is associated with radio-therapy associated neuropathy.
Embodiment 72. The method of embodiment 43, wherein the pain is associated with chemo-therapy associated neuropathy.
Embodiment 73. The method of embodiment 43, wherein the pain comprises dental pain.
Embodiment 74. The method of embodiment 43, wherein the pain is associated with primary dysmenorrhea.
Embodiment 75. The method of embodiment 4, 5, 6, 7, 9, 10, 1 1 , 12, 13,
14, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, or 74, wherein 90 mg/day of dextromethorphan is administered to the human being.
Embodiment 76. The method of embodiment 75, wherein 45 mg of dextromethorphan is administered twice a day to the human being.
Embodiment 77. The method of embodiment 75 or 76, wherein 150 mg/day of bupropion is administered to the human being.
Embodiment 78. The method of embodiment 75 or 76, wherein 180 mg/day of bupropion is administered to the human being.
Embodiment 79. The method of embodiment 75 or 76, wherein 200 mg/day of bupropion is administered to the human being.
Embodiment 80. The method of claim 123 or 124, wherein 300 mg/day of bupropion is administered to the human being. [00185] United States Provisional Application No. 61/900,354 is incorporated by reference herein in its entirety.
EXAMPLES
Example 1
[00186] Fifteen human subjects were randomized into one of two treatment groups receiving either dextromethorphan (DM) alone, or DM in combination with bupropion, as shown in Table 1 below.
Table 1. Study Design
Figure imgf000053_0001
[00187] All subjects were extensive, including ultra-rapid, metabolizers of dextromethorphan as determined by CYP2D6 genetic testing. Dextromethorphan was dosed at 12-hour intervals on Days 1 -8, with a final morning dose on Day 8. Bupropion was dosed once daily on Days 1 -3, and at 12-hour intervals thereafter, with a final morning dose on Day 8.
[00188] Plasma samples were collected for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8. Plasma samples for determination of trough concentrations of dextromethorphan were obtained approximately 12 hours after dosing on days 1 , 5, 6, and 8.
[00189] Concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion, were determined using LC-MS/MS. Pharmacokinetic parameters were calculated. [00190] Phenotypic determination of dextromethorphan metabolizer status was performed by calculating the dextromethorphan/dextrorphan metabolic ratio as described in Jurica et al. Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486-490. Plasma concentrations of dextromethorphan and dextrorphan 3 hours after dosing were used, with a dextromethorphan/dextrorphan ratio of 0.3 or greater indicating a poor metabolizer phenotype.
Results
[00191] Plasma concentrations of dextromethorphan were significantly increased with bupropion administration, as illustrated in Fig. 1 and Table 2.
Table 2. Mean Day 8 Dextromethorphan Plasma Concentrations (ng/mL)
Figure imgf000054_0001
[00192] The AUC of dextromethorphan was significantly increased with administration of bupropion as show in Figs. 2-4. As shown in Fig. 5, administration of bupropion with dextromethorphan resulted in an approximately 60-fold, 80-fold, and 175-fold increase in mean dextromethorphan AUCo-12, AUC0-24, and AUCo-inf, respectively on Day 8 as compared to administration of dextromethorphan alone. As shown in Fig. 6, the increase in dextromethorphan AUC occurred as early as Day 1 (an approximate 3-fold increase in AUC0-12)-
[00193] Trough plasma concentrations of dextromethorphan were significantly increased with administration of bupropion as illustrated in Fig. 7 and Table 3. Administration of bupropion with dextromethorphan resulted in an approximately 105-fold increase in mean trough plasma concentration of dextromethorphan on Day 8 as compared to administration of dextromethorphan alone.
[00194] Mean average plasma concentrations (Cavg) of dextromethorphan on Day 8 increased approximately 60-fold with bupropion administration as compared to administration of dextromethorphan alone. Maximum mean plasma concentrations (Cmax) were also significantly increased as illustrated in Fig. 8.
Table 3. Mean Trough Dextromethorphan Plasma Concentrations (ng/mL)
Figure imgf000055_0001
[00195] The Tmax and elimination half life (Ti/2 ei) of dextromethorphan were significantly increased with administration of bupropion on Day 8. Administration of bupropion with dextromethorphan resulted in a mean Tmax of 3.6 hours, compared to 2.3 hours for dextromethorphan alone. Administration of bupropion with dextromethorphan resulted in a mean Ti/2 ei of 27.7 hours, compared to 6.6 hours for dextromethorphan alone.
[00196] Plasma concentrations of dextrorphan were significantly decreased with bupropion administration, as illustrated in Fig. 9 and Table 4.
Table 4. Mean Day 8 Dextrorphan Plasma Concentrations (ng/i
Figure imgf000055_0002
36 I 0- 1 I 107.6
[00197] As shown in Figs. 10-1 1 , there was an approximate 78% reduction in mean dextrorphan Cmax, and an approximate 55% reduction in mean dextrorphan
AUCo-12 on Day 8 with administration of bupropion.
[00198] Phenotypic determination of dextromethorphan metabolizer status showed that no subjects in either treatment arm were poor metabolizers on Day 1 . On Day 8 however, 100% of subjects treated with bupropion had converted to poor metabolizer status as compared to 0% of subjects treated with dextromethorphan alone. The mean plasma dextromethorphan/dextrorphan metabolic ratio increased from 0.01 on Day 1 to 0.71 on Day 8 with bupropion administration. The mean ratio in the group administered DM alone was 0.00 on Day 1 and remained unchanged on Day 8.
[00199] On Day 8, average plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were at least 10 ng/mL, 200 ng/mL, 20 ng/mL, and 100 ng/mL, respectively after bupropion administration.
[00200] As used in this section, the term "fold change" or "fold increase" refers to the ratio of a value for bupropion with dextromethorphan to the same value for dextromethorphan alone (i.e. the value for bupropion with dextromethorphan divided by the same value for dextromethorphan alone).
[00201] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood in all instances as indicating both the exact values as shown and as being modified by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
[00202] The terms "a," "an," "the" and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[00203] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
[00204] Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.
[00205] In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims

1. A method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human being in need thereof, wherein the human being is an extensive metabolizer of dextromethorphan.
2. The method of claim 1 , wherein the neurological disorder is depression.
3. The method of claim 1 , wherein the neurological disorder is cough.
4. The method of claim 1 , 2, or 3, wherein the antidepressant comprises hydroxybupropion or a prodrug thereof.
5. The method of claim 1 , 2, 3, or 4, wherein the antidepressant comprises erythrohydroxybupropion or a prodrug thereof.
6. The method of claim 1 , 2, 3, 4, or 5, wherein the antidepressant comprises threohydroxybupropion or a prodrug thereof.
7. A method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering bupropion with dextromethorphan to the human being.
8. A method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
9. A method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
10. A method of increasing dextromethorphan plasma levels in a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to the human being.
11. A method of inhibiting metabolism of dextromethorphan, comprising administering bupropion to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
12. A method of inhibiting metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
13. A method of inhibiting metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
14. A method of inhibiting metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
15. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering bupropion to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as bupropion.
16. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as hydroxybupropion.
17. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as erythrohydroxybupropion.
18. A method of increasing the metabolic lifetime of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need of treatment with dextromethorphan, wherein the human being is an extensive metabolizer of dextromethorphan, and wherein dextromethorphan is present in the body of the human being at the same time as threohydroxybupropion.
19. A method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of co-administration of bupropion with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
20. The method of claim 19, wherein the dextromethorphan plasma level on the first day that bupropion and dextromethorphan are co-administered is at least twice the level that would be achieved by administering the same amount of dextromethorphan without bupropion.
21. A method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.
22. The method of claim 21 , wherein the dextromethorphan plasma level on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least twice the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
23. A method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
24. The method of claim 23, wherein the dextromethorphan plasma level on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least twice the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
25. A method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan, wherein an increase in the dextromethorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
26. The method of claim 25, wherein the dextromethorphan plasma level on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least twice the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
27. A method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for five consecutive days.
28. The method of claim 27, wherein the dextromethorphan plasma level on the fifth day that bupropion and dextromethorphan are co-administered is at least 20 times the level that would be achieved by administering the same amount of dextromethorphan without bupropion for five consecutive days.
29. A method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for five consecutive days.
30. The method of claim 29, wherein the dextromethorphan plasma level on the fifth day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 20 times the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for five consecutive days.
31. A method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.
32. The method of claim 31 , wherein the dextromethorphan plasma level on the fifth day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 20 times the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for five consecutive days.
33. A method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least five consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the fifth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for five consecutive days.
34. The method of claim 33, wherein the dextromethorphan plasma level on the fifth day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 20 times the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for five consecutive days.
35. A method of increasing dextromethorphan plasma levels comprising co-administering bupropion and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for six consecutive days.
36. The method of claim 35, wherein the dextromethorphan plasma level on the sixth day that bupropion and dextromethorphan are co-administered is at least 30 times the level that would be achieved by administering the same amount of dextromethorphan without bupropion for six consecutive days.
37. A method of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for six consecutive days.
38. The method of claim 37, wherein the dextromethorphan plasma level on the sixth day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 30 times the level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for six consecutive days.
39. A method of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.
40. The method of claim 39, wherein the dextromethorphan plasma level on the sixth day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 30 times the level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for six consecutive days.
41. A method of increasing dextromethorphan plasma levels comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least six consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the sixth day, the dextromethorphan plasma level is higher than the dextromethorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for six consecutive days.
42. The method of claim 41 , wherein the dextromethorphan plasma level on the sixth day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is at least 30 times the level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for six consecutive days.
43. A method of decreasing dextrorphan plasma levels comprising coadministering bupropion and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without bupropion.
44. The method of claim 43, wherein the dextrorphan plasma level on the first day that bupropion and dextromethorphan are co-administered is reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
45. A method of decreasing dextrorphan plasma levels comprising coadministering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the hydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.
46. The method of claim 45, wherein the dextrorphan plasma level on the first day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered is reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
47. A method of decreasing dextrorphan plasma levels comprising coadministering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the erythrohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof.
48. The method of claim 47, wherein the dextrorphan plasma level on the first day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
49. A method of decreasing dextrorphan plasma levels comprising coadministering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan, wherein the threohydroxybupropion, or a prodrug thereof, is administered on the first day of at least two days of treatment with dextromethorphan, wherein a decrease in the dextrorphan plasma level occurs on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof.
50. The method of claim 49, wherein the dextrorphan plasma level on the first day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered is reduced by at least 5% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
51. A method of decreasing dextrorphan plasma levels comprising coadministering bupropion and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without bupropion for eight consecutive days.
52. The method of claim 51 , wherein the plasma level on the eighth day that bupropion and dextromethorphan are co-administered is reduced by at least 30% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion for eight consecutive days.
53. A method of decreasing dextrorphan plasma levels comprising coadministering hydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without hydroxybupropion, or a prodrug thereof, for eight consecutive days.
54. The method of claim 53, wherein the plasma level on the eighth day that hydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered is reduced by at least 30% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion, or a prodrug thereof, for eight consecutive days.
55. A method of decreasing dextrorphan plasma levels comprising coadministering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.
56. The method of claim 55, wherein the plasma level on the eighth day that erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered is reduced by at least 30% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion, or a prodrug thereof, for eight consecutive days.
57. A method of decreasing dextrorphan plasma levels comprising coadministering threohydroxybupropion, or a prodrug thereof, and dextromethorphan, for at least eight consecutive days, to a human being in need of treatment with dextromethorphan, wherein, on the eighth day, the dextrorphan plasma level is lower than the dextrorphan plasma level that would have been achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.
58. The method of claim 57, wherein the plasma level on the eighth day that threohydroxybupropion, or a prodrug thereof, and dextromethorphan are coadministered is reduced by at least 30% as compared to the dextrorphan plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion, or a prodrug thereof, for eight consecutive days.
59. A method of reducing a trough effect of dextromethorphan comprising, co-administering bupropion with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
60. The method of claim 59, wherein, after the first co-administration of bupropion with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
61. A method of reducing a trough effect of dextromethorphan comprising, co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
62. The method of claim 61 , wherein, after the first co-administration of hydroxybupropion, or a prodrug thereof, with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
63. A method of reducing a trough effect of dextromethorphan comprising, co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
64. The method of claim 63, wherein, after the first co-administration of erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
65. A method of reducing a trough effect of dextromethorphan comprising, co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
66. The method of claim 65, wherein, after the first co-administration of threohydroxybupropion, or a prodrug thereof, with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least twice the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
67. The method of claim 1 , 2, 3, 7, 1 1 , 15, 19, 20, 27, 28, 35, 36, 43, 44, 51 , 52, 59, or 60, wherein bupropion is co-administered with dextromethorphan for at least five consecutive days, wherein, on the fifth day, dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least 40 times the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
68. The method of claim 1 , 2, 3, 4, 8, 12, 16, 21 , 22, 29, 30, 37, 38, 45, 46, 53, 54, 61 , or 62, wherein hydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least five consecutive days, wherein, on the fifth day, dextromethorphan has a plasma level 12 hours after co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
69. The method of claim 1 , 2, 3, 5, 9, 13, 17, 23, 24, 31 , 32, 39, 40, 47, 48, 55, 56, 63, or 64, wherein erythrohydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least five consecutive days, wherein, on the fifth day, dextromethorphan has a plasma level 12 hours after co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
70. The method of claim 1 , 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41 , 42, 49,
50, 57, 58, 65, 66, wherein threohydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least five consecutive days, wherein, on the fifth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 40 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
71. The method of claim 1 , 2, 3, 7, 1 1 , 15, 19, 20, 27, 28, 35, 36, 43, 44,
51 , 52, 59, 60, or 67, wherein bupropion is co-administered with dextromethorphan for at least six consecutive days, wherein, on the sixth day, dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least 50 times the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
72. The method of claim 1 , 2, 3, 4, 8, 12, 16, 21 , 22, 29, 30, 37, 38, 45, 46, 53, 54, 61 , 62, or 68, wherein hydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least six consecutive days, wherein, on the sixth day, dextromethorphan has a plasma level 12 hours after co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
73. The method of claim 1 , 2, 3, 5, 9, 13, 17, 23, 24, 31 , 32, 39, 40, 47, 48, 55, 56, 63, 64, or 69, wherein erythrohydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least six consecutive days, wherein, on the sixth day, dextromethorphan has a plasma level 12 hours after co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
74. The method of claim 1 , 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41 , 42, 49,
50, 57, 58, 65, 66, or 70, wherein threohydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least six consecutive days, wherein, on the sixth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 50 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
75. The method of claim 1 , 2, 3, 7, 1 1 , 15, 19, 20, 27, 28, 35, 36, 43, 44,
51 , 52, 59, 60, 67, or 71 , wherein bupropion is co-administered with dextromethorphan for at least seven consecutive days, wherein, on the seventh day, dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least 70 times the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
76. The method of claim 1 , 2, 3, 4, 8, 12, 16, 21 , 22, 29, 30, 37, 38, 45, 46, 53, 54, 61 , 62, 68, or 72, wherein hydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least seven consecutive days, wherein, on the seventh day, dextromethorphan has a plasma level 12 hours after coadministering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
77. The method of claim 1 , 2, 3, 5, 9, 13, 17, 23, 24, 31 , 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, or 73, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least seven consecutive days, wherein, on the seventh day, dextromethorphan has a plasma level 12 hours after co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
78. The method of claim 1 , 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41 , 42, 49,
50, 57, 58, 65, 66, 70, or 74, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least seven consecutive days, wherein, on the seventh day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 70 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
79. The method of claim 1 , 2, 3, 7, 1 1 , 15, 19, 20, 27, 28, 35, 36, 43, 44,
51 , 52, 59, 60, 67, 71 , or 75, wherein bupropion is co-administered with dextromethorphan for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level 12 hours after co-administering bupropion with dextromethorphan that is at least 80 times the plasma level that would be achieved by administering the same amount of dextromethorphan without bupropion.
80. The method of claim 1 , 2, 3, 4, 8, 12, 16, 21 , 22, 29, 30, 37, 38, 45, 46, 53, 54, 61 , 62, 68, 72, or 76, wherein hydroxybupropion, or a prodrug thereof, is coadministered with dextromethorphan for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level 12 hours after co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma level that would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.
81. The method of claim 1 , 2, 3, 5, 9, 13, 17, 23, 24, 31 , 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, 73, or 77, wherein erythrohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level 12 hours after coadministering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma level that would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.
82. The method of claim 1 , 2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41 , 42, 49, 50, 57, 58, 65, 66, 70, 74, or 78, wherein threohydroxybupropion, or a prodrug thereof, is co-administered with dextromethorphan for at least eight consecutive days, wherein, on the eighth day, dextromethorphan has a plasma level 12 hours after co-administering threohydroxybupropion, or a prodrug thereof, with dextromethorphan that is at least 80 times the plasma level that would be achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.
83. A method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
84. A method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
85. A method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
86. A method of reducing an adverse event associated with treatment by dextromethorphan, comprising co-administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human patient in need of dextromethorphan treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with dextromethorphan.
87. The method of claim 86, wherein the adverse event is somnolence.
88. A method of reducing an adverse event associated with treatment by bupropion, comprising co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, wherein the human patient is at risk of experiencing the adverse event as a result being treated with bupropion.
89. The method of claim 88, wherein the adverse event is seizure.
90. A method of correcting extensive metabolism of dextromethorphan, comprising administering bupropion to a human being in need thereof.
91. A method of correcting extensive metabolism of dextromethorphan, comprising administering hydroxybupropion, or a prodrug thereof, to a human being in need thereof.
92. A method of correcting extensive metabolism of dextromethorphan, comprising administering erythrohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
93. A method of correcting extensive metabolism of dextromethorphan, comprising administering threohydroxybupropion, or a prodrug thereof, to a human being in need thereof.
94. The method of any preceding claim, wherein bupropion is administered to the human being at least daily for at least 8 days.
95. The method of any preceding claim, wherein dextromethorphan is administered to the human being at least daily for at least 8 days.
96. The method of any preceding claim, wherein dextromethorphan is administered to the human being for the treatment of cough.
97. A method of improving antitussive properties of dextromethorphan comprising administering bupropion in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
98. A method of improving antitussive properties of dextromethorphan comprising administering hydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
99. A method of improving antitussive properties of dextromethorphan comprising administering erythrohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
100. A method of improving antitussive properties of dextromethorphan comprising administering threohydroxybupropion, or a prodrug thereof, in conjunction with administration of dextromethorphan to a human being in need of treatment for cough.
101. A method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human being in need thereof.
102. A method of treating cough comprising administering a combination of hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
103. A method of treating cough comprising administering a combination of erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
104. A method of treating cough comprising administering a combination of threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof.
105. A method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
106. A method of treating a neurological disorder comprising administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
107. A method of treating a neurological disorder comprising administering erythrohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
108. A method of treating a neurological disorder comprising administering threohydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need thereof, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days.
109. The method of any preceding claim, wherein the human being is an extensive metabolizer of dextromethorphan.
110. The method of any preceding claim, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human being, on day 8, that is at least 10 times the plasma concentration of the same amount of dextromethorphan administered without bupropion.
11 1. The method of any preceding claim, wherein bupropion, hydroxybupropion, or a prodrug of hydroxybupropion, is administered in an amount that results in an AUCo-12 of hydroxybupropion, on day 8, that is at least about 3000 ng-hr/mL.
112. The method of any preceding claim, wherein bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion, is administered in an amount that results in an AUCo-12 of erythrohydroxybupropion, on day 8, that is at least about 400 ng-hr/mL.
113. The method of any preceding claim, wherein bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion, is administered in an amount that results in an AUCo-12 of threohydroxybupropion, on day 8, that is at least about 2000 ng-hr/mL.
114. The method of any preceding claim, wherein the weight ratio of dextromethorphan to bupropion is about 0.1 to about 0.5.
115. A method of treating a neurological disorder comprising administering about 150 mg/day to about 300 mg/day of bupropion and about 15 mg/day to about 60 mg/day of dextromethorphan to a human being in need thereof.
116. The method of claim 1 15, wherein the human being is an extensive metabolizer of dextromethorphan.
117. The method of claim 1 15, wherein about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
118. The method of claim 1 15, wherein about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
119. The method of claim 1 15, wherein about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being.
120. The method of claim 1 19, wherein about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan.
121. The method of claim 1 15, wherein about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan is administered to the human being.
122. The method of claim 121 , wherein about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan is administered to the human being for about 1 to about 3 days, followed by about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.
123. An oral sustained release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, dextromethorphan, and a water soluble vehicle.
124. The oral sustained release delivery system of claim 123, comprising about 45 mg of dextromethorphan.
125. The oral sustained release delivery system of claim 123, comprising about 60 mg of dextromethorphan.
126. The oral sustained release delivery system of claim 123, 124, or 125, comprising about 70 mg to about 95 mg of bupropion.
127. The oral sustained release delivery system of claim 123, 124, or 125, comprising about 105 mg to about 200 mg of bupropion.
128. The oral sustained release delivery system of claim 123, 124, or 125, comprising about 150 mg of bupropion.
129. The oral sustained release delivery system of claim 123, 124, 125, 126, 127, or 128, wherein bupropion is in a form that allows sustained release upon swallowing the sustained release delivery system.
130. A method of decreasing the number of doses of dextromethorphan that can be administered without loss of efficacy, comprising an orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds, to a human being in need of treatment with dextromethorphan.
131. The method of claim 130, wherein bupropion is administered to the patient.
132. The method of claim 130, wherein hydroxybupropion is administered to the patient.
133. The method of claim 130, wherein erythrohydroxybupropion is administered to the patient.
134. The method of claim 130, wherein threohydroxybupropion is administered to the patient.
135. The method of claim 131 , 132, 133, or 134, wherein the patient takes dextromethorphan twice a day, and the treatment is as effective as administration of the same amount of dextromethorphan four times a day without administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds.
136. The method of claim 131 , 132, 133, or 134, wherein the patient takes dextromethorphan twice a day, and the treatment is as effective as administration of the same amount of dextromethorphan three times a day without administering bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrog of any of these compounds.
PCT/US2014/064184 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan WO2015069809A1 (en)

Priority Applications (174)

Application Number Priority Date Filing Date Title
CA2929415A CA2929415C (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
KR1020217016618A KR20210068157A (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
EP14859589.5A EP3065742A4 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
IL298972A IL298972A (en) 2013-11-05 2014-11-05 Compositions comprising dextromethorphan and bupropion or related compounds and uses thereof
EP21191390.0A EP3981403A1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
SG11201603391XA SG11201603391XA (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
KR1020227013910A KR102603013B1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
MX2016005867A MX2016005867A (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan.
EP21191393.4A EP3981404A1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
KR1020237034772A KR20230148385A (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
JP2016552474A JP6605485B2 (en) 2013-11-05 2014-11-05 Composition comprising bupropion or related composition and dextromethorphan
AU2014346807A AU2014346807B2 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
CN201480072191.0A CN106163522A (en) 2013-11-05 2014-11-05 Comprise amfebutamone or related compound and the compositions of dextromethorphan and method
NZ719892A NZ719892A (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
KR1020167013970A KR102264179B1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
MX2020004075A MX2020004075A (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan.
US14/550,618 US9198905B2 (en) 2013-11-05 2014-11-21 Compositions and methods for reducing dextrorphan plasma levels and related pharmacodynamic effects
US14/555,085 US9238032B2 (en) 2013-11-05 2014-11-26 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US14/554,988 US9205083B2 (en) 2013-11-05 2014-11-26 Compositions and methods comprising erythrohydroxybupropion and related compounds for improving the efficacy of dextromethorphan
US14/554,947 US20150126542A1 (en) 2013-11-05 2014-11-26 Compositions and Methods for Increasing the Metabolic Lifetime of Dextromethorphan and Related Pharmacodynamic Effects
US14/602,177 US9402843B2 (en) 2013-11-05 2015-01-21 Compositions and methods of using threohydroxybupropion for therapeutic purposes
US14/604,397 US9168234B2 (en) 2013-11-05 2015-01-23 Bupropion as a modulator of drug activity
US14/617,624 US9486450B2 (en) 2013-11-05 2015-02-09 Hydroxybupropion and related compounds as modulators of drug plasma levels
US14/628,062 US9402844B2 (en) 2013-11-05 2015-02-20 Methods of modulating drug plasma levels using erythrohydroxybupropion
US14/863,284 US9278095B2 (en) 2013-11-05 2015-09-23 Bupropion as a modulator of drug activity
US14/879,002 US9375429B2 (en) 2013-11-05 2015-10-08 Compositions and methods comprising erythrohydroxybupropion and related compounds for improving the efficacy of dextromethorphan
US14/878,998 US9314462B2 (en) 2013-11-05 2015-10-08 Compositions and methods for increasing dextromethorphan plasma levels and related pharmacodynamic effects
US14/978,976 US9370513B2 (en) 2013-11-05 2015-12-22 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US14/997,316 US9457025B2 (en) 2013-11-05 2016-01-15 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US15/057,983 US9408815B2 (en) 2013-11-05 2016-03-01 Bupropion as a modulator of drug activity
US15/130,807 US9421176B1 (en) 2013-11-05 2016-04-15 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
IL245504A IL245504B (en) 2013-11-05 2016-05-05 Compositions comprising dextromethorphan or related compounds and uses thereof
US15/164,746 US9457023B1 (en) 2013-11-05 2016-05-25 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/164,767 US9700528B2 (en) 2013-11-05 2016-05-25 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/182,253 US9474731B1 (en) 2013-11-05 2016-06-14 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/206,057 US9861595B2 (en) 2013-11-05 2016-07-08 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/213,283 US20160324807A1 (en) 2013-11-05 2016-07-18 Bupropion as a modulator of drug activity
US15/216,545 US20160339017A1 (en) 2013-11-05 2016-07-21 Bupropion as a modulator of drug activity
US15/224,233 US20160375008A1 (en) 2013-11-05 2016-07-29 Bupropion as a modulator of drug activity
US15/236,290 US9763932B2 (en) 2013-11-05 2016-08-12 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/238,182 US20160361305A1 (en) 2013-11-05 2016-08-16 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US15/263,138 US9700553B2 (en) 2013-11-05 2016-09-12 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/275,177 US20170007558A1 (en) 2013-11-05 2016-09-23 Hydroxybupropion and related compounds as modulators of drug plasma levels
US15/280,938 US9707191B2 (en) 2013-11-05 2016-09-29 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/599,163 US9968568B2 (en) 2013-11-05 2017-05-18 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/621,882 US10105361B2 (en) 2013-11-05 2017-06-13 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/645,939 US9867819B2 (en) 2013-11-05 2017-07-10 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/647,069 US10105327B2 (en) 2013-11-05 2017-07-11 Compositions and methods for increasing the metabolic lifetime of dextromethorphane and related pharmacodynamic effects
US15/647,852 US10080727B2 (en) 2013-11-05 2017-07-12 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/688,660 US10058518B2 (en) 2013-11-05 2017-08-28 Bupropion as a modulator of drug activity
US15/691,532 US10092560B2 (en) 2013-11-05 2017-08-30 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/691,549 US10064857B2 (en) 2013-11-05 2017-08-30 Bupropion as a modulator of drug activity
US15/695,995 US10092561B2 (en) 2013-11-05 2017-09-05 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US15/821,563 US10512643B2 (en) 2013-11-05 2017-11-22 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/842,599 US20180116980A1 (en) 2013-11-05 2017-12-14 Bupropion and dextromethorphan for treating nicotine addiction
US15/933,075 US10251879B2 (en) 2013-11-05 2018-03-22 Bupropion as a modulator of drug activity
US15/977,276 US10463634B2 (en) 2013-11-05 2018-05-11 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
AU2018203638A AU2018203638C1 (en) 2013-11-05 2018-05-23 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US16/107,472 US10806710B2 (en) 2013-11-05 2018-08-21 Bupropion as a modulator of drug activity
US16/114,886 US20190000835A1 (en) 2013-11-05 2018-08-28 Bupropion as a modulator of drug activity
US16/116,393 US10786496B2 (en) 2013-11-05 2018-08-29 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US16/119,852 US10780066B2 (en) 2013-11-05 2018-08-31 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US16/127,832 US10548857B2 (en) 2013-11-05 2018-09-11 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US16/129,531 US10881624B2 (en) 2013-11-05 2018-09-12 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US16/130,898 US20190008805A1 (en) 2013-11-05 2018-09-13 Bupropion and dextromethorphan for treating nicotine addiction
US16/133,553 US10596167B2 (en) 2013-11-05 2018-09-17 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US16/246,347 US11273133B2 (en) 2013-11-05 2019-01-11 Bupropion as a modulator of drug activity
US16/290,653 US20190192507A1 (en) 2013-11-05 2019-03-01 Bupropion as a modulator of drug activity
US16/359,958 US10881657B2 (en) 2013-11-05 2019-03-20 Bupropion as a modulator of drug activity
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
AU2019236614A AU2019236614C1 (en) 2013-11-05 2019-09-23 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US16/588,399 US20200022929A1 (en) 2013-11-05 2019-09-30 Bupropion as a modulator of drug activity
US16/681,317 US10786469B2 (en) 2013-11-05 2019-11-12 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
AU2019275593A AU2019275593B2 (en) 2013-11-05 2019-12-04 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US16/736,752 US10799497B2 (en) 2013-11-05 2020-01-07 Combination of dextromethorphan and bupropion for treating depression
US16/745,105 US20200147008A1 (en) 2013-11-05 2020-01-16 Bupropion and dextromethorphan for treating nicotine addiction
US16/821,462 US10874663B2 (en) 2013-11-05 2020-03-17 Bupropion as a modulator of drug activity
US16/821,330 US10894046B2 (en) 2013-11-05 2020-03-17 Bupropion as a modulator of drug activity
US16/822,697 US11090300B2 (en) 2013-11-05 2020-03-18 Bupropion as a modulator of drug activity
US16/822,564 US10966974B2 (en) 2013-11-05 2020-03-18 Bupropion as a modulator of drug activity
US16/823,807 US10874665B2 (en) 2013-11-05 2020-03-19 Bupropion as a modulator of drug activity
US16/823,724 US10874664B2 (en) 2013-11-05 2020-03-19 Bupropion as a modulator of drug activity
US16/825,228 US10864209B2 (en) 2013-11-05 2020-03-20 Bupropion as a modulator of drug activity
US16/825,195 US10894047B2 (en) 2013-11-05 2020-03-20 Bupropion as a modulator of drug activity
US16/826,580 US11007189B2 (en) 2013-11-05 2020-03-23 Bupropion as a modulator of drug activity
US16/826,598 US20200237751A1 (en) 2013-11-05 2020-03-23 Bupropion as a modulator of drug activity
US16/828,237 US20200237752A1 (en) 2013-11-05 2020-03-24 Bupropion as a modulator of drug activity
US16/838,829 US10772850B2 (en) 2013-11-05 2020-04-02 Bupropion as a modulator of drug activity
US16/894,713 US10898453B2 (en) 2013-11-05 2020-06-05 Bupropion as a modulator of drug activity
US16/983,873 US10945973B2 (en) 2013-11-05 2020-08-03 Bupropion as a modulator of drug activity
US17/002,017 US11541021B2 (en) 2013-11-05 2020-08-25 Bupropion as a modulator of drug activity
US17/003,777 US10933034B2 (en) 2013-11-05 2020-08-26 Bupropion as a modulator of drug activity
US17/030,129 US11065248B2 (en) 2013-11-05 2020-09-23 Bupropion as a modulator of drug activity
US17/039,551 US10966941B2 (en) 2013-11-05 2020-09-30 Bupropion as a modulator of drug activity
US17/061,047 US11020389B2 (en) 2013-11-05 2020-10-01 Bupropion as a modulator of drug activity
US17/063,364 US11123343B2 (en) 2013-11-05 2020-10-05 Bupropion as a modulator of drug activity
US17/066,310 US11229640B2 (en) 2013-11-05 2020-10-08 Combination of dextromethorphan and bupropion for treating depression
US17/068,309 US10980800B2 (en) 2013-11-05 2020-10-12 Bupropion as a modulator of drug activity
US17/070,706 US11129826B2 (en) 2013-11-05 2020-10-14 Bupropion as a modulator of drug activity
US17/071,925 US11123344B2 (en) 2013-11-05 2020-10-15 Bupropion as a modulator of drug activity
US17/075,189 US11096937B2 (en) 2013-11-05 2020-10-20 Bupropion as a modulator of drug activity
US17/087,890 US11141416B2 (en) 2013-11-05 2020-11-03 Bupropion as a modulator of drug activity
US17/092,968 US11234946B2 (en) 2013-11-05 2020-11-09 Bupropion as a modulator of drug activity
US17/095,256 US11298351B2 (en) 2013-11-05 2020-11-11 Bupropion as a modulator of drug activity
US17/097,486 US11213521B2 (en) 2013-11-05 2020-11-13 Bupropion as a modulator of drug activity
US17/099,226 US11058648B2 (en) 2013-11-05 2020-11-16 Bupropion as a modulator of drug activity
US16/950,838 US11311534B2 (en) 2013-11-05 2020-11-17 Bupropion as a modulator of drug activity
US16/952,759 US11185515B2 (en) 2013-11-05 2020-11-19 Bupropion as a modulator of drug activity
US17/100,456 US11273134B2 (en) 2013-11-05 2020-11-20 Bupropion as a modulator of drug activity
US17/103,819 US11141388B2 (en) 2013-11-05 2020-11-24 Bupropion as a modulator of drug activity
US17/115,073 US11207281B2 (en) 2013-11-05 2020-12-08 Bupropion as a modulator of drug activity
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
US17/191,014 US11285146B2 (en) 2013-11-05 2021-03-03 Bupropion as a modulator of drug activity
US17/192,192 US11191739B2 (en) 2013-11-05 2021-03-04 Bupropion as a modulator of drug activity
US17/192,563 US11197839B2 (en) 2013-11-05 2021-03-04 Bupropion as a modulator of drug activity
US17/193,340 US11253491B2 (en) 2013-11-05 2021-03-05 Bupropion as a modulator of drug activity
US17/193,306 US20210205240A1 (en) 2013-11-05 2021-03-05 Bupropion as a modulator of drug activity
US17/194,739 US11147808B2 (en) 2013-11-05 2021-03-08 Method of decreasing the fluctuation index of dextromethorphan
US17/196,338 US11253492B2 (en) 2013-11-05 2021-03-09 Bupropion as a modulator of drug activity
US17/197,971 US11291638B2 (en) 2013-11-05 2021-03-10 Bupropion as a modulator of drug activity
US17/199,112 US20210196705A1 (en) 2013-11-05 2021-03-11 Bupropion as a modulator of drug activity
US17/201,820 US11298352B2 (en) 2013-11-05 2021-03-15 Bupropion as a modulator of drug activity
US17/207,256 US11291665B2 (en) 2013-11-05 2021-03-19 Bupropion as a modulator of drug activity
US17/217,311 US11357744B2 (en) 2013-11-05 2021-03-30 Bupropion as a modulator of drug activity
AU2021202497A AU2021202497B2 (en) 2013-11-05 2021-04-23 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US17/314,647 US20210267967A1 (en) 2013-11-05 2021-05-07 Bupropion as a modulator of drug activity
US17/316,194 US11344544B2 (en) 2013-11-05 2021-05-10 Bupropion as a modulator of drug activity
IL283760A IL283760B2 (en) 2013-11-05 2021-06-07 Compositions comprising dextromethorphan and bupropion or related compounds and uses thereof
US17/373,299 US11426370B2 (en) 2013-11-05 2021-07-12 Bupropion as a modulator of drug activity
US17/380,751 US11571417B2 (en) 2013-11-05 2021-07-20 Bupropion as a modulator of drug activity
US17/395,222 US11426401B2 (en) 2013-11-05 2021-08-05 Bupropion as a modulator of drug activity
US17/405,429 US11439636B1 (en) 2013-11-05 2021-08-18 Bupropion as a modulator of drug activity
US17/468,149 US11364233B2 (en) 2013-11-05 2021-09-07 Bupropion as a modulator of drug activity
US17/470,831 US11576909B2 (en) 2013-11-05 2021-09-09 Bupropion as a modulator of drug activity
US17/471,983 US11617747B2 (en) 2013-11-05 2021-09-10 Bupropion as a modulator of drug activity
US17/473,860 US11590124B2 (en) 2013-11-05 2021-09-13 Bupropion as a modulator of drug activity
US17/482,241 US11285118B2 (en) 2013-11-05 2021-09-22 Bupropion as a modulator of drug activity
US17/498,507 US20220233518A1 (en) 2013-11-05 2021-10-11 Bupropion as a modulator of drug activity
US17/525,339 US11517543B2 (en) 2013-11-05 2021-11-12 Bupropion as a modulator of drug activity
US17/526,676 US11534414B2 (en) 2013-11-05 2021-11-15 Bupropion as a modulator of drug activity
US17/456,146 US11419867B2 (en) 2013-11-05 2021-11-22 Bupropion as a modulator of drug activity
US17/456,459 US11382874B2 (en) 2013-11-05 2021-11-24 Bupropion as a modulator of drug activity
US17/541,461 US20220233470A1 (en) 2013-11-05 2021-12-03 Bupropion as a modulator of drug activity
US17/547,050 US11433067B2 (en) 2013-11-05 2021-12-09 Bupropion as a modulator of drug activity
US17/571,110 US20220241221A1 (en) 2013-11-05 2022-01-07 Bupropion as a modulator of drug activity
US17/574,378 US11571399B2 (en) 2013-11-05 2022-01-12 Bupropion as a modulator of drug activity
US17/581,292 US11576877B2 (en) 2013-11-05 2022-01-21 Bupropion as modulator of drug activity
US17/693,711 US11617728B2 (en) 2013-11-05 2022-03-14 Bupropion as a modulator of drug activity
US17/705,930 US11478468B2 (en) 2013-11-05 2022-03-28 Bupropion as a modulator of drug activity
US17/707,221 US11517544B2 (en) 2013-11-05 2022-03-29 Bupropion as a modulator of drug activity
US17/657,832 US11497721B2 (en) 2013-11-05 2022-04-04 Bupropion as a modulator of drug activity
US17/712,970 US11510918B2 (en) 2013-11-05 2022-04-04 Bupropion as a modulator of drug activity
US17/716,796 US11541048B2 (en) 2013-11-05 2022-04-08 Bupropion as a modulator of drug activity
US17/717,516 US11524007B2 (en) 2013-11-05 2022-04-11 Bupropion as a modulator of drug activity
US17/721,827 US11517542B2 (en) 2013-11-05 2022-04-15 Bupropion as a modulator of drug activity
US17/735,470 US11524008B2 (en) 2013-11-05 2022-05-03 Bupropion as a modulator of drug activity
US17/748,475 US11596627B2 (en) 2013-11-05 2022-05-19 Bupropion as a modulator of drug activity
US17/836,560 US11628149B2 (en) 2013-11-05 2022-06-09 Bupropion as a modulator of drug activity
US17/841,274 US11969421B2 (en) 2013-11-05 2022-06-15 Bupropion as a modulator of drug activity
US17/821,342 US12109178B2 (en) 2013-11-05 2022-08-22 Bupropion as a modulator of drug activity
US17/929,147 US11779579B2 (en) 2013-11-05 2022-09-01 Bupropion as a modulator of drug activity
US17/930,829 US20230100913A1 (en) 2013-11-05 2022-09-09 Bupropion as a modulator of drug activity
US18/056,804 US20230096437A1 (en) 2013-11-05 2022-11-18 Compounds and combinations thereof for treating neurological and psychiatric conditions
US18/056,848 US20230142244A1 (en) 2013-11-05 2022-11-18 Compounds and combinations thereof for treating neurological and psychiatric conditions
US18/061,091 US20230277478A1 (en) 2013-11-05 2022-12-02 Bupropion as a modulator of drug activity
US18/062,236 US20230100008A1 (en) 2013-11-05 2022-12-06 Compounds and combinations thereof for treating neurological and psychiatric conditions
US18/062,273 US20230270740A1 (en) 2013-11-05 2022-12-06 Compounds and combinations thereof for treating neurological and psychiatric conditions
US18/063,261 US20230114111A1 (en) 2013-11-05 2022-12-08 Bupropion as a modulator of drug activity
US18/066,739 US20230131854A1 (en) 2013-11-05 2022-12-15 Bupropion as a modulator of drug activity
US18/179,196 US20230218550A1 (en) 2013-11-05 2023-03-06 Bupropion as a modulator of drug activity
AU2023203438A AU2023203438A1 (en) 2013-11-05 2023-06-01 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US18/475,841 US20240024309A1 (en) 2013-11-05 2023-09-27 Compounds and combinations thereof for treating neurological and psychiatric conditions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201361900354P 2013-11-05 2013-11-05
US61/900,354 2013-11-05

Related Parent Applications (9)

Application Number Title Priority Date Filing Date
PCT/US2014/064184 Continuation-In-Part WO2015069809A1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US14/602,177 Continuation-In-Part US9402843B2 (en) 2013-11-05 2015-01-21 Compositions and methods of using threohydroxybupropion for therapeutic purposes
US14/997,316 Continuation-In-Part US9457025B2 (en) 2013-11-05 2016-01-15 Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
US15/213,283 Continuation-In-Part US20160324807A1 (en) 2013-11-05 2016-07-18 Bupropion as a modulator of drug activity
US15/280,938 Continuation US9707191B2 (en) 2013-11-05 2016-09-29 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US15/647,069 Continuation-In-Part US10105327B2 (en) 2013-11-05 2017-07-11 Compositions and methods for increasing the metabolic lifetime of dextromethorphane and related pharmacodynamic effects
US16/116,393 Continuation-In-Part US10786496B2 (en) 2013-11-05 2018-08-29 Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US16/894,713 Continuation-In-Part US10898453B2 (en) 2013-11-05 2020-06-05 Bupropion as a modulator of drug activity
US17/574,378 Continuation US11571399B2 (en) 2013-11-05 2022-01-12 Bupropion as a modulator of drug activity

Related Child Applications (3)

Application Number Title Priority Date Filing Date
PCT/US2014/064184 Continuation-In-Part WO2015069809A1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan
US14/550,616 Continuation-In-Part US9279944B1 (en) 2014-11-21 2014-11-21 Communication connectors having tethered protective caps
US14/550,618 Continuation-In-Part US9198905B2 (en) 2013-11-05 2014-11-21 Compositions and methods for reducing dextrorphan plasma levels and related pharmacodynamic effects

Publications (1)

Publication Number Publication Date
WO2015069809A1 true WO2015069809A1 (en) 2015-05-14

Family

ID=53042051

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2014/064184 WO2015069809A1 (en) 2013-11-05 2014-11-05 Compositions and methods comprising bupropion or related compounds and dextromethorphan

Country Status (12)

Country Link
EP (3) EP3981403A1 (en)
JP (4) JP6605485B2 (en)
KR (4) KR20210068157A (en)
CN (7) CN106163522A (en)
AU (6) AU2014346807B2 (en)
CA (3) CA2929415C (en)
IL (3) IL298972A (en)
MX (3) MX2016005867A (en)
MY (1) MY179696A (en)
NZ (5) NZ758431A (en)
SG (4) SG11201603391XA (en)
WO (1) WO2015069809A1 (en)

Cited By (59)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016081027A1 (en) 2014-11-21 2016-05-26 Antecip Bioventures Ii Llc Methods of modulating drug plasma levels using erythrohydroxybupropion
WO2017165845A1 (en) * 2016-03-24 2017-09-28 Antecip Bioventures Ii Llc Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
CN111343980A (en) * 2017-10-04 2020-06-26 新凯治疗有限责任公司 Dextromethorphan transdermal delivery device
US20200289499A1 (en) * 2014-09-14 2020-09-17 Avanir Pharmaceuticals, Inc. Pharmaceutical compositions comprising a dextromethorphan compound and quinidine for the treatment of agitation in dementia
US11123344B2 (en) 2013-11-05 2021-09-21 Axsome Therapeutics, Inc. Bupropion as a modulator of drug activity
US11129826B2 (en) 2013-11-05 2021-09-28 Axsome Therapeutics, Inc. Bupropion as a modulator of drug activity
WO2021202419A1 (en) * 2020-03-30 2021-10-07 Antecip Bioventures Ii Llc Use of bupropion and dextromethorphan combinations for treating neurological disorders
US11141388B2 (en) 2013-11-05 2021-10-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11147808B2 (en) 2013-11-05 2021-10-19 Antecip Bioventures Ii Llc Method of decreasing the fluctuation index of dextromethorphan
US11191739B2 (en) 2013-11-05 2021-12-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11197839B2 (en) 2013-11-05 2021-12-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11207281B2 (en) 2013-11-05 2021-12-28 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11229640B2 (en) 2013-11-05 2022-01-25 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US11234946B2 (en) 2013-11-05 2022-02-01 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11253491B2 (en) 2013-11-05 2022-02-22 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11253492B2 (en) 2013-11-05 2022-02-22 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11273133B2 (en) 2013-11-05 2022-03-15 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11285118B2 (en) 2013-11-05 2022-03-29 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11291665B2 (en) 2013-11-05 2022-04-05 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11298351B2 (en) 2013-11-05 2022-04-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11298352B2 (en) 2013-11-05 2022-04-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11311534B2 (en) 2013-11-05 2022-04-26 Antecip Bio Ventures Ii Llc Bupropion as a modulator of drug activity
US11344544B2 (en) 2013-11-05 2022-05-31 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11357744B2 (en) 2013-11-05 2022-06-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11364233B2 (en) 2013-11-05 2022-06-21 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
CN114712356A (en) * 2019-01-07 2022-07-08 安泰赛普生物风投二代有限责任公司 Combination of dextromethorphan and bupropion for the treatment of depression
US11382874B2 (en) 2013-11-05 2022-07-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
WO2022155591A1 (en) * 2021-01-18 2022-07-21 Antecip Bioventures Ii Llc Combination of an antidepressant and dextromethorphan for neuropsychiatric conditions
US11419867B2 (en) 2013-11-05 2022-08-23 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11426401B2 (en) 2013-11-05 2022-08-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11426370B2 (en) 2013-11-05 2022-08-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11433067B2 (en) 2013-11-05 2022-09-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11439636B1 (en) 2013-11-05 2022-09-13 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11478468B2 (en) 2013-11-05 2022-10-25 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11497721B2 (en) 2013-11-05 2022-11-15 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11510918B2 (en) 2013-11-05 2022-11-29 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11517543B2 (en) 2013-11-05 2022-12-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11517542B2 (en) 2013-11-05 2022-12-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11524007B2 (en) 2013-11-05 2022-12-13 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11534414B2 (en) 2013-11-05 2022-12-27 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11541048B2 (en) 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11541021B2 (en) 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11571399B2 (en) 2013-11-05 2023-02-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11571417B2 (en) 2013-11-05 2023-02-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11576877B2 (en) 2013-11-05 2023-02-14 Antecip Bioventures Ii Llc Bupropion as modulator of drug activity
US11576909B2 (en) 2013-11-05 2023-02-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11590124B2 (en) 2013-11-05 2023-02-28 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11596627B2 (en) 2013-11-05 2023-03-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11617747B2 (en) 2013-11-05 2023-04-04 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11617728B2 (en) 2013-11-05 2023-04-04 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
RU2795729C2 (en) * 2017-10-04 2023-05-11 Шинкей Терапьютикс, Инк. Dextromethorphan transdermal delivery device
US11717518B1 (en) 2022-06-30 2023-08-08 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US11730706B1 (en) 2022-07-07 2023-08-22 Antecip Bioventures Ii Llc Treatment of depression in certain patient populations
US11844797B1 (en) 2023-04-20 2023-12-19 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US11896563B2 (en) 2020-12-01 2024-02-13 Antecip Bioventures Ii Llc Bupropion and dextromethorphan for reduction of suicide risk in depression patients
US11969421B2 (en) 2013-11-05 2024-04-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11986444B2 (en) 2022-06-30 2024-05-21 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US20240269130A1 (en) * 2019-01-07 2024-08-15 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US12109178B2 (en) 2013-11-05 2024-10-08 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2929415C (en) * 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Compositions and methods comprising bupropion or related compounds and dextromethorphan
CN114340608B (en) * 2020-07-20 2023-10-31 深圳信立泰药业股份有限公司 Pharmaceutical composition and application thereof
CN112999350A (en) * 2021-02-23 2021-06-22 北京斯利安药业有限公司 Pharmaceutical composition, compound preparation, and preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350756A (en) 1991-06-17 1994-09-27 Smith Richard A Use of a cytochrome oxidase inhibitor to increase the cough-suppressing activity of dextromorphan
WO2009006194A1 (en) 2007-06-28 2009-01-08 Avanir Pharmaceuticals Pharmaceutical compositions for the treatment of involuntary emotional expression disorder
WO2012118562A1 (en) 2011-03-02 2012-09-07 Rhine Pharmaceuticals, Llc Compositions and methods for treating depression, adhd and other central nervous system disorders employing novel bupropion compounds, and methods for production and use of novel bupropion compounds and formulations
WO2013158680A2 (en) 2012-04-16 2013-10-24 Antecip Bioventures Ii Llc Compositions and methods comprising celecoxib or related compounds and dextromethorphan

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU7472898A (en) * 1997-05-07 1998-11-27 Algos Pharmaceutical Corporation Composition and method combining an antidepressant with an nmda receptor antagonist, for treating neuropathic pain
US6207674B1 (en) * 1999-12-22 2001-03-27 Richard A. Smith Dextromethorphan and oxidase inhibitor for weaning patients from narcotics and anti-depressants
US6780871B2 (en) * 2001-01-29 2004-08-24 Albany Medical College Methods and compositions for treating addiction disorders
TWI326214B (en) * 2002-07-17 2010-06-21 Avanir Pharmaceuticals Inc Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders
CA2641392A1 (en) * 2006-02-03 2007-08-16 Avanir Pharmaceuticals Pharmaceutical compositions for treating depression, anxiety and neurodegenerative disorders
CA2929415C (en) * 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Compositions and methods comprising bupropion or related compounds and dextromethorphan

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5350756A (en) 1991-06-17 1994-09-27 Smith Richard A Use of a cytochrome oxidase inhibitor to increase the cough-suppressing activity of dextromorphan
WO2009006194A1 (en) 2007-06-28 2009-01-08 Avanir Pharmaceuticals Pharmaceutical compositions for the treatment of involuntary emotional expression disorder
WO2012118562A1 (en) 2011-03-02 2012-09-07 Rhine Pharmaceuticals, Llc Compositions and methods for treating depression, adhd and other central nervous system disorders employing novel bupropion compounds, and methods for production and use of novel bupropion compounds and formulations
WO2013158680A2 (en) 2012-04-16 2013-10-24 Antecip Bioventures Ii Llc Compositions and methods comprising celecoxib or related compounds and dextromethorphan

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KOTLYAR ET AL., J CLINICAL PSYCHOPHARMACOL, vol. 25, 2005, pages 3
KOTLYAR M. ET AL.: "Inhibition of CYP2D6 activity by bupropion .", J. CLINICAL PSYCHOPHARMACOLOGY, vol. 25, no. 3, 2005, pages 226 - 229, XP055340875 *
REESE ET AL., DRUG METAB DISPOS, vol. 36, no. 7, 2008
REESE M.J. ET AL.: "An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction.", DRUG METAB DISPOS., vol. 36, no. 7, July 2008 (2008-07-01), pages 1198 - 1201, XP055340876 *

Cited By (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11433067B2 (en) 2013-11-05 2022-09-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11617728B2 (en) 2013-11-05 2023-04-04 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US12109178B2 (en) 2013-11-05 2024-10-08 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11969421B2 (en) 2013-11-05 2024-04-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11439636B1 (en) 2013-11-05 2022-09-13 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11779579B2 (en) 2013-11-05 2023-10-10 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11628149B2 (en) 2013-11-05 2023-04-18 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11129826B2 (en) 2013-11-05 2021-09-28 Axsome Therapeutics, Inc. Bupropion as a modulator of drug activity
US11617747B2 (en) 2013-11-05 2023-04-04 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11596627B2 (en) 2013-11-05 2023-03-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11590124B2 (en) 2013-11-05 2023-02-28 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11141388B2 (en) 2013-11-05 2021-10-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11147808B2 (en) 2013-11-05 2021-10-19 Antecip Bioventures Ii Llc Method of decreasing the fluctuation index of dextromethorphan
US11191739B2 (en) 2013-11-05 2021-12-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11197839B2 (en) 2013-11-05 2021-12-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11207281B2 (en) 2013-11-05 2021-12-28 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11229640B2 (en) 2013-11-05 2022-01-25 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
US11234946B2 (en) 2013-11-05 2022-02-01 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11253491B2 (en) 2013-11-05 2022-02-22 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11253492B2 (en) 2013-11-05 2022-02-22 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11273133B2 (en) 2013-11-05 2022-03-15 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11285118B2 (en) 2013-11-05 2022-03-29 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11291665B2 (en) 2013-11-05 2022-04-05 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11298351B2 (en) 2013-11-05 2022-04-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11298352B2 (en) 2013-11-05 2022-04-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11311534B2 (en) 2013-11-05 2022-04-26 Antecip Bio Ventures Ii Llc Bupropion as a modulator of drug activity
US11344544B2 (en) 2013-11-05 2022-05-31 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11357744B2 (en) 2013-11-05 2022-06-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11364233B2 (en) 2013-11-05 2022-06-21 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11123344B2 (en) 2013-11-05 2021-09-21 Axsome Therapeutics, Inc. Bupropion as a modulator of drug activity
US11576909B2 (en) 2013-11-05 2023-02-14 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11576877B2 (en) 2013-11-05 2023-02-14 Antecip Bioventures Ii Llc Bupropion as modulator of drug activity
US11382874B2 (en) 2013-11-05 2022-07-12 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11571417B2 (en) 2013-11-05 2023-02-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11478468B2 (en) 2013-11-05 2022-10-25 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11419867B2 (en) 2013-11-05 2022-08-23 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11426401B2 (en) 2013-11-05 2022-08-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11426370B2 (en) 2013-11-05 2022-08-30 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11571399B2 (en) 2013-11-05 2023-02-07 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11541021B2 (en) 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11541048B2 (en) 2013-11-05 2023-01-03 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11497721B2 (en) 2013-11-05 2022-11-15 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11510918B2 (en) 2013-11-05 2022-11-29 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11517543B2 (en) 2013-11-05 2022-12-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11517542B2 (en) 2013-11-05 2022-12-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11517544B2 (en) 2013-11-05 2022-12-06 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11524007B2 (en) 2013-11-05 2022-12-13 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11524008B2 (en) 2013-11-05 2022-12-13 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US11534414B2 (en) 2013-11-05 2022-12-27 Antecip Bioventures Ii Llc Bupropion as a modulator of drug activity
US20200289499A1 (en) * 2014-09-14 2020-09-17 Avanir Pharmaceuticals, Inc. Pharmaceutical compositions comprising a dextromethorphan compound and quinidine for the treatment of agitation in dementia
AU2015350559C1 (en) * 2014-11-21 2019-07-11 Antecip Bioventures Ii Llc Methods of modulating drug plasma levels using erythrohydroxybupropion
WO2016081027A1 (en) 2014-11-21 2016-05-26 Antecip Bioventures Ii Llc Methods of modulating drug plasma levels using erythrohydroxybupropion
AU2015350559B2 (en) * 2014-11-21 2018-12-06 Antecip Bioventures Ii Llc Methods of modulating drug plasma levels using erythrohydroxybupropion
EP3220909B1 (en) 2014-11-21 2020-09-02 Antecip Bioventures II LLC Bupropion for modulating drug plasma levels of dextrometorphan
WO2017165845A1 (en) * 2016-03-24 2017-09-28 Antecip Bioventures Ii Llc Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
EP4360628A3 (en) * 2016-03-24 2024-10-23 Antecip Bioventures II LLC Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
CN111343980A (en) * 2017-10-04 2020-06-26 新凯治疗有限责任公司 Dextromethorphan transdermal delivery device
EP3691641A4 (en) * 2017-10-04 2021-04-07 Shinkei Therapeutics LLC Dextromethorphan transdermal delivery device
US11382869B2 (en) 2017-10-04 2022-07-12 Shinkei Therapeutics Llc Dextromethorphan transdermal delivery device
RU2795729C2 (en) * 2017-10-04 2023-05-11 Шинкей Терапьютикс, Инк. Dextromethorphan transdermal delivery device
CN111343980B (en) * 2017-10-04 2024-02-27 新凯治疗有限公司 Dextromethorphan transdermal delivery device
CN114712356A (en) * 2019-01-07 2022-07-08 安泰赛普生物风投二代有限责任公司 Combination of dextromethorphan and bupropion for the treatment of depression
CN114712357A (en) * 2019-01-07 2022-07-08 安泰赛普生物风投二代有限责任公司 Combination of dextromethorphan and bupropion for the treatment of depression
CN114712358A (en) * 2019-01-07 2022-07-08 安泰赛普生物风投二代有限责任公司 Combination of dextromethorphan and bupropion for the treatment of depression
US20240269130A1 (en) * 2019-01-07 2024-08-15 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression
WO2021202419A1 (en) * 2020-03-30 2021-10-07 Antecip Bioventures Ii Llc Use of bupropion and dextromethorphan combinations for treating neurological disorders
JP2023519965A (en) * 2020-03-30 2023-05-15 アンテシップ バイオベンチャーズ トゥー エルエルシー Use of a combination of bupropion and dextromethorphan to treat neurological disorders
US11896563B2 (en) 2020-12-01 2024-02-13 Antecip Bioventures Ii Llc Bupropion and dextromethorphan for reduction of suicide risk in depression patients
WO2022155591A1 (en) * 2021-01-18 2022-07-21 Antecip Bioventures Ii Llc Combination of an antidepressant and dextromethorphan for neuropsychiatric conditions
US11925636B2 (en) 2022-06-30 2024-03-12 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US11986444B2 (en) 2022-06-30 2024-05-21 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US12036191B1 (en) 2022-06-30 2024-07-16 Antecip Bioventures Ii Llc Treatment of poor metabolizers of dextromethorphan with a combination of bupropion and dextromethorphan
US11717518B1 (en) 2022-06-30 2023-08-08 Antecip Bioventures Ii Llc Bupropion dosage forms with reduced food and alcohol dosing effects
US11883373B1 (en) 2022-07-07 2024-01-30 Antecip Bioventures Ii Llc Treatment of depression in certain patient populations
US11839612B1 (en) 2022-07-07 2023-12-12 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US12042473B2 (en) 2022-07-07 2024-07-23 Antecip Bioventures Ii Llc Compounds and combinations thereof for treating neurological and psychiatric conditions
US11730706B1 (en) 2022-07-07 2023-08-22 Antecip Bioventures Ii Llc Treatment of depression in certain patient populations
US11844797B1 (en) 2023-04-20 2023-12-19 Antecip Bioventures Ii Llc Combination of dextromethorphan and bupropion for treating depression

Also Published As

Publication number Publication date
KR20230148385A (en) 2023-10-24
IL283760B2 (en) 2023-05-01
IL245504A0 (en) 2016-06-30
NZ719892A (en) 2021-07-30
SG10201911808QA (en) 2020-01-30
KR20160070158A (en) 2016-06-17
JP2023129646A (en) 2023-09-14
NZ758431A (en) 2021-07-30
JP2021169527A (en) 2021-10-28
KR102264179B1 (en) 2021-06-11
CN113797205A (en) 2021-12-17
IL283760A (en) 2021-07-29
EP3065742A4 (en) 2017-04-05
MY179696A (en) 2020-11-11
AU2018203638A1 (en) 2018-06-14
KR20210068157A (en) 2021-06-08
SG10201911816XA (en) 2020-01-30
AU2018203638B2 (en) 2019-07-18
CA3154845A1 (en) 2015-05-14
CN110251517A (en) 2019-09-20
AU2019275593A1 (en) 2020-01-02
AU2023203438A1 (en) 2023-07-06
AU2021202497B2 (en) 2023-03-02
EP3065742A1 (en) 2016-09-14
CA3175703A1 (en) 2015-05-14
AU2018203638C1 (en) 2019-10-24
NZ758432A (en) 2021-07-30
AU2019275593B2 (en) 2021-01-28
KR20220054909A (en) 2022-05-03
CN110279682A (en) 2019-09-27
NZ758425A (en) 2021-07-30
AU2014346807A1 (en) 2016-05-19
NZ758428A (en) 2021-07-30
JP6927601B2 (en) 2021-09-01
JP2016535786A (en) 2016-11-17
AU2021202497A1 (en) 2021-05-27
CN110327338A (en) 2019-10-15
JP6605485B2 (en) 2019-11-13
CA2929415A1 (en) 2015-05-14
SG11201603391XA (en) 2016-05-30
JP2020023543A (en) 2020-02-13
CN113750098A (en) 2021-12-07
CA3154845C (en) 2023-02-28
KR102603013B1 (en) 2023-11-15
CN106163522A (en) 2016-11-23
MX2016005867A (en) 2016-07-15
MX2021015234A (en) 2022-05-26
EP3981403A1 (en) 2022-04-13
IL298972A (en) 2023-02-01
IL283760B1 (en) 2023-01-01
EP3981404A1 (en) 2022-04-13
SG10201810888XA (en) 2019-01-30
IL245504B (en) 2021-06-30
AU2019236614B2 (en) 2021-07-15
AU2019236614A1 (en) 2019-10-17
MX2020004075A (en) 2021-12-10
CN113750099A (en) 2021-12-07
AU2014346807B2 (en) 2018-03-22
AU2019236614C1 (en) 2021-10-14
CA2929415C (en) 2023-01-03

Similar Documents

Publication Publication Date Title
AU2021202497B2 (en) Compositions and methods comprising bupropion or related compounds and dextromethorphan
US9370513B2 (en) Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects
US9457025B2 (en) Compositions and methods comprising bupropion or related compounds for sustained delivery of dextromethorphan
AU2015350559C1 (en) Methods of modulating drug plasma levels using erythrohydroxybupropion
US9486450B2 (en) Hydroxybupropion and related compounds as modulators of drug plasma levels

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14859589

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2929415

Country of ref document: CA

Ref document number: 2016552474

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2016/005867

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 245504

Country of ref document: IL

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2014859589

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2014859589

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2014346807

Country of ref document: AU

Date of ref document: 20141105

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20167013970

Country of ref document: KR

Kind code of ref document: A