Dosage forms and methods for enantiomerically enriched or pure bupropion

Abstract

Dosage forms of enantiomerically enriched (S)-bupropion or enantiomerically enriched (R)-bupropion are described herein. The (S)-bupropion or the (R)-bupropion may be rich in deuterium, or may have a natural isotope abundance. These dosage forms may be administered upon eating or fasting to treat conditions described herein, to achieve certain pharmacokinetic parameters of bupropion or bupropion metabolites, and / or to increase dextromethorphan plasma levels.

Description

[0001] This application is a divisional of patent application number 201980026874.5, filed February 25, 2019, having the title “Dosage Forms and Methods for Enantiomerically Enriched or Pure Bupropion,” which is a national stage entry of PCT International Application number PCT / US2019 / 019445, which claims priority to U.S. Provisional Patent Application number 62 / 634,718, filed February 23, 2018; U.S. Provisional Patent Application number 62 / 794,469, filed January 18, 2019; and U.S. Provisional Patent Application number 62 / 809,480, filed February 22, 2019, the entire contents of each of which are incorporated herein by reference.

[0002] Cross Reference to Related Applications

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 634,718, filed February 23, 2018; U.S. Provisional Patent Application No. 62 / 794,469, filed January 18, 2019; and U.S. Provisional Patent Application No. 62 / 809,480, filed February 22, 2019, the entire contents of each of which are incorporated herein by reference. SUMMARY

[0004] Described herein are dosage forms of enantiomerically enriched (S)-bupropion or enantiomerically enriched (R)-bupropion. The (S)-bupropion or the (R)-bupropion can be enriched with deuterium, or can have natural isotopic abundance. These dosage forms can be administered with or without food to treat the conditions described herein, to achieve certain pharmacokinetic parameters of bupropion or bupropion metabolites, and / or to increase dextromethorphan plasma levels.

[0005] Some embodiments include a method of delivering bupropion or a metabolite thereof to the plasma, the method comprising orally administering to a human a dosage form containing about 50 mg to about 100 mg of at least 95% enantiomerically pure (S)-bupropion at least once a day.

[0006] Some embodiments include a method of providing bupropion to the plasma of a human, the method comprising: selecting a human patient in need of bupropion who has pharmacokinetic characteristics provided by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of at least 95% enantiomerically pure (S)-bupropion at the first dosing frequency to achieve the same pharmacokinetic characteristics that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once a day or twice a day; and wherein the second amount is about 40% to about 60% of the first amount.

[0007] Some embodiments include a method of treating a condition treatable with racemic bupropion, the method comprising: selecting a human patient having a condition treatable by oral administration of a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of at least 95% enantiomeric pure (S)-bupropion at the first dosing frequency to achieve the same therapeutic effect that would be achieved by administration of the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once a day or twice a day; and wherein the second amount is about 40% to about 60% of the first amount.

[0008] Some embodiments include a method of increasing plasma levels of (S)-bupropion and dextromethorphan, the method comprising orally administering dextromethorphan and at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day to a human in need of treatment with both (S)-bupropion and dextromethorphan, wherein the method achieves (S)-bupropion C 最大 max in the human that is at least about 90 ng / mL, wherein the method is effective to increase the (S)-bupropion C 最大 max by at least 3-fold compared to (R)-bupropion C 最大 max produced by administration of the same amount of (R)-bupropion to the human.

[0009] Some embodiments include a method of increasing plasma levels of (R,R)-hydroxybupropion and dextromethorphan, the method comprising orally administering dextromethorphan and at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day to a human in need of treatment with both (R,R)-hydroxybupropion and dextromethorphan, wherein the method achieves (R,R)-hydroxybupropion C 最大 max in the human that is at least about 700 ng / mL, wherein the method is effective to increase the (R,R)-hydroxybupropion C 最大 max by at least 3-fold compared to (R)-bupropion C 最大 max produced by administration of the same amount of (R)-bupropion to the human.

[0010] Some embodiments include a method of increasing plasma levels of (S)-bupropion, the method comprising orally administering at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day to a human in need of treatment with (S)-bupropion, wherein the method achieves (S)-bupropion C 最小 max in the human that is at least about 20 ng / mL, wherein the method is effective to increase the (S)-bupropion C 最小 max by at least 3-fold compared to (R)-bupropion C 最小at least 3-fold.

[0011] Some embodiments include a method of increasing plasma levels of (R,R)-hydroxybupropion, the method comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion at least about 90 mg of at least 95% enantiomeric purity of (S)-bupropion at least once a day, wherein the method achieves (R,R)-hydroxybupropion Cmax in the human of at least about 700 ng / mL. 最小 wherein the method is effective to increase the (R,R)-hydroxybupropion Cmax in the human by at least 3-fold compared to administration of the same amount of (R)-bupropion to the human. 最小 (R,R)-hydroxybupropion Cmax in the human of at least about 700 ng / mL. 最小 at least 3-fold.

[0012] Some embodiments include a method of treating a central nervous system (CNS) disorder in a human, the method comprising administering to the human a dosage form comprising a therapeutically effective amount of at least about 95% enantiomeric purity of (S)-bupropion and dextromethorphan.

[0013] Some embodiments include a method of achieving increased plasma levels of (S)-bupropion while increasing plasma levels of dextromethorphan, the method comprising administering to a human in need of treatment with bupropion a dosage form comprising a therapeutically effective amount of at least about 95% enantiomeric purity of (S)-bupropion and dextromethorphan.

[0014] Some embodiments include a dosage form comprising at least about 95% enantiomeric purity of (R)-bupropion and dextromethorphan, wherein oral administration of the dosage form to a human provides an increased increase in plasma levels of dextromethorphan in the human compared to oral administration of a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0015] Some embodiments include a method of increasing an increased plasma level of dextromethorphan in a human, the method comprising administering to the human a dosage form comprising at least about 95% enantiomeric purity of (R)-bupropion and dextromethorphan, wherein the dosage form provides an increased increase in plasma levels of dextromethorphan in the human compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0016] Some embodiments include a method of treating a central nervous system (CNS) disorder in a human, the method comprising administering to the human in need of treatment of the CNS disorder a dosage form comprising a therapeutically effective amount of at least about 95% enantiomeric purity of (S)-bupropion and dextromethorphan, wherein the human is not receiving dextromethorphan.

[0017] Some embodiments include a method of increasing plasma levels of (S)-bupropion, the method comprising administering to a human in need of treatment with bupropion a dosage form comprising a therapeutically effective amount of at least about 95% enantiomerically pure (S)-bupropion, wherein the dosage form does not contain dextromethorphan.

[0018] Some embodiments include a method of increasing plasma levels of (S)-bupropion, the method comprising orally administering to a human in need of treatment with (S)-bupropion and dextromethorphan an oral dosage form comprising at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion, wherein the method achieves a C level of (S)-bupropion of at least about 90 ng / mL in the human. 最大 wherein said method effectively makes said (S)-bupropion C 最大 (R)-bupropion C is produced by administering a dosage form containing the same amount of (R)-bupropion to the human. 最大 at least a 3-fold increase compared to a 3-fold increase in the patient's risk of developing dextromethorphan, wherein the person is not receiving dextromethorphan.

[0019] Some embodiments include a method of increasing plasma levels of (R,R)-hydroxybupropion, the method comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion and dextromethorphan an oral dosage form comprising at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion, wherein the method achieves a plasma level of (R,R)-hydroxybupropion of at least about 90 ng / mL. 最大 wherein said method effectively makes said (R,R)-hydroxybupropion C 最大 (R,R)-hydroxybupropion C produced by administering a dosage form containing the same amount of (R)-bupropion to the human 最大 at least a 3-fold increase compared to a 3-fold increase in the patient's risk of developing dextromethorphan, wherein the person is not receiving dextromethorphan.

[0020] Some embodiments include an oral dosage form comprising at least 95% enantiomeric excess of (R)-bupropion and dextromethorphan, wherein the dosage form provides an increased increase in dextromethorphan plasma levels in the human compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0021] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when orally administered to a human daily for at least eight consecutive days, increases the human's dextromethorphan plasma level on day 1 or day 8 to a substantially greater extent than a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan.

[0022] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 1, that is at least 150% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 1. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8.

[0023] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 1, that is at least 150% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 1. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8.

[0024] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 1, that is at least 150% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 1. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8.

[0025] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 1, that is at least 150% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 1. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8.

[0026] Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 1, that is at least 150% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 1. 最大 Some embodiments include an oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form results in an average dextromethorphan Cmax in a human when orally administered to the human at least for 8 consecutive days when taken every day, on day 8, that is at least 25% greater than a reference oral dosage form when orally administered to the human at least for 8 consecutive days when taken every day, on day 8.

[0027] Some embodiments include a method of increasing dextromethorphan plasma levels on day 1 or day 8, the method comprising orally administering a dosage form containing (R)-bupropion and dextromethorphan, the dosage form increasing the dextromethorphan plasma levels to a substantially greater extent than a reference dosage form when orally administered to a human at least 8 consecutive days per day, wherein the reference dosage form contains the same amount of bupropion as (S)-bupropion and the same amount of dextromethorphan.

[0028] Some embodiments include a method of treating a neuropsychiatric condition, the method comprising administering to a human in need thereof a dosage form described in any of the preceding paragraphs.

[0029] Some embodiments include a method of treating a cold or cough, the method comprising administering to a human in need thereof a dosage form described in any of the preceding paragraphs.

[0030] Some embodiments include a method of reducing pain, the method comprising administering to a human in need thereof a dosage form described in any of the preceding paragraphs.

[0031] Some embodiments include a method of treating addiction, the method comprising administering to a human in need thereof a dosage form described in any of the preceding paragraphs.

[0032] Some embodiments include a method of treating a human, the method comprising orally administering to a human having a condition treatable with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice per day, wherein the amount of (S)-bupropion is selected to be about 20% to about 70% of the amount of racemic bupropion that would be administered to treat the same condition in the same human.

[0033] Some embodiments include a method of providing a therapeutically effective plasma level of (R,R)-hydroxybupropion, the method comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion at least 95% enantiomeric purity of (S)-bupropion once or twice per day, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human, and wherein the method achieves at least about 500 ng / mL of (R,R)-hydroxybupropion C 最大 .

[0034] Some embodiments include a method of treating a human, the method comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the (S)-bupropion is the only active agent used to treat the human.

[0035] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing about 50 mg to about 100 mg of at least 95% enantiomeric pure (S)-bupropion.

[0036] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric pure (S)-bupropion, wherein the method achieves at least about 60 ng / mL of (S)-bupropion C 最大 .

[0037] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric pure (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human.

[0038] Some embodiments include a method of providing a therapeutically effective plasma level of (R,R)-hydroxybupropion comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion once or twice a day at least 95% enantiomeric pure (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human.

[0039] Some embodiments include a method of providing a therapeutically effective plasma level of (R,R)-hydroxybupropion comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion once or twice a day at least 95% enantiomeric pure (S)-bupropion, wherein the method achieves at least about 500 ng / mL of (R,R)-hydroxybupropion C 最大 .

[0040] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric pure (S)-bupropion, wherein the method achieves at least about 70 ng / mL of (S)-bupropion C 最大 .

[0041] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves an (S)-bupropion AUC of at least about 600 ng h / mL 0-12 .

[0042] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves an (R,R)-hydroxybupropion C of at least about 800 ng / mL 最大 .

[0043] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves an (R,R)-hydroxybupropion AUC of at least about 8,000 ng h / mL 0-12 .

[0044] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves an erythrohydroxybupropion C of at least about 90 ng / mL 最大 .

[0045] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves an erythrohydroxybupropion AUC of at least about 1,000 ng h / mL 0-12 .

[0046] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves a threohydroxybupropion C of at least about 450 ng / mL 最大 .

[0047] Some embodiments include a method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a hydroxybupropion AUC of at least about 5,000 ng h / mL 0-12 .

[0048] Some embodiments include a dosage form comprising (S)-bupropion in at least 95% enantiomeric purity.

[0049] Some embodiments include a method of increasing the plasma level of (S)-bupropion or a metabolite thereof comprising administering to a human in need of treatment with bupropion or a metabolite thereof any dosage form described herein.

[0050] Some embodiments include a method of treating a neurological disorder comprising administering to a human in need thereof a dosage form described in any of the preceding paragraphs.

[0051] Some embodiments include a method of increasing the plasma level of dextromethorphan comprising administering to a human in need of treatment by dextromethorphan a combination of (R)-bupropion and dextromethorphan, wherein the (R)-bupropion is at least 95% enantiomeric pure.

[0052] Some embodiments include a method of delivering (S)-bupropion to the plasma of a human comprising orally administering to the human a dosage form containing (S)-bupropion in at least 95% enantiomeric purity.

[0053] Some embodiments include a method of delivering both (R)-bupropion and (S)-bupropion to the plasma of a human comprising orally administering to the human a dosage form containing (S)-bupropion in at least 95% enantiomeric purity, wherein the (R)-bupropion C 最大 is within 20% of what would be produced by administering to the human the same amount of racemic bupropion. 最大 .

[0054] Some embodiments include a method of delivering bupropion to the plasma of a human comprising orally administering to the human a dosage form containing (S)-bupropion in at least 95% enantiomeric purity, wherein the (R)-bupropion AUC 0-12 is within 20% of what would be produced by administering to the human the same amount of racemic bupropion. 0-12 .

[0055] Some embodiments include a method of delivering bupropion into the plasma of a human comprising: orally administering to the human a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the (R,R)-hydroxybupropion C 最大 (R,R)-hydroxybupropion C 最大 within 20% of that which would be produced by administering to the human the same amount of racemic bupropion. DETAILED DESCRIPTION

[0056] Some dosage forms contain (S)-bupropion in enantiomeric excess, or enantiomeric purity. For example, (S)-bupropion can be at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomeric purity, up to (nearly) 100% enantiomeric purity. (S)-bupropion that is 99.99% enantiomeric purity (or enantiomeric excess, or 99.99% ee) contains 99.99% (S)-bupropion and 0.005% [[0.01%]] (R)-bupropion. For convenience, any of the foregoing can be referred to as "(S)-bupropion." Such dosage forms can be used to treat conditions in which increased levels of (S)-bupropion and / or (R,R)-hydroxybupropion are therapeutically beneficial, or in which the human is in need of treatment with (S)-bupropion and / or (R,R)-hydroxybupropion. In addition, increased levels of (S)-bupropion or (R,R)-hydroxybupropion can be used to increase the bioavailability of dextromethorphan plasma or to increase dextromethorphan plasma levels, for example, by co-administering (S)-bupropion with dextromethorphan. Thus, co-administration of (S)-bupropion in enantiomeric excess or enantiomeric purity with dextromethorphan in the same dosage form or in separate dosage forms can be used to treat conditions responsive to dextromethorphan alone or to the combination of (S)-bupropion and dextromethorphan. However, for some treatments, it can not be desirable to use dextromethorphan with (S)-bupropion or (R,R)-hydroxybupropion. Thus, some dosage forms are substantially free of dextromethorphan, and some treatments involve administering (S)-bupropion without co-administration of dextromethorphan.

[0057] Some embodiments include a method of providing a pharmacokinetic equivalent of racemic bupropion to the blood plasma of a human, the method comprising: selecting a human patient in need of a pharmacokinetic profile provided by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of at least 95% enantiomeric pure (S)-bupropion at the first dosing frequency to achieve the same pharmacokinetic profile that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once per day or twice per day; and wherein the second amount is about 20-70%, about 40-60%, about 45-55%, or about 50% of the first amount. For example, if a particular pharmacokinetic profile can be achieved by orally administering a dosage form containing 150 mg of racemic bupropion and the second amount is 40-60% of the first amount, the second amount is 60-90 mg. Thus, in this case, 60-90 mg of (S)-bupropion should be administered once per day to achieve the same pharmacokinetic profile that would be achieved by administering 150 mg of racemic bupropion once per day; or 60-90 mg of (S)-bupropion should be administered twice per day to achieve the same pharmacokinetic profile that would be achieved by administering 150 mg of racemic bupropion twice per day.

[0058] Some embodiments include a method of treating a condition treatable with racemic bupropion, the method comprising: selecting a human patient having a condition treatable by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of at least 95% enantiomeric pure (S)-bupropion at the first dosing frequency to achieve the same therapeutic efficacy that would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once per day or twice per day; and wherein the second amount is about 40-60%, about 45-55%, or about 50% of the first amount. For example, if a condition can be treated by orally administering a dosage form containing 150 mg of racemic bupropion and the second amount is 40-60% of the first amount, the second amount is 60-90 mg. Thus, in this case, 60-90 mg of (S)-bupropion should be administered once per day to treat the condition to achieve the same therapeutic efficacy that would be achieved by administering 150 mg of racemic bupropion once per day; or 60-90 mg of (S)-bupropion should be administered twice per day to treat the condition to achieve the same therapeutic efficacy that would be achieved by administering 150 mg of racemic bupropion twice per day.

[0059] For purposes of the present disclosure, two dosage forms have the same pharmacokinetic profile if a dosage form containing enantiomeric pure (S)-bupropion is recognized by the FDA as bioequivalent to a dosage form containing racemic bupropion.

[0060] In some embodiments, (S)-bupropion C 最大 , (R)-bupropion C 最大 , a combination of (S)-bupropion and (R)-bupropion C 最大 , (R,R)-hydroxybupropion C 最大 , (S,S)-hydroxybupropion C 最大 , a combination of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion C 最大 , threohydroxybupropion C 最大 , erythrohydroxybupropion C 最大 , (S)-bupropion AUC 0-12 , (R)-bupropion AUC 0-12 , a combination of (S)-bupropion and (R)-bupropion AUC 0-12 , (R,R)-hydroxybupropion AUC 0-12 , (S,S)-hydroxybupropion AUC 0-12 , a combination of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion AUC 0-12 , threohydroxybupropion AUC 0-12 , erythrohydroxybupropion AUC 0-12 , or any combination thereof, are within 20% of each other. If the value for one dosage form is 1, then if the value for a second dosage form is within the range of 0.8-1.2, then the two dosage forms are considered to be within 20% of each other.

[0061] Some dosage forms contain (R)-bupropion in enantiomeric excess, or enantiomerically pure (R)-bupropion. For example, (R)-bupropion can be at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99% enantiomerically pure, up to (nearly) 100% enantiomerically pure. For convenience, any of the foregoing can be referred to as "(R)-bupropion." Such dosage forms can be used to increase the bioavailability of dextromethorphan plasma, or to increase dextromethorphan plasma levels, for example, by co-administering (R)-bupropion with dextromethorphan. Thus, co-administration of (R)-bupropion in enantiomeric excess, or enantiomerically pure (R)-bupropion, with dextromethorphan, in a single dosage form or separate dosage forms, can be used to treat conditions responsive to dextromethorphan.

[0062] The above dosage forms and methods can be incorporated into methods for reducing adverse events associated with treatment by bupropion, increasing bupropion plasma levels (e.g., increasing (S)-bupropion plasma levels), reducing the amount or number of doses of bupropion that need to be administered without loss of efficacy, improving the therapeutic profile of bupropion, reducing the valley effect of bupropion, or other methods.

[0063] The dosage forms and methods described above in relation to dextromethorphan can be incorporated into methods for increasing dextromethorphan plasma levels, prolonging the metabolic lifetime of dextromethorphan, reducing adverse events associated with treatment by dextromethorphan, reducing the amount or number of doses of dextromethorphan that need to be administered without loss of efficacy, reducing dextromethorphan plasma levels, improving the therapeutic profile of dextromethorphan, inhibiting the metabolism of dextromethorphan, correcting the extensive metabolism of dextromethorphan, improving the antitussive properties of dextromethorphan, treating cough, reducing the valley effect of dextromethorphan, or other methods.

[0064] In addition, the above dosage forms and methods can be applied to neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, and related conditions.

[0065] Administration of enantiomerically enriched (S)-bupropion or enantiomerically enriched (R)-bupropion and / or dextromethorphan as described above or elsewhere in the present disclosure can occur one or more times a day, or over several days, e.g., consecutive days, e.g., by oral administration. For example, enantiomerically enriched (S)-bupropion alone or in combination with dextromethorphan can be administered once or twice a day for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days. Alternatively, enantiomerically enriched (R)-bupropion alone or in combination with dextromethorphan can be administered once or twice a day for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days. A patient can fast before and / or after oral administration of a dosage form containing (S)-bupropion or (R)-bupropion and / or dextromethorphan.

[0066] In some embodiments, the above treatment can include administration of a dosage form containing (R)-bupropion or (S)-bupropion alone or in combination with dextromethorphan once a day for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice a day treatment. For example, a dosage form containing (R)-bupropion or (S)-bupropion can be administered once a day on days 1, 2, and 3, followed by twice a day administration of the dosage form starting on day 4, and continuing twice a day administration of the dosage form for an extended period of time, for example, for 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90 days or more consecutive days, or for the remainder of the treatment period. Starting with once a day dosing for a shorter period of time, followed by increasing the frequency of dosing to twice a day, can help reduce the risk of seizures.

[0067] (S)-bupropion has the structure shown below.

[0068]

[0069] Unless otherwise specified, reference to a compound (e.g., (S)-bupropion, (R)-bupropion, or dextromethorphan) herein by structure, name, or any other means includes a pharmaceutically acceptable salt; an alternative solid form, such as a polymorph, crystal, solvate, hydrate, etc.; a tautomer; a deuterium-modified compound, such as deuterium-modified dextromethorphan; or any chemical that rapidly converts to a compound described herein under conditions in which the compound is used as described herein.

[0070] For dosage forms comprising (S)-bupropion in enantiomeric excess, any suitable amount of (S)-bupropion can be used. In some embodiments, the dosage form contains at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, about 4-90 mg, about 50-100 mg, about 50-150 mg, about 70-95 mg, about 50-70 mg, about 60-80 mg, about 60-90 mg, about 70-80 mg, about 70-74 mg, about 72-76 mg, about 74-76 mg, about 74-78 mg, about 70-90 mg, about 90-110 mg, about 90-120 mg, about 100-200 mg, about 100-140 mg, about 140-160 mg, about 160-200 mg, about 104-106 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 145-155 mg, about 148-152 mg, about 150-200 mg, about 200-400 mg, about 250-350 mg, about 280-320 mg, about 290-310 mg, about 200-250 mg, about 250-300 mg, about 70 mg, about 75 mg, about 80 mg, about 100 mg, about 105 mg, about 110 mg, about 150 mg, about 10-50 mg, about 50-100 mg, about 40-90 mg, about 70-95 mg, or about 50-150 mg of (S)-bupropion, or any amount within a range bounded by any of these values. Ranges of amounts of (S)-Bu obtained by combining any of the above ranges or endpoints are also contemplated, particularly if the obtained range encompasses or is near one or more of the following values for the amount of (S)-bupropion in the dosage form: about 50 mg, about 60 mg, about 75 mg, or about 90 mg, about 105 mg, or about 150 mg. These values are values that are believed to have particular utility. Dosage forms containing an amount of (S)-bupropion described above can be administered once, twice, or three times per day for a daily dose that is 1, 2, or 3 times the amount of any of the above doses or any of the dose ranges, e.g., a daily dose of 180-240 mg that is 2 times 90-120 mg, or a daily dose of 270-360 mg that is 3 times 90-120 mg. Any daily dose obtained by combining any of the above dose ranges or endpoints and multiplying the result by 1, 2, or 3 is also contemplated, particularly if the obtained range encompasses or is near one or more of the following values: about 150 mg, about 210 mg, or about 250 mg. These values are values that are believed to have particular utility.

[0071] Some solid compositions can comprise at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, about 10-30%, about 30-50%, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% by weight of (S)-bupropion.

[0072] In some embodiments, the dosage form can be free or substantially free of any active agent or drug other than (S)-bupropion. For example, the dosage form can contain less than 10%, less than 5%, less than 1%, or less than 0.1% by weight of any other active agent as compared to the weight of (S)-bupropion. In some embodiments, the dosage form can contain less than 10%, less than 5%, less than 1%, or less than 0.1% by weight of dextromethorphan, or be free of dextromethorphan, as compared to the weight of (S)-bupropion. Alternatively, (S)-bupropion can be combined with another compound (e.g., dextromethorphan) in the dosage form.

[0073] Administering (S)-bupropion can be used to increase (S)-bupropion plasma levels by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, about 5-20-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold or more, about 10-15-fold, about 10-25-fold, about 5-20-fold, about 20-30-fold, about 30-40-fold, about 40-50-fold, about 50-60-fold, about 60-70-fold, about 70-80-fold, about 80-90-fold, about 90-100-fold, about 100-110-fold, about 110-120-fold, about 120-130-fold, about 130-140-fold, about 140-150-fold, about 150-160-fold, about 160-170-fold, about 170-180-fold, about 180-190-fold, or about 190-200-fold, as compared to (R)-bupropion plasma levels obtained by administering to a human a dosage form containing the same amount of (R)-bupropion.

[0074] In some embodiments, the method is effective to increase the AUC 0-12 , for example, the mean AUC 0-12 , the mean AUC 0-12 , the median AUC 0-12 , or the individual AUC 0-12The (R)-bupropion AUC obtained by administering a dosage form containing the same amount of (R)-bupropion to humans is 0-12 Compared to the above, the increase is at least about 1.1 times, at least about 1.2 times, at least about 1.3 times, at least about 1.4 times, at least about 1.5 times, at least about 1.6 times, at least about 1.7 times, at least about 1.8 times, at least about 1.9 times, at least about 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 8 times, at least about 10 times, about 10 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 50 times, at least about 100 times, at least about 150 times, at least about 200 times, or more, about 10 -15 times, about 10-25 times, about 5-20 times, about 20-30 times, about 30-40 times, about 40-50 times, about 50-60 times, about 60-70 times, about 70-80 times, about 80-90 times, about 90-100 times, about 100-110 times, about 110-120 times, about 120-130 times, about 130-140 times, about 140-150 times, about 150-160 times, about 160-170 times, about 170-180 times, about 180-190 times, or about 190-200 times.

[0075] In some embodiments, the method achieves an AUC of (S)-bupropion, or a combination of (S)-bupropion and (R)-bupropion of at least about 300 ng hr / mL, at least about 400 ng hr / mL, at least about 500 ng hr / mL, at least about 600 ng hr / mL, at least about 700 ng hr / mL, at least about 750 ng hr / mL, at least about 800 ng hr / mL, at least about 850 ng hr / mL, at least about 900 ng hr / mL, at least about 950 ng hr / mL, at least about 1,000 ng hr / mL, at least about 1,100 ng hr / mL, at least about 1,200 ng hr / mL, up to about 1,200 ng hr / mL, up to about 1,300 ng hr / mL, up to about 1,400 ng hr / mL, up to about 1,500 ng hr / mL, up to about 1,600 ng hr / mL, up to about 1,700 ng hr / mL, up to about 1,800 ng hr / mL, about 300-400 ng hr / mL, about 400-500 ng hr / mL, about 500-600 ng hr / mL, about 600-700 ng hr / mL, about 700-800 ng hr / mL, about 800-900 ng hr / mL, about 900-1,000 ng hr / mL, about 1,000-1,100 ng hr / mL, about 1,100-1,200 ng hr / mL, about 1,200-1,300 ng hr / mL, about 1,300-1,400 ng hr / mL, about 1,400-1,500 ng hr / mL, about 1,500-1,600 ng hr / mL, about 1,600-1,700 ng hr / mL, about 1,700-1,800 ng hr / mL, about 300-600 ng hr / mL, about 600-900 ng hr / mL, about 900-1,200 ng hr / mL, about 1,200-1,500 ng hr / mL, about 1,500-1,800 ng hr / mL, about 300-800 ng hr / mL, about 800-1,300 ng hr / mL, about 1,300-1,800 ng hr / mL, or about 300-1,800 ng hr / mL. 0-12 , for example, the mean AUC 0-12 , the mean AUC 0-12 , the median AUC 0-12 , or the individual AUC 0-12 . AUC 0-12 ranges obtained by combining any of the above ranges or endpoints are also contemplated, particularly if the resulting range encompasses or is close to an AUC 0-12one or more of the following values: 350 ng hr / mL, 400 ng hr / mL, 750 ng hr / mL, 900 ng hr / mL, 1,150 ng hr / mL, or 1,400 ng hr / mL. These values are those that are believed to have particular utility. The target AUC range can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.

[0076] In some embodiments, the method is effective to increase the Cmax of (S)-bupropion by at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 8 fold, about 5-20 fold, at least about 10 fold, about 10 fold, at least about 20 fold, at least about 25 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human. 最大 , for example, mean C 最大 , mean C 最大 , median C 最大 , or individual C 最大 is increased by at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 8 fold, about 5-20 fold, at least about 10 fold, about 10 fold, at least about 20 fold, at least about 25 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human.

[0077] In some embodiments, the method achieves a Cmax (e.g., mean Cmax, average Cmax, median Cmax, or individual Cmax) of (S)-bupropion or a combined Cmax of (S)-bupropion and (R)-bupropion of at least about 30 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, at least about 105 ng / mL, at least about 110 ng / mL, at least about 115 ng / mL, at least about 120 ng / mL, at least about 125 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, up to about 130 ng / mL, up to about 140 ng / mL, up to about 150 ng / mL, up to about 160 ng / mL, up to about 170 ng / mL, up to about 180 ng / mL, up to about 190 ng / mL, up to about 200 ng / mL, up to about 210 ng / mL, up to about 220 ng / mL, about 30-40 ng / mL, about 40-50 ng / mL, about 50-60 ng / mL, about 60-70 ng / mL, about 70-80 ng / mL, about 80-90 ng / mL, about 90-100 ng / mL, about 100-110 ng / mL, about 110-120 ng / mL, about 120-130 ng / mL, about 130-140 ng / mL, about 140-150 ng / mL, about 150-160 ng / mL, about 160-170 ng / mL, about 170-180 ng / mL, about 180-190 ng / mL, about 190-200 ng / mL, about 200-210 ng / mL, about 210-220 ng / mL, about 50-70 ng / mL, about 70-90 ng / mL, about 30-60 ng / mL, about 60-90 ng / mL, about 90-120 ng / mL, about 120-160 ng / mL, about 160-220 ng / mL, about 30-90 ng / mL, about 90-150 ng / mL, about 150-220 ng / mL, about 30-110 ng / mL, about 130-190 ng / mL, about 110-220 ng / mL, or about 30-220 ng / mL. 最大 Cmax of (S)-bupropion or a combined Cmax of (S)-bupropion and (R)-bupropion obtained by combining any of the above ranges or endpoints is also contemplated, particularly if the resulting range encompasses or is close to a Cmax of (S)-bupropion or a combined Cmax of (S)-bupropion and (R)-bupropion of about 30 ng / mL, about 40 ng / mL, about 50 ng / mL, about 60 ng / mL, about 70 ng / mL, about 80 ng / mL, about 90 ng / mL, about 100 ng / mL, about 110 ng / mL, about 120 ng / mL, about 130 ng / mL, about 140 ng / mL, about 150 ng / mL, about 160 ng / mL, about 170 ng / mL, about 180 ng / mL, about 190 ng / mL, about 200 ng / mL, about 210 ng / mL, about 220 ng / mL, about 50-70 ng / mL, about 70-90 ng / mL, about 30-60 ng / mL, about 60-90 ng / mL, about 90-120 ng / mL, about 120-160 ng / mL, about 160-220 ng / mL, about 30-90 ng / mL, about 90-150 ng / mL, about 150-220 ng / mL, about 30-110 ng / mL, about 130-190 ng / mL, about 110-220 ng / mL, or about 30-220 ng / mL. 最大 最大 ​one or more of the following values: 45 ng / mL, 90 ng / mL, 130 ng / mL, 160 ng / mL, or 190 ng / mL. These values are values that are believed to have particular utility. The target Cmax 最大 range.

[0078] In some embodiments, the method is effective to produce a Cmax 最小 , e.g., mean Cmax 最小 , mean Cmax 最小 , median Cmax 最小 , or individual Cmax 最小 of (S)-bupropion that is at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 8 fold, at least about 10 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 10-15 fold, about 10-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, greater than the Cmax

[0079] In some embodiments, the method achieves a Cmax 最小 , e.g., mean Cmax 最小 , mean Cmax 最小 , median Cmax 最小 , or individual Cmax 最小 of (S)-bupropion of at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, about 20-60 ng / mL, about 25-30 ng / mL, about 30-35 ng / mL, about 35-40 ng / mL, about 30-40 ng / mL, about 40-45 ng / mL, about 45-50 ng / mL, about 30-50 ng / mL, about 40-50 ng / mL, or about 50-60 ng / mL. Cmax 最小Ranges are also contemplated, particularly if the ranges obtained encompass or approach one or more of the following values: 20 ng / mL, 30 ng / mL, 40 ng / mL, or 50 ng / mL. These values are values that are believed to have particular utility. 最小

[0080] Administration of (S)-bupropion can be used to increase the plasma level of (R,R)-hydroxybupropion by at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 3 fold, at least about 5 fold, at least about 10 fold, at least about 15 fold, at least about 20 fold, at least about 40 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold or more, about 5-10 fold, about 5-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human.

[0081] Administration of (S)-bupropion can be used to increase the AUC 0-12 , for example the mean AUC 0-12 , the mean AUC 0-12 , the median AUC 0-12 , or the individual AUC 0-12 of (R,R)-hydroxybupropion by at least about 1.1 fold, at least about 1.5 fold, at least about 2 fold, at least about 3 fold, at least about 5 fold, at least about 10 fold, at least about 15 fold, at least about 20 fold, at least about 40 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold or more, about 5-10 fold, about 5-25 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human.

[0082] ​In some embodiments, the method achieves an AUC of (R,R)-hydroxybupropion, or a combination of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion of at least about 1,000 ng·hr / mL, at least about 3,000 ng·hr / mL, at least about 4,000 ng·hr / mL, at least about 6,000 ng·hr / mL, at least about 7,000 ng·hr / mL, at least about 7,500 ng·hr / mL, at least about 8,000 ng·hr / mL, at least about 8,500 ng·hr / mL, at least about 9,000 ng·hr / mL, at least about 9,500 ng·hr / mL, at least about 10,000 ng·hr / mL, at least about 12,000 ng·hr / mL, at least about 13,000 ng·hr / mL, about 4,000-6,000 ng·hr / mL, about 6,000-8,000 ng·hr / mL, about 8,000-10,000 ng·hr / mL, about 10,000-12,000 ng·hr / mL, about 12,000-14,000 ng·hr / mL, about 14,000-16,000 ng·hr / mL, about 16,000-18,000 ng·hr / mL, about 18,000-20,000 ng·hr / mL, about 20,000-22,000 ng·hr / mL, about 22,000-24,000 ng·hr / mL, about 4,000-10,000 ng·hr / mL, about 10,000-16,000 ng·hr / mL, about 16,000-24,000 ng·hr / mL, about 4,000-24,000 ng·hr / mL, up to about 14,000 ng·hr / mL, up to about 16,000 ng·hr / mL, up to about 18,000 ng·hr / mL, up to about 20,000 ng·hr / mL, up to about 22,000 ng·hr / mL, up to about 24,000 ng·hr / mL, or up to about 30,000 ng·hr / mL 0-12 , for example, the mean AUC 0-12 , the mean AUC 0-12 , the median AUC 0-12 , or the individual AUC 0-12 . AUC 0-12 ranges obtained by combining any of the above ranges or endpoints are also contemplated, particularly if the resulting range encompasses or is close to an AUC 0-12one or more of the following values: 4,000 ng-hr / mL, 5,000 ng-hr / mL, 10,000 ng-hr / mL, 13,400 ng-hr / mL, 16,000 ng-hr / mL, or 22,000 ng-hr / mL. These values are those that are believed to have particular utility. The target AUC range can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.

[0083] In some embodiments, the method is effective to increase the Cmax of (R,R)-hydroxybupropion by at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, about 6 fold, at least about 10 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 5-10 fold, about 10-20 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human. 最大 , for example, mean C 最大 , mean C 最大 , median C 最大 , or individual C 最大 is increased by at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, about 6 fold, at least about 10 fold, at least about 20 fold, at least about 50 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 5-10 fold, about 10-20 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human.

[0084] In some embodiments, the method achieves a Cmax of (R,R)-hydroxybupropion, or (S,S)-hydroxybupropion and (R,R)-hydroxybupropion of at least about 90 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, at least about 900 ng / mL, at least about 1,000 ng / mL, at least about 1,100 ng / mL, at least about 1,200 ng / mL, at least about 1,300 ng / mL, up to about 1,400 ng / mL, up to about 1,500 ng / mL, up to about 1,600 ng / mL, up to about 1,700 ng / mL, up to about 1,800 ng / mL, up to about 1,900 ng / mL, up to about 2,000 ng / mL, up to about 2,100 ng / mL, up to about 2,200 ng / mL, up to about 2,300 ng / mL, about 300-400 ng / mL, about 400-500 ng / mL, about 500-600 ng / mL, about 600-700 ng / mL, about 700-800 ng / mL, about 800-900 ng / mL, about 900-1,000 ng / mL, about 1,000-1,100 ng / mL, about 1,100-1,200 ng / mL, about 1,200-1,300 ng / mL, about 1,300-1,400 ng / mL, about 1,400-1,500 ng / mL, about 1,500-1,600 ng / mL, about 1,600-1,700 ng / mL, about 1,700-1,800 ng / mL, about 1,800-1,900 ng / mL, about 1,900-2,000 ng / mL, about 2,000-2,100 ng / mL, about 2,100-2,200 ng / mL, about 2,200-2,300 ng / mL, about 300-800 ng / mL, about 800-1,300 ng / mL, about 1,300-2,300 ng / mL, or about 300-2,300 ng / mL. 最大 , for example, average C 最大 , mean C 最大 , median C 最大 , or individual C 最大 . Cmax obtained by combining any of the above ranges or endpoints. 最大Ranges are also contemplated, particularly if the range obtained encompasses or is close to one or more of the following values below Cmax: 400 ng / mL, 950 ng / mL, 1,100 ng / mL, 1,250 ng / mL, 1,400 ng / mL, or 2,100 ng / mL. These values are values that are believed to have particular utility. The target C 最大 range.

[0085] Administration of (S)-bupropion can be used to increase the C 最小 , for example, the average C 最小 , the mean C 最小 , the median C 最小 , or the individual C 最小 at least about 1.1 fold, at least about 1.2 fold, at least about 1.3 fold, at least about 1.4 fold, at least about 1.5 fold, at least about 1.6 fold, at least about 1.7 fold, at least about 1.8 fold, at least about 1.9 fold, at least about 2 fold, at least about 2.5 fold, at least about 3 fold, at least about 4 fold, at least about 5 fold, at least about 10 fold, at least about 20 fold, at least about 50 fold, at least about 60 fold, at least about 100 fold, at least about 150 fold, at least about 200 fold, or more, about 1-5 fold, about 5-10 fold, about 5-20 fold, about 20-30 fold, about 30-40 fold, about 40-50 fold, about 50-60 fold, about 60-70 fold, about 70-80 fold, about 80-90 fold, about 90-100 fold, about 100-110 fold, about 110-120 fold, about 120-130 fold, about 130-140 fold, about 140-150 fold, about 150-160 fold, about 160-170 fold, about 170-180 fold, about 180-190 fold, or about 190-200 fold, compared to administration of a dosage form containing the same amount of (R)-bupropion to a human.

[0086] In some embodiments, the method achieves a Cmax of (R,R)-hydroxybupropioneranging from at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, at least about 900 ng / mL, at least about 1,000 ng / mL, at least about 1,100 ng / mL, at least about 1,200 ng / mL, up to about 1,300 ng / mL, up to about 1,400 ng / mL, up to about 1,500 ng / mL, up to about 1,600 ng / mL, up to about 1,700 ng / mL, up to about 1,800 ng / mL, up to about 1,900 ng / mL, up to about 2,000 ng / mL, up to about 2,100 ng / mL, up to about 2,200 ng / mL, up to about 2,300 ng / mL, about 200-300 ng / mL, about 300-400 ng / mL, about 400-500 ng / mL, about 500-600 ng / mL, about 600-700 ng / mL, about 700-800 ng / mL, about 800-900 ng / mL, about 900-1,000 ng / mL, about 1,000-1,100 ng / mL, about 1,100-1,200 ng / mL, about 1,200-1,300 ng / mL, about 1,300-1,400 ng / mL, about 1,400-1,500 ng / mL, about 1,500-1,600 ng / mL, about 300-700 ng / mL, about 700-1,100 ng / mL, about 1,100-1,600 ng / mL, or about 800-1,200 ng / mL. 最小 For example, average C 最小 , mean C 最小 , median C 最小 , or individual C 最小 . C 最小 ranges obtained by combining any of the above ranges or endpoints are also contemplated, particularly if the obtained range encompasses or is near one or more of the following values for C 最小 : 350 ng / mL, 600 ng / mL, 800 ng / mL, 1,000 ng / mL, 1,200 ng / mL, or 1,400 ng / mL. These values are values that are believed to have particular utility.

[0087] Administration of (S)-bupropion to a human can result in (R,R)-hydroxybupropion being at least 90%, at least 95%, at least 97%, at least 97.2%, at least 97.4%, at least 97.6%, at least 97.8%, or at least 98% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human's plasma.

[0088] In some embodiments, the method achieves an AUC of erythrohydrobupropion of at least about 500 ng hr / mL, at least about 600 ng hr / mL, at least about 800 ng hr / mL, at least about 1,000 ng hr / mL, at least about 1,200 ng hr / mL, at least about 1,400 ng hr / mL, at least about 1,500 ng hr / mL, at least about 1,600 ng hr / mL, at least about 1,800 ng hr / mL, at least about 2,000 ng hr / mL, up to about 1,400 ng hr / mL, up to about 1,600 ng hr / mL, up to about 1,800 ng hr / mL, up to about 2,000 ng hr / mL, up to about 2,200 ng hr / mL, up to about 2,400 ng hr / mL, up to about 2,600 ng hr / mL, up to about 2,800 ng hr / mL, up to about 3,000 ng hr / mL, about 500-600 ng hr / mL, about 600-800 ng hr / mL, about 800-1,000 ng hr / mL, about 1,000-1,200 ng hr / mL, about 1,200-1,400 ng hr / mL, about 1,400-1,600 ng hr / mL, about 1,600-1,800 ng hr / mL, about 1,800-2,000 ng hr / mL, about 2,000-2,200 ng hr / mL, about 2,200-2,400 ng hr / mL, about 2,400-2,600 ng hr / mL, about 2,600-2,800 ng hr / mL, about 2,800-3,000 ng hr / mL, about 500-1,000 ng hr / mL, about 1,000-1,500 ng hr / mL, about 1,500-2,000 ng hr / mL, about 2,000-2,500 ng hr / mL, about 2,500-3,000 ng hr / mL, about 500-1,500 ng hr / mL, about 1,500-3,000 ng hr / mL, about 2,000-3,000 ng hr / mL, or about 500-3,000 ng hr / mL. 0-12 , for example, mean AUC 0-12 , mean AUC 0-12 , median AUC0-12 or individual AUC 0-12 AUC obtained by combining any of the above ranges or endpoints 0-12 Ranges are also contemplated, particularly if the obtained range encompasses or is close to an AUC 0-12 one or more of the following values: 500 ng-hr / mL, 1,300 ng-hr / mL, 1,500 ng-hr / mL, 1,800 ng-hr / mL, or 2,600 ng-hr / mL. These values are values that are believed to have particular utility. The target AUC range can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.

[0089] In some embodiments, the method achieves a Cmaxof at least about 40 ng / mL, at least about 60 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 120 ng / mL, at least about 140 ng / mL, at least about 160 ng / mL, at least about 180 ng / mL, at least about 200 ng / mL, up to about 160 ng / mL, up to about 180 ng / mL, up to about 200 ng / mL, up to about 220 ng / mL, up to about 240 ng / mL, up to about 260 ng / mL, up to about 280 ng / mL, about 40-60 ng / mL, about 60-80 ng / mL, about 80-100 ng / mL, about 100-120 ng / mL, about 120-140 ng / mL, about 140-160 ng / mL, about 160-180 ng / mL, about 180-200 ng / mL, about 200-220 ng / mL, about 220-240 ng / mL, about 240-260 ng / mL, about 260-280 ng / mL, about 280-300 ng / mL, about 40-100 ng / mL, about 100-150 ng / mL, about 150-200 ng / mL, about 200-250 ng / mL, about 250-280 ng / mL, about 40-120 ng / mL, about 120-200 ng / mL, about 200-280 ng / mL, or about 40-280 ng / mL of the erythro-hydroxybupropion. 最大 , for example, a mean C 最大 , a mean C 最大 , a median C 最大 or individual C 最大 . Ranges of C 最大 are also contemplated, particularly if the obtained range encompasses or is close to a C 最大one or more of the following values: 60 ng / mL, 120 ng / mL, 130 ng / mL, 200 ng / mL, or 240 ng / mL. These values are values that are believed to have particular utility. The target C 最大 range.

[0090] In some embodiments, the method achieves an AUCs of S-hydroxybupropioneranging from at least 1,000 ng hr / mL, at least about 2,000 ng hr / mL, at least about 3,000 ng hr / mL, at least about 4,000 ng hr / mL, at least about 5,000 ng hr / mL, at least about 6,000 ng hr / mL, at least about 7,000 ng hr / mL, at least about 8,000 ng hr / mL, up to about 8,000 ng hr / mL, up to about 9,000 ng hr / mL, up to about 10,000 ng hr / mL, up to about 11,000 ng hr / mL, up to about 12,000 ng hr / mL, up to about 13,000 ng hr / mL, up to about 14,000 ng hr / mL, up to about 15,000 ng hr / mL, about 2,000-15,000 ng hr / mL, about 2,000-3,000 ng hr / mL, about 3,000-4,000 ng hr / mL, about 4,000-5,000 ng hr / mL, about 5,000-6,000 ng hr / mL, about 6,000-7,000 ng hr / mL, about 7,000-8,000 ng hr / mL, about 8,000-9,000 ng hr / mL, about 9,000-10,000 ng hr / mL, about 10,000-11,000 ng hr / mL, about 11,000-12,000 ng hr / mL, about 12,000-13,000 ng hr / mL, about 13,000-14,000 ng hr / mL, about 14,000-15,000 ng hr / mL, about 2,000-6,000 ng hr / mL, about 6,000-10,000 ng hr / mL, about 10,000-15,000 ng hr / mL, about 2,000-9,000 ng hr / mL, or about 9,000-15,000 ng hr / mL. 0-12 , for example, the mean AUC 0-12 , the mean AUC 0-12 , the median AUC 0-12 , or the individual AUC 0-12 . AUCs obtained by combining any of the above ranges or endpoints.0-12 Ranges are also contemplated, particularly if the obtained range encompasses or is close to an AUC 0-12 of one or more of the following values: 3,000 ng-hr / mL, 6,000 ng-hr / mL, 8,000 ng-hr / mL, or 12,000 ng-hr / mL. These values are values that are believed to be of particular interest. The target AUC range can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later.

[0091] In some embodiments, the method achieves a Cmaxof at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 450 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, up to about 800 ng / mL, up to about 900 ng / mL, up to about 1,000 ng / mL, up to about 1,100 ng / mL, up to about 1,200 ng / mL, up to about 1,300 ng / mL, up to about 1,400 ng / mL, about 200-300 ng / mL, about 300-400 ng / mL, about 400-500 ng / mL, about 500-600 ng / mL, about 600-700 ng / mL, about 700-800 ng / mL, about 800-900 ng / mL, about 900-1000 ng / mL, about 1,000-1,100 ng / mL, about 1,100-1,200 ng / mL, about 1,200-1,300 ng / mL, about 1,300-1,400 ng / mL, about 200-500 ng / mL, about 500-800 ng / mL, about 800-1,100 ng / mL, about 1,100-1,400 ng / mL, about 200-800 ng / mL, about 800-1400 ng / mL, 400-600 ng / mL, or about 200-1,400 ng / mL of the S-hydroxymetelol. 最大 For example, the average Cmax 最大 , the mean Cmax 最大 , the median Cmax 最大 , or the individual Cmax 最大 . Ranges of Cmaxobtained by combining any of the above ranges or endpoints are also contemplated, particularly if the obtained range encompasses or is close to a Cmax 最大 of one or more of the following values: 3,000 ng-hr / mL, 6,000 ng-hr / mL, 8,000 ng-hr / mL, or 12,000 ng-hr / mL. These values are values that are believed to be of particular interest. The target AUC range can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or later. 最大one or more of the following values: 300 ng / mL, 500 ng / mL, 600 ng / mL, 900 ng / mL, or 1,200 ng / mL. These values are those that are believed to be of particular interest. The target C 最大 range.

[0092] (R)-Bupropion has the structure shown below.

[0093]

[0094] For dosage forms comprising (R)-bupropion in enantiomeric excess, any suitable amount of (R)-bupropion can be used. In some embodiments, the dosage form contains at least about 80 mg, at least about 90 mg, at least about 100 mg, about 90-110 mg, about 100-200 mg, about 100-150 mg, about 100-140 mg, about 140-160 mg, about 160-200 mg, about 104-106 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 145-155 mg, about 148-152 mg, about 150-200 mg, about 200-400 mg, about 250-350 mg, about 280-320 mg, about 290-310 mg, about 200-250 mg, about 250-300 mg, about 100 mg, about 105 mg, about 110 mg, or about 150 mg of (R)-bupropion, or any amount within a range bounded by any of these values. Such dosage forms can be administered with dextromethorphan, which can be administered in a separate dosage form or in the same dosage form as the (R)-bupropion. Dosage forms containing an amount of (R)-bupropion described above can be administered once, twice, or three times a day for an amount per daily dose that is 1, 2, or 3 times any of the amounts of doses described above or any of the dose ranges.

[0095] In some embodiments, the dosage form can be free or substantially free of any active pharmaceutical agent or drug other than (R)-bupropion and / or dextromethorphan. For example, the dosage form can contain less than 10 wt%, less than 5 wt%, less than 1 wt%, or less than 0.1 wt% of any other active pharmaceutical agent compared to the weight of (R)-bupropion plus dextromethorphan.

[0096] Some solid compositions can comprise at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 60% (w / w) to about 70% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) of (R)-bupropion.

[0097] As described above, depending on the particular therapeutic need, the dosage form containing enantiomeric excess (S)-bupropion or enantiomeric excess (R)-bupropion can be administered with dextromethorphan, or can contain dextromethorphan.

[0098] Dextromethorphan has the structure shown below.

[0099]

[0100] Unless otherwise noted, reference to a compound herein by structure, name, or any other means, e.g., (S)-bupropion, (R)-bupropion, and / or dextromethorphan, includes a pharmaceutically acceptable salt; an alternative solid form, e.g., polymorph, crystal, solvate, hydrate, etc.; a tautomer; a deuterium-modified compound, e.g., deuterium-modified dextromethorphan; or any chemical that rapidly converts to the compound described herein under the conditions in which the compound is used as described herein.

[0101] Dextromethorphan can be enriched in deuterium, or can have natural isotopic abundance.

[0102] Dextromethorphan is used as a cough suppressant. According to FDA’s dextromethorphan product labeling requirements under OTC monograph [21 CFR 341.74], dextromethorphan should be dosed 6 times per day (once every 4 hours), 4 times per day (once every 6 hours), or 3 times per day (once every 8 hours).

[0103] Dextromethorphan is rapidly metabolized in human liver. This rapid hepatic metabolism can limit systemic drug exposure in individuals who are extensive metabolizers of dextromethorphan. A human can be: 1) an extensive metabolizer of dextromethorphan - those metabolizers who rapidly metabolize dextromethorphan; 2) a poor metabolizer of dextromethorphan - those metabolizers who only poorly metabolize dextromethorphan; or 3) an intermediate metabolizer of dextromethorphan - those metabolizers whose metabolism of dextromethorphan is somewhere between extensive and poor metabolizers. Extensive metabolizers can also be ultra-rapid metabolizers. Extensive metabolizers of dextromethorphan comprise a large fraction of the human population. Dextromethorphan (DM) can be metabolized, for example, to dextrorphan (DX). The DM / DX ratio can be used to represent the degree of metabolism of dextromethorphan. A lower DM / DX ratio indicates a higher degree of metabolism of dextromethorphan. Humans with a DM / DX ratio < 0.3 are generally considered to be phenotypically extensive metabolizers.

[0104] Dextromethorphan plasma levels are significantly higher in poor or intermediate metabolizers compared to extensive metabolizers of dextromethorphan when given the same oral dose of dextromethorphan. Low dextromethorphan plasma concentrations can limit its clinical utility as a single agent for extensive metabolizers of dextromethorphan and possibly intermediate metabolizers. Some therapeutically active compounds, including antidepressants, such as (S)-bupropion or (R)-bupropion, inhibit the metabolism of dextromethorphan and increase dextromethorphan plasma concentrations, thereby can improve the therapeutic efficacy of dextromethorphan. Similarly, (S)-bupropion or (R)-bupropion can allow dextromethorphan to be given less frequently without loss of therapeutic efficacy, for example, 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. Also, (S)-bupropion or (R)-bupropion can allow dextromethorphan to be given in a smaller amount per dose or total dose or both.

[0105] Dosage forms containing dextromethorphan used for this purpose, administered as an adjunctive dosage form or in combination with (S)-bupropion or (R)-bupropion as a single dosage form, can contain any suitable amount of dextromethorphan, such as about 1-150 mg, about 10-100 mg, about 10-50 mg, about 20-50 mg, about 10-20, about 15-25, about 20-30, about 25-35, about 30-40, about 35-45, about 30-50 mg, about 40-50 mg, about 43-48 mg, about 44-46 mg, about 50-100 mg, about 50-80 mg, about 80-100 mg, about 85-95 mg, about 88-92 mg, about 100-150 mg, about 30 mg, about 45 mg, or about 60 mg of dextromethorphan, or any amount of dextromethorphan within a range bounded by any of these values. Dosage forms containing an amount of dextromethorphan described above can be administered once, twice, or three times a day for a daily dose that is 1, 2, or 3 times the amount of any of the above described doses or any of the dose ranges.

[0106] Some solid compositions can comprise at least about 5% (w / w), at least about 10% (w / w), at least about 20% (w / w), at least about 50% (w / w), at least about 70% (w / w), at least about 80%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), about 30% (w / w) to about 50% (w / w), about 30% (w / w) to about 40% (w / w), about 40% (w / w) to about 50% (w / w), about 50% (w / w) to about 80% (w / w), about 50% (w / w) to about 60% (w / w), about 60% (w / w) to about 70% (w / w), about 70% (w / w) to about 80% (w / w), or about 80% (w / w) to about 90% (w / w) dextromethorphan.

[0107] (S)-bupropion, (R)-bupropion, and / or dextromethorphan can 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 can be determined by, for example, the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0108] (S)-bupropion, (R)-bupropion and / or dextromethorphan can be administered to human patients in a variety of forms suitable for the selected route of administration, such as oral or parenteral. In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial (including transdermal); ophthalmic; sublingual; and buccal, and topical (including ophthalmic); transdermal; ocular; rectal; and nasal.

[0109] (S)-bupropion, (R)-bupropion and / or dextromethorphan can be formulated for oral administration, for example, with an inert diluent or edible carrier, or they can be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the food of the diet. For oral therapeutic administration, the active compound can be mixed with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0110] Tablets, lozenges, pills, capsules, and the like containing (S)-bupropion, (R)-bupropion, and / or dextromethorphan may also contain one or more of the following: a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; a sweetener such as sucrose, lactose, or saccharin; or a flavoring such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage form is a capsule, it may contain a liquid carrier in addition to the materials of the types mentioned above. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain the active compound, sucrose as a sweetener, methylparaben and propylparaben as preservatives, a dye, and a flavoring such as cherry or orange flavoring. It may be desirable for the substances in dosage forms or pharmaceutical compositions to be pharmaceutically pure and substantially non-toxic in the amounts employed.

[0111] Some compositions or dosage forms may be liquid, or may comprise a solid phase dispersed in a liquid.

[0112] (S)-bupropion, (R)-bupropion, and / or dextromethorphan can be formulated for parenteral 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. Dispersions can also comprise oil dispersed in or in glycerol, liquid polyethylene glycol, and mixtures thereof. Under normal conditions of storage and use, these preparations may contain a preservative to prevent microbial growth.

[0113] Dosage forms or compositions containing both (S)-bupropion or (R)-bupropion and dextromethorphan can be a blend or mixture of bupropion and dextromethorphan, either individually or in a vehicle. For example, (S)-bupropion or (R)-bupropion and dextromethorphan can be dispersed within each other or together within a vehicle. The dispersion can comprise a mixture of solid materials in which the individual small particles are essentially one compound, but the small particles are dispersed within each other, such as can occur if two powders of two different drugs are blended with a solid vehicle material and the blending is carried out in solid form. In some embodiments, dextromethorphan and (S)-bupropion or (R)-bupropion can be substantially uniformly dispersed within the composition or dosage form. Alternatively, dextromethorphan and (S)-bupropion or (R)-bupropion can be in separate domains or phases within the composition or dosage form. For example, one drug can be in a coating, while the other drug can be in a core within the coating. For example, one drug can be formulated for sustained release, and the other drug can be formulated for immediate release.

[0114] Some embodiments include administering a tablet containing (S)-bupropion or (R)-bupropion in a form to provide sustained release and dextromethorphan, if present, in a form to provide immediate release. While there are many ways to achieve sustained release of bupropion, in some embodiments, (S)-bupropion or (R)-bupropion is mixed with hydroxypropyl methylcellulose. For example, particles of (S)-bupropion or (R)-bupropion can be blended with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., Avicel® ) to form a mixture of blended powders. This can then be mixed with immediate release dextromethorphan in a single tablet.

[0115] Administering a combination of (R)-bupropion and dextromethorphan to a person in need of treatment by dextromethorphan can result in increased levels of dextromethorphan compared to administering the same dose of (S)-bupropion and the same amount of dextromethorphan. In some embodiments, the C 最大 (eg, mean C 最大 , mean C 最大 , median C 最大 , or individual C 最大 ) or AUC 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or AUC 0-∞ (eg, mean AUC 0-∞ , mean AUC 0-∞median AUC 0-∞ , or individual AUC 0-∞ ) is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 80%, at least about 100%, at least about 150%, or at least about 200%. Such an increase can be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, or day 8 of treatment, or later. In some embodiments, the increase is observed on day 1. In some embodiments, the increase is observed on day 8.

[0116] In some embodiments, the combination of (R)-bupropion and dextromethorphan can achieve, for example, from about 30-150 ng-hr / mL, about 50-100 ng-hr / mL, about 80-100 ng-hr / mL, about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL, about 1000 ng-hr / mL to about 1300 ng-hr / mL dextromethorphan AUC 0-12 (average AUC 0-12 , mean AUC 0-12median AUC 0-12 , or any dextromethorphan AUC 0-12 within a range bounded by any of these values. 0-12 .

[0117] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC of about 400-425 ng hr / mL, about 425-450 ng hr / mL, about 400-450 ng hr / mL, about 450-475 ng hr / mL, about 475-500 ng hr / mL, about 450-500 ng hr / mL, about 500-510 ng hr / mL, about 510-520 ng hr / mL, about 520-530 ng hr / mL, about 530-540 ng hr / mL, about 540-560 ng hr / mL, about 500-550 ng hr / mL, about 550-575 ng hr / mL, about 575-600 ng hr / mL, about 550-600 ng hr / mL, about 600-650 ng hr / mL, about 650-700 ng hr / mL, about 700-750 ng hr / mL, about 750-800 ng hr / mL, about 800-820 ng hr / mL, about 820-840 ng hr / mL, about 840-850 ng hr / mL, about 800-850 ng hr / mL, about 850-860 ng hr / mL, about 860-870 ng hr / mL, about 870-880 ng hr / mL, about 880-890 ng hr / mL, about 890-900 ng hr / mL, about 850-900 ng hr / mL, about 900-910 ng hr / mL, about 910-930 ng hr / mL, about 930-950 ng hr / mL, about 900-950 ng hr / mL, about 950-1000 ng hr / mL on day 5. 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 , or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0118] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 6 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0119] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 7 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0120] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 8 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL, about 1000 ng-hr / mL to about 1300 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0121] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 9 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0122] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 10 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0123] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan AUC on day 11 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0124] In some embodiments, the combination of (R)-bupropion and dextromethorphan can achieve, for example, at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 2-20 ng / mL, 5-10 ng / mL, about 10-15 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, or about 56-57 ng / mL on day 1 through day 60. g / mL, about 50-55ng / mL, about 55-58ng / mL, about 58-60ng / mL, about 55-60ng / mL, about 60-65ng / mL, about 65-70ng / mL, about 70-75ng / mL, about 75-80ng / mL, about 80-82ng / mL, about 82-84ng / mL, about 84-85ng / mL, about 80-85ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, about 100-110 ng / mL of dextromethorphan C 最大 (For example, average C 最大 , mean C 最大 , median C 最大 or individual C 最大 ), or any C within a range bounded by any of these values 最大 .

[0125] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 5, a dextromethorphan C 最大 (average C 最大 , mean C 最大 , median C 最大 or individual C 最 max) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL.

[0126] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 6, a dextromethorphan C 最大 (average C 最大 , mean C 最大 , median C 最大 or individual C 最 max) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL.

[0127] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 7, a dextromethorphan C 最大 (average C 最大 , mean C 最大 , median C 最大 or individual C 最 max) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL.

[0128] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 8, a dextromethorphan C 最大 ( e.g., mean C 最大 , mean C 最大 , median C 最大 , or individual C 最大 ) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, about 100-110 ng / mL.

[0129] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 9, a dextromethorphan C 最大 (average C 最大 , mean C 最大 , median C 最大 or individual C 最 max) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL.

[0130] In some embodiments, the combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve, e.g., on day 10, a dextromethorphan C 最大 (average C 最大 , mean C 最大 , median C 最大 or individual C 最 max) of at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL.

[0131] In some embodiments, the combination of (R)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice daily and about 50-150 mg of (R)-bupropion twice daily, can achieve, for example, at least about 10 ng / mL, at least about 20 ng / mL, at least about 30 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, or about 55-56 ng / mL on day 11. 4 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL , about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL of dextromethorphan C 最大 (For example, average C 最大 , mean C 最大 , median C 最大 or individual C 最 , or any Cmax within a range bounded by any of these values.

[0132] The dextromethorphan fluctuation index value FI (%) can be determined by the following equation:

[0133]

[0134] In some embodiments, a combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan FI(%) value, e.g., a mean FI(%) value, a median FI(%) value, or an individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30% on Day 8.

[0135] In some embodiments, a combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan FI(%) value, e.g., a mean FI(%) value, a median FI(%) value, or an individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30% on Day 9.

[0136] In some embodiments, a combination of (R)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (R)-bupropion twice a day, can achieve a dextromethorphan FI(%) value, e.g., a mean FI(%) value, a median FI(%) value, or an individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30% on Day 10.

[0137] Although administration of a combination of (R)-bupropion and dextromethorphan to a person in need of treatment by dextromethorphan can result in increased levels of dextromethorphan compared to administration of the same amount of a combination of (S)-bupropion and dextromethorphan, administration of a combination of (S)-bupropion and dextromethorphan can still result in an increase in dextromethorphan plasma levels compared to administration of dextromethorphan without (S)-bupropion.

[0138] In some embodiments, administration of a combination of (R)-bupropion and dextromethorphan to a person in need of treatment by dextromethorphan can result in increased levels of dextromethorphan compared to administration of the same amount of a combination of racemic bupropion and dextromethorphan. In some embodiments, this increase can be significant or substantial.

[0139] In some embodiments, the combination of (S)-varenicline and dextromethorphan can achieve, for example, from day 1 to day 60, a dextromethorphan AUC of about 10-50 ng-hr / mL, about 20-40 ng-hr / mL, about 30-100 ng-hr / mL, about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL, about 1000-1100 ng-hr / mL 0-12 (average AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0140] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 5 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (about mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0141] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 6 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0142] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 7 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 (eg, mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0143] In some embodiments, the combination of (S)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice daily and about 50-150 mg of (S)-bupropion twice daily, can achieve about 400-425 ng·hr / mL, about 425-450 ng·hr / mL, about 400-450 ng·hr / mL, about 450-475 ng·hr / mL, about 475-500 ng·hr / mL, about 4 50-500 ng·hr / mL, about 500-510 ng·hr / mL, about 510-520 ng·hr / mL, about 520-530 ng·hr / mL, about 530-540 ng·hr / mL, about 540-560 ng·hr / mL, about 500-550 ng·hr / mL, about 550-575 ng·hr / mL, about 575-600 ng·hr / mL, about 550-600 ng·hr / mL, about 600- 650 ng·hr / mL, about 650-700 ng·hr / mL, about 700-750 ng·hr / mL, about 750-800 ng·hr / mL, about 800-820 ng·hr / mL, about 820-840 ng·hr / mL, about 840-850 ng·hr / mL, about 800-850 ng·hr / mL, about 850-860 ng·hr / mL, about 860-870 ng·hr / mL, about 870-88 0 ng·hr / mL, about 880-890 ng·hr / mL, about 890-900 ng·hr / mL, about 850-900 ng·hr / mL, about 900-910 ng·hr / mL, about 910-930 ng·hr / mL, about 930-950 ng·hr / mL, about 900-950 ng·hr / mL, about 950-1000 ng·hr / mL, and about 1000-1100 ng·hr / mL of dextromethorphan 0-12 (e.g. average AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ), or any dextromethorphan AUC within a range bounded by any of these values 0-12 .

[0144] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 9 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 .

[0145] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 10 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0146] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan AUC on day 11 of about 400-425 ng-hr / mL, about 425-450 ng-hr / mL, about 400-450 ng-hr / mL, about 450-475 ng-hr / mL, about 475-500 ng-hr / mL, about 450-500 ng-hr / mL, about 500-510 ng-hr / mL, about 510-520 ng-hr / mL, about 520-530 ng-hr / mL, about 530-540 ng-hr / mL, about 540-560 ng-hr / mL, about 500-550 ng-hr / mL, about 550-575 ng-hr / mL, about 575-600 ng-hr / mL, about 550-600 ng-hr / mL, about 600-650 ng-hr / mL, about 650-700 ng-hr / mL, about 700-750 ng-hr / mL, about 750-800 ng-hr / mL, about 800-820 ng-hr / mL, about 820-840 ng-hr / mL, about 840-850 ng-hr / mL, about 800-850 ng-hr / mL, about 850-860 ng-hr / mL, about 860-870 ng-hr / mL, about 870-880 ng-hr / mL, about 880-890 ng-hr / mL, about 890-900 ng-hr / mL, about 850-900 ng-hr / mL, about 900-910 ng-hr / mL, about 910-930 ng-hr / mL, about 930-950 ng-hr / mL, about 900-950 ng-hr / mL, about 950-1000 ng-hr / mL 0-12 ( e.g., mean AUC 0-12 , mean AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 ) or any dextromethorphan AUC 0-12 within a range bounded by any of these values.

[0147] In some embodiments, the combination of (S)-bupropion and dextromethorphan can achieve, for example, about 1-10 ng / mL, about 2-5 ng / mL, about 5-10 ng / mL, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 56-57 ng / mL, about 58-61 ng / mL, about 59-62 ng / mL, about 60-61 ng / mL, about 61-62 ng / mL, about 62-63 ng / mL, about 64-65 ng / mL, about 66-67 ng / mL, about 68-69 ng / mL, about 70-71 ng / mL, about 71-72 ng / mL, about 72-73 ng / mL, about 73-74 ng / mL, about 74-75 ng / mL mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, about 100-110 ng / mL of dextromethorphan C 最大 (For example, average C 最大 , mean C 最大 , median C 最大 or individual C 最大 ), or any C within a range bounded by any of these values 最大 .

[0148] In some embodiments, the combination of (S)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice daily and about 50-150 mg of (S)-bupropion twice daily, can achieve, for example, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL on day 5.

[0015] The present invention provides a dextromethorphan Cmax (e.g., an average Cmax, mean Cmax, median Cmax, or individual Cmax) of about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any Cmax within a range bounded by any of these values. 最大 .

[0149] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a Cmax of dextromethorphan of about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any Cmax of dextromethorphan within a range bounded by any of these values (e.g., average Cmax, mean Cmax, median Cmax, or individual Cmax), e.g., on day 6. 最大 .

[0150] In some embodiments, the combination of (S)-bupropion and dextromethorphan, for example, by administering about 30-60 mg of dextromethorphan twice daily and about 50-150 mg of (S)-bupropion twice daily, can achieve, for example, about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL on day 7.

[0015] The present invention provides a dextromethorphan Cmax (e.g., an average Cmax, mean Cmax, median Cmax, or individual Cmax) of about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any Cmax within a range bounded by any of these values. 最大 .

[0151] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan C 最大 ( e.g., mean C 最大 , mean C 最大 , median C 最大 , or individual C 最 max in a range bounded by any of these values.

[0152] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a Cmax of dextromethorphan of about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any Cmax of dextromethorphan within a range bounded by any of these values (e.g., average Cmax, mean Cmax, median Cmax, or individual Cmax), e.g., on day 9. 最大 .

[0153] In some embodiments, the combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a Cmax of dextromethorphan of about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any Cmax of dextromethorphan within a range bounded by any of these values (e.g., average Cmax, mean Cmax, median Cmax, or individual Cmax), e.g., on day 10. 最大 .

[0154] In some embodiments, a combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice per day and about 50-150 mg of (S)-bupropion twice per day, can achieve a dextromethorphan Cmax (e.g., mean Cmax, median Cmax, or individual Cmax), or any Cmax value within a range bounded by any of these values, of about 40-43 ng / mL, about 43-45 ng / mL, about 40-45 ng / mL, about 45-48 ng / mL, about 48-50 ng / mL, about 45-50 ng / mL, about 50-51 ng / mL, about 51-52 ng / mL, about 52-53 ng / mL, about 53-54 ng / mL, about 54-56 ng / mL, about 50-55 ng / mL, about 55-58 ng / mL, about 58-60 ng / mL, about 55-60 ng / mL, about 60-65 ng / mL, about 65-70 ng / mL, about 70-75 ng / mL, about 75-80 ng / mL, about 80-82 ng / mL, about 82-84 ng / mL, about 84-85 ng / mL, about 80-85 ng / mL, about 85-86 ng / mL, about 86-87 ng / mL, about 87-88 ng / mL, about 88-89 ng / mL, about 89-90 ng / mL, about 85-90 ng / mL, about 90-91 ng / mL, about 91-93 ng / mL, about 93-95 ng / mL, about 90-95 ng / mL, about 95-100 ng / mL, or any value within a range bounded by any of these values, e.g., on day 11. 最大 .

[0155] In some embodiments, a combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice per day and about 50-150 mg of (S)-bupropion twice per day, can achieve a dextromethorphan FI(%) value, e.g., mean FI(%) value, median FI(%) value, or individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30%, e.g., on day 8.

[0156] In some embodiments, a combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan FI(%) value, e.g., a mean FI(%) value, a median FI(%) value, or an individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30% on day 9.

[0157] In some embodiments, a combination of (S)-bupropion and dextromethorphan, e.g., by administering about 30-60 mg of dextromethorphan twice a day and about 50-150 mg of (S)-bupropion twice a day, can achieve a dextromethorphan FI(%) value, e.g., a mean FI(%) value, a median FI(%) value, or an individual FI(%) value, or any FI(%) value within a range bounded by any of these values, of less than 100%, less than 50%, less than 40%, less than 30%, about 20-50%, about 20-40%, about 20-30% on day 10.

[0158] Examples of neurological or central nervous system disorders that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, affective disorders, psychotic disorders, brain function disorders, motor disorders, dementia, motor neuron disorders, neurodegenerative disorders, seizure disorders, and headaches.

[0159] Mood disorders that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, depression, major depression, treatment-resistant depression, and treatment-resistant bipolar depression, bipolar disorders (including cyclothymia), seasonal affective disorder, mood disorder, chronic depression (dysthymia), psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), and attention deficit / hyperactivity disorder (AD / HD), bipolar and manic disorders, obsessive-compulsive disorder, binge eating disorder, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, addictive disorders, substance addiction or abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar affect, and emotional lability.

[0160] Depression can be manifested by depressive symptoms. These symptoms can include psychological changes such as changes in mood, intense feelings of sadness, hopelessness, mental slowing, difficulty concentrating, pessimistic worry, agitation, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal ideation or attempts, and / or self-deprecation. Physical symptoms of depression can include insomnia, loss of appetite, anorexia, weight loss, weight gain, decreased energy and sex drive, fatigue, restlessness, aches, pains, headaches, cramps, digestive problems, and / or hormonal circadian rhythm abnormalities.

[0161] Some patients can still have an inadequate or no response to treatment even after treatment with medications such as antidepressants. Treatment-resistant depression (TRD) or treatment refractory depression is a condition that is often associated with patients who have failed treatment with at least two antidepressants. Part of the diagnosis of TRD is for patients who have an inadequate response to treatment with antidepressants after an appropriate dose and an appropriate course of therapy. TRD can be more difficult to treat due to comorbidities of other medical or psychological illnesses, such as drug / alcohol abuse or eating disorders or misdiagnosis of TRD. Some TRD patients have an inadequate response to 1, 2, 3, or more trials of antidepressant treatment, or have had no response or an inadequate response to 1, 2, 3, or more previous antidepressant treatments. In some embodiments, the patient undergoing treatment for treatment-resistant depression has failed treatment with at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more antidepressant therapies.

[0162] Improvements in efficacy that can be achieved through enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, Montgomery-Asberg Depression Rating Scale (MADRS), Brief Happiness and Life Satisfaction Questionnaire, Measure of Impairment in Functioning, Sheehan Disability Scale, Patient Rated Inventory of Side Effects (PRISE), Columbia-Suicide Severity Rating Scale (C-SSRS), Quick Inventory of Depressive Symptomatology, Self-Report (QID(S)-SR), Clinical Global Impression (CGI), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), 17-item Hamilton Rating Scale for Depression (HAM-D17), Massachusetts General Hospital Antidepressant Treatment Response Questionnaire (MGH ATRQ), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QID(S)-SR16), Sheehan Disability Scale (SDS), Clinical Global Impression of Severity of Illness (CGI-S), Clinical Global Impression of Change (CGI-C), EuroQOL 5 Dimension 5 Level (EQ-5D-5L), Patient Global Impression of Change (PGI-C), Patient Global Impression of Improvement (PGI-I), Patient Global Impression of Severity of Illness (PGI-S), Patient Global Impression of Treatment Emergent Symptoms (PGI-TESS), Patient Global Impression of Well-Being (PGI-WB), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression of Work and Social Functioning (PGI-WSF), Patient Global Impression ofEQ-5D-5L), Patient Global Impression of Change (PGIC), 7-item Generalized Anxiety Disorder (GAD-7), Clinical Global Impressions-Improvement (CGI-1), Sheehan Disability Scale (SDS), 16-item Quick Inventory of Depressive Symptomatology-Self Report (QID(S)-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPFQ-Cognitive Subscale (4- to 7-item), Brief Psychiatric Rating Scale (BPRS), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Task (RAVLT), Trail Making Test (TMT), Stroop Colour Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time (CRT), etc.

[0163] Patients who can benefit from the treatments described herein include pediatric patients, e.g., patients under about 18 years old, about 0-5 years old, about 5-10 years old, about 10-12 years old, or about 12-18 years old; adult patients, e.g., patients between about 18-65 years old, about 18-30 years old, about 30 to 50 years old, about 50-65 years old; and geriatric patients, e.g., patients over 65 years old, about 65-75 years old, about 75-90 years old; or over 90 years old.

[0164] Treatment of TRD with enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan can result in a decrease in depressive symptoms of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any percentage decrease bounded by any of these values or a range bounded by any of these values.

[0165] Psychiatric disorders that can be treated using enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, anxiety disorders such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, hypomania, unipolar depression, depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypy, aggression in Alzheimer’s disease, agitation, and agitation in Alzheimer’s disease.

[0166] Agitation associated with Alzheimer’s disease occurs as the disease progresses. Agitation can manifest as inappropriate verbal, emotional, and / or physical behavior. Inappropriate behavior can include, but is not limited to, incoherent rambling, inappropriate emotional responses, demands for attention, threats, restlessness, frustration, screaming, repetitive questioning, mood swings, abusive language, physical outbursts, emotional distress, fidgeting, shredding, sleep disturbances, delusions, hallucinations, pacing, wandering, searching, rummaging, repetitive body movements, hoarding, shadowing caregivers, hitting, scratching, biting, aggression, hyperactivity, and / or kicking.

[0167] In some embodiments, treatment with the enhanced bioavailability or increased plasma levels of (S)-bupropion, the enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or the enhanced bioavailability or increased plasma levels of dextromethorphan treatment to treat agitation associated with Alzheimer’s disease can result in a reduction of symptoms associated with agitation of at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, up to about 100%, or any percent reduction within a range bounded by any of these values.

[0168] Measures to improve efficacy on agitation that can be improved by treatment with enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, Neuropsychiatric Inventory-Clinician rating scale (NPI-C), overall and all domains; Neuropsychiatric Inventory-Clinician rating scale (NPI-C) Agitation domain; Cohen-Mansfield Agitation Inventory (CMAI); Cornell Scale for Depression in Dementia (CSDD); Neuropsychiatric Inventory (NPI Agitation / Aggressive Behavior domain); concomitant medications (frequent use of concomitant medications); Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADC(S)-ADL);Neuropsychiatric Inventory (NPI) domains and NPI total score (range 0-144), including NPI-C apathy domain, NPI caregiver distress for agitation / aggression, Modified Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change Agitation (mADC(S)-CGIC agitation), Patient Global Impression of Change (PGIC) (assessed by caregiver), Dementia Quality of Life (DEMQOL), Quality of Life-Alzheimer’s disease measure (QoL-AD), Zarit Burden Scale, Resource Utilization in Dementia (RUD), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADA(S)-Cog), Mini-mental State Examination (MMSE), Caregiver Strain Index (CSI), Individual Domain of the Neuropsychiatric Inventory (NPI), Total Neuropsychiatric Inventory (NPI) score, Neuropsychiatric Inventory (NPI domains of agitation / aggression), Neuropsychiatric Inventory (NPI domains of caregiver distress), etc.

[0169] Substance addiction abuse that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, drug dependence, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars, and / or pipes, e-cigarettes, and chewing tobacco addiction.

[0170] Cerebral dysfunction that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, conditions involving intellectual impairment, such as senile dementia, Alzheimer’s type dementia, memory impairment, amnesia / loss of memory syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, speech disorder, voice spasms, Parkinson’s disease, Lennox-Gastaut syndrome, autism, hyperkinetic syndrome, and schizophrenia. Cerebral dysfunction also includes conditions caused by cerebrovascular diseases, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, and the like, wherein symptoms include disturbance of consciousness, senile dementia, coma, decreased attention, and speech disorder.

[0171] Movement disorders that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia, cerebral palsy, chorea, Huntington’s disease, rheumatic chorea, Sydenham’s chorea, dyskinesia, tardive dyskinesia, dystonia, spasticity, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson’s disease, restless leg syndrome (RLS), tremor, essential tremor, Tourette’s syndrome, and Wilson’s disease.

[0172] Dementias that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington’s disease, Wernicke-Korsakoff Syndrome, and Pick’s disease.

[0173] Motor neuron diseases that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophies, Tay-Sach’s disease, Sandoff disease, and hereditary spastic paraplegia.

[0174] Neurodegenerative diseases that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, Alzheimer’s disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedrich’s ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), multiple sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, Wilson’s disease, Menkes disease, adrenoleukodystrophy, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, pontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barre syndrome, and spastic paraplesia.

[0175] Seizure disorders that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, seizures, non-epileptic seizures, epilepsy, febrile convulsions; partial seizures, including but not limited to simple partial seizures, Jacksonian seizures, complex partial seizures, and partial status epilepticus; 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.

[0176] Types of headaches that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include, but are not limited to, migraine, tension, and cluster headaches.

[0177] Other neurological disorders that can be treated by enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan include Rett Syndrome, autism, tinnitus, disorders of consciousness, 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; urinary incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0178] In some embodiments, enhanced bioavailability or increased plasma levels of (S)-bupropion, enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or enhanced bioavailability or increased plasma levels of dextromethorphan can be used to treat pain, joint pain, pain associated with sickle cell disease, pseudobulbar affect, depression (including treatment-resistant depression), disorders related to memory and cognition, schizophrenia, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Rhett’s syndrome, seizures, coughing (including chronic cough), and the like.

[0179] In some embodiments, the enhanced bioavailability or increased plasma levels of (S)-bupropion, the enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or the enhanced bioavailability or increased plasma levels of dextromethorphan can be used to treat refractory depression.

[0180] The enhanced bioavailability or increased plasma levels of (S)-bupropion, the enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or the enhanced bioavailability or increased plasma levels of dextromethorphan can be used to treat any type of pain or provide relief from the pain including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritic pain, complex regional pain syndrome, and the like.

[0181] In some embodiments, the enhanced bioavailability or increased plasma levels of (S)-bupropion, the enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or the enhanced bioavailability or increased plasma levels of dextromethorphan can be used to relieve neuropathic pain.

[0182] Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, and the like. Other causes of neuropathic pain include cancer-related pain, lumbar radiculopathy, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and chemotherapy- or radiation-related neuropathy, and the like.

[0183] In some embodiments, the enhanced bioavailability or increased plasma levels of (S)-bupropion, the enhanced bioavailability or increased plasma levels of (R,R)-hydroxybupropion, and / or the enhanced bioavailability or increased plasma levels of dextromethorphan can be administered to relieve fibromyalgia.

[0184] Adverse events associated with bupropion or dextromethorphan that can be avoided or reduced by the methods described herein include central nervous system adverse events, gastrointestinal events, or another adverse event associated with either of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, light-headedness, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased agitation or excitement, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, fatigue, incoordination, tiredness, euphoria, nervousness, insomnia, sleep disorder, seizure, excitation, catatonic-like state, hysteria, hallucination, delusion, delirium, headache and / or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and / or tongue protrusion.

[0185] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcer hemorrhage, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, feeling of fullness, indigestion, bloating, gastric hyperacidity, dry mouth, gastrointestinal discomfort, and stomach pain.

[0186] Other adverse events that can be reduced or avoided by the methods described herein include abnormal sensations of spinning and movement, agitation, arm weakness, bloating, blurred vision, burning sensation in the eyes, ear ringing, changes in vital signs (including, but not limited to, heart rate, respiratory rate, body temperature, blood pressure), cold feeling, constipation, difficulty concentrating, difficulty sleeping, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feeling feverish, feeling lightheaded, feeling more agitated than usual, feeling more fatigued than usual, feeling fatigued, hand shaking, hand weakness, headache, heartburn, hot flashes, increased blood pressure, increased skin sensitivity, increased skin sensitivity of the head and face, involuntary muscle contractions, involuntary whole-body muscle contractions, knee pain, leg weakness, lightheadedness, loose stools, loss of appetite, lower back pain, menstrual irregularities, metallic taste, more saliva than usual, mucosal dryness, nasal congestion, nausea, nasal discharge, slight pressure feeling in the eyes, shakiness when stretching or yawning, skin sensitivity, skin sensitivity of the arms, face, and / or head, sleep difficulties, soft stools, stomach pain, stomach discomfort, sweating of the hands and / or feet, throat irritation, throat pain, tinnitus, tremors, and / or weakness. Any one of these side effects or groups of these side effects can also be referred to or grouped according to corresponding, equivalent, or other related terms in the Medical Dictionary for Regulatory Activities (MedRA).

[0187] The term “treating” or “treatment” includes any action or process that diagnoses, cures, alleviates, treats, or prevents a disease or illness in a human or other animal, or otherwise affects the structure or any function of the body of a human or other animal.

[0188] Patients who can benefit from the treatments described herein include pediatric patients, such as patients under about 18 years old, about 0-5 years old, about 5-10 years old, about 10-12 years old, or about 12-18 years old; adult patients, such as patients between about 18-65 years old, about 18-30 years old, about 30 to 50 years old, about 50-65 years old; and geriatric patients, such as patients over 65 years old, about 65-75 years old, about 75-90 years old; or over 90 years old.

[0189] The entire contents of U.S. Patent No. 9,867,819, issued January 16, 2018 to Herriot Tabuteau, entitled “Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamics effects,” from application number 15 / 645,939, filed July 10, 2017, is incorporated herein by reference. In particular, the amounts and dosing regimens of bupropion described in U.S. Patent No. 9,867,819 can be applied to (S)-bupropion or (R)-bupropion described herein. Additionally, the amounts and dosing regimens of dextromethorphan described in U.S. Patent No. 9,867,819 can be applied herein. Furthermore, the conditions that can be treated with the dosage forms described in U.S. Patent No. 9,867,819 can also be treated in a similar manner using the dosage forms and methods described herein.

[0190] The following embodiments are contemplated:

[0191] Embodiment 1. A method of delivering bupropion or a metabolite thereof to the plasma, the method comprising orally administering to a human at least once a day a dosage form containing about 50 mg to about 100 mg of at least 95% enantiomeric pure (S)-bupropion.

[0192] Embodiment 2. A method of providing bupropion to the plasma of a human, the method comprising:

[0193] selecting a human patient in need of the pharmacokinetic profile provided by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and

[0194] orally administering a dosage form containing a second amount of at least 95% enantiomeric pure (S)-bupropion at the first dosing frequency to achieve the same pharmacokinetic profile that would be achieved by administering the reference dosage form at the first dosing frequency;

[0195] wherein the first dosing frequency is once a day or twice a day; and

[0196] wherein the second amount is about 40% to about 60% of the first amount.

[0197] Embodiment 3. A method of treating a disease treatable with racemic bupropion, the method comprising:

[0198] a human patient having a condition treatable by oral administration at a first dosing frequency of a reference dosage form containing a first amount of racemic bupropion; and

[0199] oral administration at the first dosing frequency of a dosage form containing a second amount of at least 95% enantiomeric purity of (S)-bupropion to achieve the same therapeutic effect that would be achieved by administration of the reference dosage form at the first dosing frequency;

[0200] wherein the first dosing frequency is once a day or twice a day; and

[0201] wherein the second amount is about 40% to about 60% of the first amount.

[0202] Embodiment 4. The method of embodiment 1, wherein the human is in need of treatment with (S)-bupropion.

[0203] Embodiment 5. The method of embodiments 1, 2, 3, or 4, wherein the method achieves (S)-bupropion C 最大 .

[0204] Embodiment 6. The method of embodiments 1, 2, 3, 4, or 5, wherein the method is effective to increase the (S)-bupropion C 最大 by at least 5-fold as compared to (R)-bupropion C 最大 resulting from administration of the same amount of (R)-bupropion to the human.

[0205] Embodiment 7. The method of embodiments 1, 2, 3, 4, 5, or 6, wherein the method achieves (R,R)-hydroxybupropion C 最大 .

[0206] Embodiment 8. The method of embodiments 1, 2, 3, 4, 5, 6, or 7, wherein the method is effective to increase the (R,R)-hydroxybupropion C 最小 by at least 3-fold as compared to (R,R)-hydroxybupropion C 最小 resulting from administration of the same amount of (R)-bupropion to the human.

[0207] Embodiment 9. The method of embodiments 1, 2, 3, 4, 5, 6, 7, or 8, wherein the dosage form is administered once a day.

[0208] Embodiment 10. The method of embodiments 1, 2, 3, 4, 5, 6, 7, or 8, wherein the dosage form is administered twice a day.

[0209] Embodiment 11. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the (R,R)-hydroxybupropion present in the plasma of the human is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human.

[0210] Embodiment 12. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, effective to provide a therapeutically effective plasma level of (R,R)-hydroxybupropion.

[0211] Embodiment 13. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, effective to provide a therapeutically effective plasma level of (S)-bupropion.

[0212] Embodiment 14. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the human is in need of treatment with (R,R)-hydroxybupropion.

[0213] Embodiment 15. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the method achieves at least about 500 ng / mL of (R,R)-hydroxybupropion C 最大 .

[0214] Embodiment 16. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dosage form is administered for at least 8 consecutive days.

[0215] Embodiment 17. The method of embodiment 16, wherein the dosage form is administered for at least 14 consecutive days.

[0216] Embodiment 18. The method of embodiment 16, wherein the dosage form is administered for at least 21 consecutive days.

[0217] Embodiment 19. The method of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the dosage form contains about 60 mg to about 90 mg of (S)-bupropion.

[0218] Embodiment 20. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by the dosage form administered twice a day for at least the next 4 to 7 consecutive days, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0219] Embodiment 21. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the dosage form is administered once a day for 1 to 7 consecutive days, followed by the dosage form administered twice a day for at least the next 7 consecutive days, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0220] Embodiment 22. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.

[0221] Embodiment 23. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the method achieves at least about 70 ng / mL of (S)-bupropion Cmax in the human. 最大 .

[0222] Embodiment 24. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the method achieves at least about 400 ng·hr / mL of (S)-bupropion AUCt in the human. 0-12 .

[0223] Embodiment 25. The method of Embodiment 24, wherein the method achieves about 500 ng·hr / mL to about 900 ng·hr / mL of (S)-bupropion AUCt in the human. 0-12 .

[0224] Embodiment 26. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the dosage form provides sustained release of the (S)-bupropion.

[0225] Embodiment 27. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the dosage form further contains dextromethorphan.

[0226] Embodiment 28. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein the dosage form contains about 70 mg to about 80 mg of the (S)-bupropion.

[0227] Embodiment 29. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the method achieves at least about 600 ng / mL of (R,R)-hydroxybupropion Cmaxin the human. 最大 .

[0228] Embodiment 30. The method of Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, wherein the method achieves at least about 7000 ng·hr / mL of (R,R)-hydroxybupropion AUCin the human. 0-12 .

[0229] Embodiment 31. The method of Embodiment 30, wherein the method achieves at least about 8000 ng·hr / mL of (R,R)-hydroxybupropion AUCin the human. 0-12 .

[0230] Embodiment 32. A method of increasing the plasma levels of (S)-bupropion and dextromethorphan, the method comprising orally administering to a human in need of treatment with both (S)-bupropion and dextromethorphan dextromethorphan and at least about 90 mg of (S)-bupropion that is at least 95% enantiomeric pure at least once a day, wherein the method achieves at least about 90 ng / mL of (S)-bupropion Cmaxin the human. 最大 wherein the method is effective to increase the (S)-bupropion Cmaxin the human at least 3-fold compared to the (R)-bupropion Cmaxresulting from administration of the same amount of (R)-bupropion to the human. 最大 最大 . ​

[0231] Embodiment 33. The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.

[0232] Embodiment 34. The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 14 consecutive days.

[0233] Embodiment 35. The method of embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0234] Embodiment 36. The method of embodiment 33, 34, or 35, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by at least 4 to 7 consecutive days of twice-a-day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0235] Embodiment 37. The method of embodiment 33, 34, or 35, wherein the dosage form is administered once a day for 1 to 7 consecutive days, followed by at least 7 consecutive days of twice-a-day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0236] Embodiment 38. The method of embodiment 32, 33, 34, 35, 36, or 37, wherein (S)-bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.

[0237] Embodiment 39. The method of embodiment 32, 33, 34, 35, 36, 37, or 38, wherein the (S)-bupropion Cmax in the human is at least about 110 ng / mL. 最大

[0238] Embodiment 40. The method of embodiment 32, 33, 34, 35, 36, 37, 38, or 39, wherein the method achieves an (S)-bupropion AUC 0-12 .

[0239] Embodiment 41. The method of embodiment 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)-bupropion.

[0240] ​Embodiment 42. A method of increasing plasma levels of (R,R)-hydroxybupropion and dextromethorphan, comprising orally administering dextromethorphan and at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day to a person in need of treatment with both (R,R)-hydroxybupropion and dextromethorphan, wherein the method achieves (R,R)-hydroxybupropion Cmax in the person of at least about 700 ng / mL. 最大 wherein the method is effective to increase the (R,R)-hydroxybupropion Cmax in the person by at least 3-fold compared to administration of the same amount of (R)-bupropion to the person. 最大 最大 Embodiment 42. A method of increasing plasma levels of (R,R)-hydroxybupropion and dextromethorphan, comprising orally administering dextromethorphan and at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day to a person in need of treatment with both (R,R)-hydroxybupropion and dextromethorphan, wherein the method achieves (R,R)-hydroxybupropion Cmax in the person of at least about 700 ng / mL.

[0241] Embodiment 43. The method of embodiment 42, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.

[0242] Embodiment 44. The method of embodiment 42, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 21 consecutive days.

[0243] Embodiment 45. The method of embodiment 42, 43, or 44, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0244] Embodiment 46. The method of embodiment 42, 43, 44, or 45, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by at least the next 4 to 7 consecutive days of twice a day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0245] Embodiment 47. The method of embodiment 42, 43, 44, 45, or 46, wherein the dosage form is administered once a day for 1 to 7 consecutive days, followed by at least the next 7 consecutive days of twice a day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0246] Embodiment 48. The method of embodiment 42, 43, 44, 45, 46, or 47, wherein (S)-bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.

[0247] Embodiment 49. The method of embodiment 42, 43, 44, 45, 46, 47, or 48, wherein the (R,R)-hydroxybupropion Cmax in the person is at least about 900 ng / mL. 最大

[0248] ​​Embodiment 50. The method of Embodiments 42, 43, 44, 45, 46, 47, 48, or 49, wherein the method achieves an (R,R)-hydroxybupropion AUC of at least about 10,000 ng-hr / mL in the human 0-12 .

[0249] Embodiment 51. The method of Embodiments 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)-bupropion.

[0250] Embodiment 52. A method of increasing plasma levels of (S)-bupropion, the method comprising orally administering to a human in need of treatment with (S)-bupropion at least about 90 mg of (S)-bupropion that is at least 95% enantiomeric pure at least once a day, wherein the method achieves an (S)-bupropion C 最小 max of at least about 20 ng / mL. 最小 at least 3-fold greater than a (R)-bupropion C 最小 max produced by administration of the same amount of (R)-bupropion to the human.

[0251] Embodiment 53. The method of Embodiment 52, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.

[0252] Embodiment 54. The method of Embodiment 52, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 14 consecutive days.

[0253] Embodiment 55. The method of Embodiments 52, 53, or 54, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0254] Embodiment 56. The method of Embodiments 52, 53, 54, or 55, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by at least the next 4 to 7 consecutive days of twice a day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0255] Embodiment 57. The method of Embodiments 52, 53, 54, 55, or 56, wherein the dosage form is administered once a day for 1 to 7 consecutive days, followed by at least the next 7 consecutive days of twice a day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0256] Embodiment 58. The method of Embodiments 52, 53, 54, 55, 56, or 57, wherein (S)-bupropion is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-bupropion.

[0257] Embodiment 59. The method of Embodiments 52, 53, 54, 55, 56, 57, or 58, wherein the method achieves at least about 110 ng / mL of (S)-bupropion Cmaxin the human. 最大 .

[0258] Embodiment 60. The method of Embodiments 52, 53, 54, 55, 56, 57, 58, or 59, wherein the method achieves at least about 800 ng·hr / mL of (S)-bupropion AUCtauin the human. 0-12 .

[0259] Embodiment 61. The method of Embodiments 52, 53, 54, 55, 56, 57, 58, 59, or 60, wherein (S)-bupropion is administered in a dosage form that provides sustained release of the (S)-bupropion.

[0260] Embodiment 62. A method of increasing the plasma level of (R,R)-hydroxybupropion, the method comprising orally administering to a human in need of treatment with (R,R)- hydroxybupropion at least about 90 mg of at least 95% enantiomeric pure (S)-bupropion at least once a day, wherein the method achieves at least about 700 ng / mL of (R,R)- hydroxybupropion Cmaxin the human. 最小 wherein the method is effective to increase the (R,R)-hydroxybupropion Cmaxin the human at least 3-fold compared to the (R,R)-hydroxybupropion Cmaxresulting from administration of the same amount of (R)-bupropion to the human. 最小 最小 .

[0261] Embodiment 63. The method of Embodiment 62, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 8 consecutive days.

[0262] Embodiment 64. The method of Embodiment 62, wherein the dextromethorphan and the (S)-bupropion are co-administered for at least 21 consecutive days.

[0263] Embodiment 65. The method of Embodiments 62, 63, or 64, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0264] ​Embodiment 66. The method of Embodiments 62, 63, 64, or 65, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by the dosage form administered twice a day for at least the next 4 to 7 consecutive days, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0265] Embodiment 67. The method of Embodiments 62, 63, 64, 65, or 66, wherein the dosage form is administered once a day for 1 to 7 consecutive days, followed by the dosage form administered twice a day for at least the next 7 consecutive days, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0266] Embodiment 68. The method of Embodiments 62, 63, 64, 65, 66, or 67, wherein (S)- varenicline is administered in a dosage form containing about 100 mg to about 110 mg of the (S)-varenicline.

[0267] Embodiment 69. The method of Embodiments 62, 63, 64, 65, 66, 66, 67, or 68, wherein the method achieves at least about 900 ng / mL of (R,R)-hydroxyvarenicline Cmax in the human. 最大 .

[0268] Embodiment 70. The method of Embodiments 62, 63, 64, 65, 66, 67, 68, or 69, wherein the method achieves at least about 10,000 ng·hr / mL of (R,R)-hydroxyvarenicline AUC in the human. 0-12 .

[0269] Embodiment 71. The method of Embodiments 62, 63, 64, 65, 66, 67, 68, 69, or 70, wherein (S)-varenicline is administered in a dosage form that provides sustained release of the (S)-varenicline.

[0270] Embodiment 72. A method of treating a central nervous system (CNS) disorder in a human, comprising administering to the human for whom the CNS disorder is to be treated a dosage form comprising a therapeutically effective amount of (S)-varenicline that is at least about 95% enantiomeric pure and dextromethorphan.

[0271] Embodiment 73. The method of Embodiment 72, wherein the CNS disorder comprises depression.

[0272] Embodiment 74. The method of Embodiment 72, wherein the CNS disorder comprises treatment-resistant depression.

[0273] Embodiment 75. The method of Embodiment 72, wherein the CNS disorder comprises an addictive disorder.

[0274] Embodiment 76. The method of embodiment 72, wherein the CNS disorder comprises nicotine addiction.

[0275] Embodiment 77. The method of embodiment 72, wherein the CNS disorder comprises alcohol addiction.

[0276] Embodiment 78. The method of embodiment 72, wherein the CNS disorder comprises Alzheimer’s disease.

[0277] Embodiment 79. The method of embodiment 72, 73, 74, 75, 76, 77, or 78, wherein the dosage form is in the form of a tablet, a capsule, or a syrup.

[0278] Embodiment 80. The method of embodiment 72, 73, 74, 75, 76, 77, 78, or 79, wherein the dosage form is administered orally to the human.

[0279] Embodiment 81. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, or 80, wherein the dosage form is administered orally to the human every day.

[0280] Embodiment 82. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, or 81, wherein the dosage form is administered orally to the human once a day.

[0281] Embodiment 83. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, or 82, wherein the dosage form is administered orally to the human twice a day.

[0282] Embodiment 84. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, or 83, wherein the dosage form is administered orally to the human under fasted conditions.

[0283] Embodiment 85. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, or 84, wherein the dosage form is administered orally to the human every day for at least 8 consecutive days.

[0284] Embodiment 86. The method of embodiment 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85, wherein the dosage form contains about 100 mg to about 200 mg of the (S)-varenicline.

[0285] Embodiment 87. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 86, wherein the dosage form contains about 104 mg to about 106 mg of the (S)-bupropion.

[0286] Embodiment 88. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, or 87, wherein the dosage form contains about 148 mg to about 152 mg of the (S)-bupropion.

[0287] Embodiment 89. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88, wherein both the (S)-bupropion and the dextromethorphan are in the dosage form.

[0288] Embodiment 90. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89, wherein the dosage form contains about 10 mg to about 50 mg of the dextromethorphan.

[0289] Embodiment 91. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90, wherein the dosage form contains about 44 mg to about 46 mg of the dextromethorphan.

[0290] Embodiment 92. The method of Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, or 91, wherein the dosage form is well-tolerated.

[0291] Embodiment 93. A method of achieving increased plasma levels of (S)-bupropion while increasing plasma levels of dextromethorphan, the method comprising administering to a person in need of treatment with bupropion a dosage form comprising a therapeutically effective amount of (S)-bupropion that is at least about 95% enantiomeric pure and dextromethorphan.

[0292] Embodiment 94. The method of Embodiment 93, wherein the method is effective to achieve increased plasma levels of (S)-bupropion compared to administration of the same amount of racemic bupropion. 最大 .

[0293] Embodiment 95. The method of embodiment 93 or 94, wherein the method is effective to achieve at least 3 times higher (S)-bupropion C 最大 than would be produced by administering to the human a dosage form containing the same amount of (R)-bupropion. 最大

[0294] Embodiment 96. The method of embodiment 93, 94, or 95, wherein the method is effective to achieve an increased (S)-bupropion AUC 0-12 compared to administration of the same amount of racemic bupropion.

[0295] Embodiment 97. The method of embodiment 96, wherein the method is effective to achieve at least 3 times higher (S)-bupropion AUC 0-12 than would be produced by administering to the human a dosage form containing the same amount of (R)-bupropion. 0-12

[0296] Embodiment 98. The method of embodiment 95, 96, or 97, wherein the dosage form is administered at least once a day for at least 8 consecutive days.

[0297] Embodiment 99. The method of embodiment 95, 96, 97, or 98, wherein the dosage form is administered once a day for 1 to 3 consecutive days, followed by at least 4 to 7 consecutive days of twice a day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0298] Embodiment 100. The dosage form of embodiment 95, 96, 97, 98, or 99, wherein the dosage form is well-tolerated.

[0299] Embodiment 101. A dosage form comprising at least about 95% enantiomeric purity of (R)-bupropion and dextromethorphan, wherein oral administration of the dosage form to a human provides an increased increase in dextromethorphan plasma levels in the human compared to oral administration of a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0300] Embodiment 102. The dosage form of embodiment 101, wherein the dosage form contains about 100 mg to about 200 mg of (R)-bupropion.

[0301] Embodiment 103. The dosage form of embodiment 102, wherein the dosage form contains about 104 mg to about 106 mg of (R)-bupropion.

[0302] ​​Embodiment 104. The dosage form of embodiment 102, wherein the dosage form contains about 148 mg to about 152 mg of (R)-bupropion.

[0303] Embodiment 105. The dosage form of embodiment 101, 102, 103, or 104, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.

[0304] Embodiment 106. The dosage form of embodiment 105, wherein the dosage form contains about 44 mg to about 46 mg of dextromethorphan.

[0305] Embodiment 107. The dosage form of embodiment 101, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.

[0306] Embodiment 108. The dosage form of embodiment 101, 102, 103, 104, 105, 106, or 107, wherein the dosage form is administered orally to the human once a day.

[0307] Embodiment 109. The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, or 108, wherein the dosage form is administered orally to the human once a day.

[0308] Embodiment 110. The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, or 108, wherein the dosage form is administered orally to the human twice a day.

[0309] Embodiment 111. The dosage form of embodiment 109 or 110, wherein the dosage form is administered orally to the human at least for 8 consecutive days a day.

[0310] Embodiment 112. The dosage form of embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, or 111, wherein the dosage form is administered orally to the human under fasted conditions.

[0311] Embodiment 113. The dosage form of embodiment 111, wherein the dosage form achieves at least about 80 ng / mL of dextromethorphan Cmaxin the human on the eighth day of orally administering the dosage form to the human for 8 consecutive days a day. 最大 .

[0312] Embodiment 114. The dosage form of embodiment 113, wherein the dosage form is in the form of a syrup, a tablet, a capsule, a spray, or a lozenge.

[0313] Embodiment 115. The dosage form of Embodiment 113 or 114, wherein the dosage form is used to treat a neuropsychiatric condition in the human in need thereof.

[0314] Embodiment 116. The dosage form of Embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used to treat a cold or cough in the human in need thereof.

[0315] Embodiment 117. The dosage form of Embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used to reduce pain in the human in need thereof.

[0316] Embodiment 118. The dosage form of Embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, wherein the dosage form is used to treat addiction in the human in need thereof.

[0317] Embodiment 119. The dosage form of Embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, or 118, wherein the dosage form is well-tolerated when administered to the human.

[0318] Embodiment 120. A method of increasing the elevated dextromethorphan plasma level in a human, the method comprising administering to the human a dosage form comprising at least about 95% enantiomeric purity of (R)-bupropion and dextromethorphan, wherein the dosage form provides an increased elevation of the dextromethorphan plasma level in the human compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0319] Embodiment 121. The method of Embodiment 120, wherein the dosage form contains about 100 mg to about 200 mg of (R)-bupropion.

[0320] Embodiment 122. The method of Embodiment 120, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion.

[0321] Embodiment 123. The method of Embodiment 120, wherein the dosage form contains about 148 mg to about 152 mg of (R)-bupropion.

[0322] Embodiment 124. The method of Embodiments 120, 121, 122, or 123, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.

[0323] Embodiment 125. The method of Embodiment 124, wherein the dosage form contains about 40 mg to about 50 mg of dextromethorphan.

[0324] Embodiment 126. The method of Embodiment 125, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.

[0325] Embodiment 127. The method of Embodiments 120, 121, 122, 123, 124, 125, or 126, wherein the dosage form is administered orally to the human under fasted conditions.

[0326] Embodiment 128. The method of Embodiments 120, 121, 122, 123, 124, 125, 126, or 127, wherein the dosage form is well-tolerated.

[0327] Embodiment 129. A method of treating a central nervous system (CNS) disorder in a human, the method comprising administering to the human for which the CNS disorder is to be treated a dosage form comprising a therapeutically effective amount of (S)-bupropion that is at least about 95% enantiomeric pure and dextromethorphan, wherein the human is not receiving dextromethorphan.

[0328] Embodiment 130. The method of Embodiment 129, wherein the CNS disorder comprises depression.

[0329] Embodiment 131. The method of Embodiments 129 or 130, wherein the CNS disorder comprises treatment-resistant depression.

[0330] Embodiment 132. The method of Embodiments 129, 130, or 131, wherein the CNS disorder is an addictive disorder.

[0331] Embodiment 133. The method of Embodiment 132, wherein the CNS disorder is nicotine addiction.

[0332] Embodiment 134. The method of Embodiment, wherein the CNS disorder is alcohol addiction.

[0333] Embodiment 135. The method of Embodiment 132, wherein the CNS disorder is Alzheimer’s disease.

[0334] Embodiment 136. The method of embodiment 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form does not contain an active pharmaceutical agent other than (S)-bupropion.

[0335] Embodiment 137. The method of embodiment 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form contains less than 0.1% of any active pharmaceutical agent other than (S)-bupropion.

[0336] Embodiment 138. The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, or 137, wherein the dosage form is in the form of a tablet, a capsule, or a syrup.

[0337] Embodiment 139. The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, or 138, wherein the dosage form is orally administered to the human once a day.

[0338] Embodiment 140. The method of embodiment 139, wherein the dosage form is orally administered to the human once a day.

[0339] Embodiment 141. The method of embodiment 139, wherein the dosage form is orally administered to the human twice a day.

[0340] Embodiment 142. The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, or 141, wherein the dosage form is orally administered to the human under fasted conditions.

[0341] Embodiment 143. The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, or 142, wherein the dosage form is orally administered to the human at least for 8 consecutive days a day.

[0342] Embodiment 144. The method of embodiment 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, or 143, wherein the dosage form contains about 100 mg to about 200 mg of (S)-bupropion.

[0343] Embodiment 145. The method of embodiment 144, wherein the dosage form contains about 104 mg to about 106 mg of (S)-bupropion.

[0344] Embodiment 146. The method of embodiment 144, wherein the dosage form contains about 148 mg to about 152 mg of (S)-bupropion.

[0345] Embodiment 147. A method of increasing plasma levels of (S)-bupropion, comprising administering to a person in need of treatment with bupropion a dosage form comprising a therapeutically effective amount of (S)-bupropion that is at least about 95% enantiomeric pure, wherein the dosage form does not contain dextromethorphan.

[0346] Embodiment 148. The method of embodiment 147, wherein the method is effective to increase (S)-bupropion C 最大 .

[0347] Embodiment 149. The method of embodiment 147 or 148, wherein the method is effective to increase the (S)-bupropion C 最大 at least 3-fold compared to (R)-bupropion C 最大 resulting from administration of a dosage form containing the same amount of (R)-bupropion to the person.

[0348] Embodiment 150. The method of embodiment 147, 148, or 149, wherein the method is effective to increase (S)-bupropion AUC 0-12 .

[0349] Embodiment 151. The method of embodiment 147, 148, 149, or 150, wherein the method is effective to increase the (S)-bupropion AUC 0-12 at least 3-fold compared to (R)-bupropion AUC 0-12 resulting from administration of a dosage form containing the same amount of (R)-bupropion to the person.

[0350] Embodiment 152. The method of embodiment 147, 148, 149, 150, or 151, wherein the dosage form is administered at least once a day for at least 8 consecutive days.

[0351] Embodiment 153. The method of embodiment 152, wherein the oral dosage form is administered once a day for 1 to 3 consecutive days, followed by at least 4 to 7 consecutive days of twice-a-day administration of the dosage form, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0352] Embodiment 154. The dosage form of embodiment 147, 148, 149, 150, 151, 152, or 153, wherein the dosage form is well-tolerated.

[0353] Embodiment 155. A method of increasing plasma levels of (S)-bupropion, the method comprising orally administering to a human in need of treatment with (S)-bupropion and dextromethorphan an oral dosage form comprising at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion, wherein the method achieves a C level of (S)-bupropion of at least about 90 ng / mL in the human. 最大 wherein said method effectively makes said (S)-bupropion C 最大 (R)-bupropion C is produced by administering a dosage form containing the same amount of (R)-bupropion to the human. 最大 at least a 3-fold increase compared to a 3-fold increase in the patient's risk of developing dextromethorphan, wherein the person is not receiving dextromethorphan.

[0354] Embodiment 156. The method of embodiment 155, wherein the oral dosage form is administered for at least 8 consecutive days.

[0355] Embodiment 157. The method of embodiment 156, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, and then the dosage form is administered twice daily for at least the next 4 to 7 consecutive days, such that the dosage form is administered once daily or twice daily for a total of at least 8 consecutive days.

[0356] Embodiment 158. The method of embodiment 155, 156, or 157, wherein the dosage form contains from about 100 mg to about 110 mg of (S)-bupropion.

[0357] Embodiment 159. The method of embodiment 155, 156, 157, or 158, wherein the (S)-bupropion C in the human 最大 is at least about 110 ng / mL.

[0358] Embodiment 160. A method of increasing plasma levels of (R,R)-hydroxybupropion, the method comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion and dextromethorphan an oral dosage form containing at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion, wherein the method achieves a plasma level of (R,R)-hydroxybupropion C of at least about 90 ng / mL. 最大 wherein said method effectively makes said (R,R)-hydroxybupropion C 最大 (R,R)-hydroxybupropion C produced by administering a dosage form containing the same amount of (R)-bupropion to the human 最大 at least a 3-fold increase compared to a 3-fold increase in the patient's risk of developing dextromethorphan, wherein the person is not receiving dextromethorphan.

[0359] Embodiment 161. The method of embodiment 160, wherein the oral dosage form is administered for at least 8 consecutive days.

[0360] Embodiment 162. The method of embodiment 161, wherein the oral dosage form is administered once a day for 1 to 3 consecutive days, followed by administration of the dosage form twice a day for at least the next 4 to 7 consecutive days, such that the dosage form is administered once a day or twice a day for a total of at least 8 consecutive days.

[0361] Embodiment 163. The method of embodiment 160, 161, or 162, wherein the dosage form contains about 100 mg to about 110 mg of (S)-bupropion.

[0362] Embodiment 164. An oral dosage form comprising (R)-bupropion and dextromethorphan in at least a 95% enantiomeric excess, wherein the dosage form provides an increased increase in the person's plasma levels of dextromethorphan compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0363] Embodiment 165. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form can increase the person's plasma levels of dextromethorphan to a substantially greater extent on day 1 or day 8 when administered orally to a person each day for at least 8 consecutive days compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan.

[0364] Embodiment 166. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when administered orally to a person each day for at least 8 consecutive days, increases the person's mean dextromethorphan C 最大 max on day 1 by at least 150% compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as (S)-bupropion and the same amount of dextromethorphan.

[0365] Embodiment 167. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when administered orally to a person each day for at least 8 consecutive days, increases the person's mean dextromethorphan C 最大 max on day 8 by at least 25% compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as (S)-bupropion and the same amount of dextromethorphan.

[0366] Embodiment 168. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when administered orally to a person each day for at least 8 consecutive days, increases the person's mean dextromethorphan C 最大 max on day 8 by at least 20-fold compared to a reference oral dosage form on day 1, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan.

[0367] Embodiment 169. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when orally administered to a human each day for at least 8 consecutive days, achieves a mean dextromethorphan Cmax in the human on day 1 that is at least 60% greater compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan. 最大 Embodiment 169. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when orally administered to a human each day for at least 8 consecutive days, achieves a mean dextromethorphan Cmax in the human on day 1 that is at least 60% greater compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan.

[0368] Embodiment 170. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when orally administered to a human each day for at least 8 consecutive days, achieves a mean dextromethorphan Cmax in the human on day 8 that is at least 20% greater compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan. 最大 Embodiment 169. An oral dosage form comprising (R)-bupropion and dextromethorphan, wherein the dosage form, when orally administered to a human each day for at least 8 consecutive days, achieves a mean dextromethorphan Cmax in the human on day 1 that is at least 60% greater compared to a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion as racemic bupropion and the same amount of dextromethorphan.

[0369] Embodiment 171. A method of increasing dextromethorphan plasma levels on day 1 or day 8, the method comprising orally administering a dosage form containing (R)-bupropion and dextromethorphan, which, when orally administered to a human each day for at least 8 consecutive days, increases the dextromethorphan plasma levels to a much greater extent compared to orally administering a reference dosage form, wherein the reference dosage form contains the same amount of bupropion as (S)-bupropion and the same amount of dextromethorphan.

[0370] Embodiment 172. The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the (R)-bupropion in the dosage form is at least 95% enantiomeric pure.

[0371] Embodiment 173. The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the (S)-bupropion in the reference dosage form is at least 95% enantiomeric pure.

[0372] Embodiment 174. The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the dosage form contains about 100 mg to about 150 mg of (R)-bupropion.

[0373] Embodiment 175. The dosage form or method of embodiment 174, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion.

[0374] Embodiment 176. The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, or 171, wherein the dosage form contains about 10 mg to about 50 mg dextromethorphan.

[0375] Embodiment 177. The dosage form or method of embodiment 176, wherein the dosage form contains about 40 mg to about 50 mg dextromethorphan.

[0376] Embodiment 178. The dosage form or method of claim 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is administered orally once a day.

[0377] Embodiment 179. The dosage form or method of embodiment 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is administered orally twice a day.

[0378] Embodiment 180. The dosage form or method of embodiment 178 or 179, wherein the dosage form is administered orally for at least 8 consecutive days.

[0379] Embodiment 181. The dosage form or method of embodiment 180, wherein the dosage form contains about 100 mg to about 110 mg (R)-bupropion and about 40 mg to about 50 mg dextromethorphan.

[0380] Embodiment 182. The dosage form or method of embodiment 180 or 181, wherein the oral dosage form achieves a mean dextromethorphan C 最大 .

[0381] Embodiment 183. The dosage form or method of embodiment 180, 181, or 182, wherein the dosage form is in the form of a syrup, a tablet, a capsule, a spray, or a lozenge.

[0382] Embodiment 184. A method of treating a neuropsychiatric condition, the method comprising administering to a human in need thereof a dosage form according to any preceding embodiment.

[0383] Embodiment 185. A method of treating a cold or a cough, the method comprising administering to a human in need thereof a dosage form according to any preceding embodiment.

[0384] Embodiment 186. A method of reducing pain, comprising administering to a person in need thereof a dosage form according to any preceding embodiment.

[0385] Embodiment 187. A method of treating addiction, comprising administering to a person in need thereof a dosage form according to any preceding embodiment.

[0386] Embodiment 188. A method of treating a person, comprising orally administering to a person having a condition treatable with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the amount of (S)-bupropion is selected to be about 20% to about 70% of the amount of racemic bupropion that would be administered to treat the same condition in the same person.

[0387] Embodiment 189. A method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion, comprising orally administering to a person in need of treatment with (R,R)-hydroxybupropion at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person, and wherein the method achieves (R,R)-hydroxybupropion C 最大 .

[0388] Embodiment 190. A method of treating a person, comprising orally administering to a person in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the (S)-bupropion is the only active agent used to treat the person.

[0389] Embodiment 191. A method of treating a person, comprising orally administering to a person in need of treatment with (S)-bupropion a dosage form containing about 50 mg to about 100 mg of at least 95% enantiomeric purity of (S)-bupropion once or twice a day.

[0390] Embodiment 192. A method of treating a person, comprising orally administering to a person in need of treatment with (S)-bupropion a dosage form containing at least 95% enantiomeric purity of (S)-bupropion once or twice a day, wherein the method achieves at least about 60 ng / mL of (S)-bupropion C 最大 .

[0391] Embodiment 193. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human.

[0392] Embodiment 194. A method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion once or twice a day at least 95% enantiomeric purity of (S)-bupropion, wherein (R,R)-hydroxybupropion is at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the human.

[0393] Embodiment 195. A method of providing therapeutically effective plasma levels of (R,R)-hydroxybupropion comprising orally administering to a human in need of treatment with (R,R)-hydroxybupropion once or twice a day at least 95% enantiomeric purity of (S)-bupropion, wherein the method achieves at least about 500 ng / mL of (R,R)-hydroxybupropion C 最大 .

[0394] Embodiment 196. The method of any preceding embodiment, e.g., Embodiments 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, or 195, wherein the human is not administered dextromethorphan.

[0395] Embodiment 197. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the method achieves at least about 70 ng / mL of (S)-bupropion C 最大 .

[0396] Embodiment 198. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion once or twice a day a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the method achieves at least about 600 ng·h / mL of (S)-bupropion AUC 0- 12.

[0397] Embodiment 199. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a (R,R)-hydroxybupropion Cmax of at least about 800 ng / mL.

[0398] Embodiment 200. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a (R,R)-hydroxybupropion AUC of at least about 8,000 ng-h / mL. 0-12 .

[0399] Embodiment 201. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a meso-hydroxybupropion Cmax of at least about 90 ng / mL. 最 Large.

[0400] Embodiment 202. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a meso-hydroxybupropion AUC of at least about 1,000 ng-h / mL. 0-12 .

[0401] Embodiment 203. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a (S,S)-hydroxybupropion Cmax of at least about 450 ng / mL.

[0402] Embodiment 204. A method of treating a human comprising orally administering to a human in need of treatment with (S)-bupropion a dosage form containing (S)-bupropion in at least 95% enantiomeric purity once or twice a day, wherein the method achieves a (S,S)-hydroxybupropion AUC of at least about 5,000 ng-h / mL. 0-12 .

[0403] Embodiment 205. A dosage form comprising (S)-bupropion in at least 95% enantiomeric purity.

[0404] Embodiment 206. The dosage form according to Embodiment 205, containing from about 100 mg to about 200 mg of (S)-bupropion.

[0405] Embodiment 207. The dosage form of any preceding embodiment, wherein the dosage form contains less than 0.1% of any other active pharmaceutical agent.

[0406] Embodiment 208. The dosage form of any preceding embodiment, further comprising dextromethorphan.

[0407] Embodiment 209. The dosage form of embodiment 208, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.

[0408] Embodiment 210. A method of increasing the plasma level of (S)-bupropion or a metabolite thereof, the method comprising administering to a person in need of treatment with bupropion or a metabolite thereof, a dosage form according to embodiment 205, 206, 207, 208, or 209.

[0409] Embodiment 211. The method of any preceding embodiment, wherein the method is effective to increase the (S)-bupropion C 最大 .

[0410] Embodiment 212. The method of any preceding embodiment, wherein the method is effective to increase the (S)-bupropion C 最大 at least 3-fold compared to the (R)-bupropion C 最大 resulting from administration to the person of a dosage form containing the same amount of (R)-bupropion.

[0411] Embodiment 213. The method of any preceding embodiment, wherein the method is effective to increase the (S)-bupropion AUC 0-12 .

[0412] Embodiment 214. The method of any preceding embodiment, wherein the method is effective to increase the (S)-bupropion AUC 0-12 at least 3-fold compared to the (R)-bupropion AUC 0-12 resulting from administration to the person of a dosage form containing the same amount of (R)-bupropion.

[0413] Embodiment 215. The method of any preceding embodiment, wherein the method is effective to increase the (R,R)-hydroxybupropion C 最大 .

[0414] Embodiment 216. The method of any preceding embodiment, wherein the method is effective to increase the (R,R)-hydroxybupropion C 最大 at least 3-fold compared to the (R,R)-hydroxybupropion C resulting from administration to the person of a dosage form containing the same amount of (R)-bupropion.最大 at least 3-fold compared to administration of a dosage form containing the same amount of (R)-bupropion to the human.

[0415] Embodiment 217. The method of any preceding embodiment, wherein the method is effective to increase the (R,R)-hydroxybupropion AUC 0-12 .

[0416] Embodiment 218. The method of embodiment 13, wherein the method is effective to increase the (R,R)-hydroxybupropion AUC 0-12 at least 3-fold compared to administration of a dosage form containing the same amount of (R)-bupropion to the human. 0-12 at least 3-fold compared to administration of a dosage form containing the same amount of (R)-bupropion to the human.

[0417] Embodiment 219. The method of any preceding embodiment, wherein the dosage form is administered at least once per day for at least 8 consecutive days.

[0418] Embodiment 220. A method of treating a neurological disorder, comprising administering to a human in need thereof a dosage form of any preceding embodiment.

[0419] Embodiment 221. The method of embodiment 16, wherein the neurological disorder is depression.

[0420] Embodiment 222. A method of increasing dextromethorphan plasma levels, comprising administering to a human in need of treatment by dextromethorphan a combination of (R)-bupropion and dextromethorphan, wherein the (R)-bupropion is at least 95% enantiomeric pure.

[0421] Embodiment 223. The method of embodiment 18, wherein the dextromethorphan C 最大 is increased by at least 20% compared to administration of the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0422] Embodiment 224. A method of delivering (S)-bupropion into the plasma of a human, comprising: orally administering to the human a dosage form containing (S)-bupropion that is at least 95% enantiomeric pure.

[0423] Embodiment 225. A method of delivering both (R)-bupropion and (S)-bupropion into the plasma of a human, comprising: orally administering to the human a dosage form containing (S)-bupropion that is at least 95% enantiomeric pure, wherein the (R)-bupropion C 最大 is within 20% of what would be produced by administration of the same amount of racemic bupropion to the human. 最大 .

[0424] Embodiment 226. A method of delivering bupropion into the plasma of a human comprising: orally administering to the human a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the (R)-bupropion AUC 0-12 of (R)-bupropion that would be produced by administration of the same amount of racemic bupropion to the human is within 20%. 0-12

[0425] Embodiment 227. A method of delivering bupropion into the plasma of a human comprising: orally administering to the human a dosage form containing at least 95% enantiomeric purity of (S)-bupropion, wherein the (R,R)-hydroxybupropion C 最大 of (R,R)-hydroxybupropion that would be produced by administration of the same amount of racemic bupropion to the human is within 20%. 最大

[0426] Embodiment 228. The method of embodiments 224, 225, 226, or 227, wherein the (S)- bupropion is administered for at least 8 consecutive days.

[0427] Embodiment 229. The method of embodiment 228, wherein the (S)-bupropion is administered for at least 14 consecutive days.

[0428] Embodiment 230. The method of embodiments 224, 225, 226, 227, 228, or 229, wherein the dosage form contains about 50 mg to about 150 mg of (S)-bupropion.

[0429] Embodiment 231. The method of embodiments 224, 225, 226, 227, 228, or 229, wherein the dosage form contains about 40 mg to about 90 mg of (S)-bupropion.

[0430] Embodiment 232. The method of any preceding embodiment, wherein administration of the dosage form produces a combined C 最大 of (S)-bupropion and (R)-bupropion of at least about 100 ng / mL on day 8.

[0431] Embodiment 233. The method of any preceding embodiment, wherein administration of the dosage form produces a combined AUC 0-12 of (S)-bupropion and (R)-bupropion of at least about 800 ng·hr / mL on day 8.

[0432] ​​Embodiment 234. The method of any preceding embodiment, wherein administration of the dosage form results in a combined Cmax of (S,S)-hydroxybupropion and (R,R)- hydroxybupropion of at least about 1,000 ng / mL on Day 8 最大 .

[0433] Embodiment 235. The method of any preceding embodiment, wherein administration of the dosage form results in a combined AUC of (S,S)-hydroxybupropion and (R,R)- hydroxybupropion of at least about 10,000 ng·hr / mL on Day 8 0-12 .

[0434] Embodiment 236. The method of any preceding embodiment, wherein administration of the dosage form results in a Cmax of erythro-hydroxybupropion of at least about 100 ng / mL on Day 8 最大 .

[0435] Embodiment 237. The method of any preceding embodiment, wherein administration of the dosage form results in an AUC of erythro-hydroxybupropion of at least about 1,500 ng·hr / mL on Day 8 0-12 .

[0436] Embodiment 238. The method of any preceding embodiment, wherein administration of the dosage form results in a Cmax of threo-hydroxybupropion of at least about 600 ng / mL on Day 8 最大 .

[0437] Embodiment 239. The method of any preceding embodiment, wherein administration of the dosage form results in a combined AUC of threo-hydroxybupropion of at least about 5,000 ng·hr / mL on Day 8 0-12 .

[0438] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as amount, AUC values, and so forth used in the specification and claims are to be understood as approximations as if modified by the phrase “about.” Accordingly, unless indicated otherwise, the numerical parameters listed in the specification and attached claims are approximations. At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. It will be further understood that the members of the groups are collectively intended to be enunciated by the recitation of the word “comprising” preceding the term “group,” unless the context indicates otherwise.

[0439] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the application (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 application and does not pose a limitation on any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the application.

[0440] Groupings of alternative elements or embodiments of the application disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other alternative elements found herein. One or more members of a group can 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 herein deemed to contain the group as modified thus fulfilling the written description requirement.

[0441] Certain embodiments are described herein, including the best mode known to the inventors of carrying out the application. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art once the nature of the application has been disclosed herein. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the application to be practiced with the scope and intent commonly applied to claims of the patent laws. Accordingly, the claims include all modifications and equivalents of the subject matter recited therein as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless other expressly stated otherwise herein.

[0442] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the present application. Other modifications that can be employed are within the scope of the application. As one skilled in the art will readily appreciate, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains" or "containing", or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus. Further, unless specifically stated otherwise, the term "or" as used herein refers to a non-exclusive or, i.e., there is an "or" between a first option and a second option and that the first option can be utilized independently from the second option, the second option can be utilized independently from the first option, and both the first and second options can be utilized at the same time.

Claims

1. A dosage form comprising at least 95% enantiomeric purity of (S)-bupropion.

2. The dosage form of claim 1, which contains from about 50 mg to about 100 mg of (S)-bupropion.

3. The dosage form of claim 1, which contains from about 100 mg to about 200 mg of (S)-bupropion.

4. The dosage form of claim 1, 2, or 3, wherein the dosage form contains less than 0.1% of any other active pharmaceutical agent.

5. The dosage form of claim 1, 2, 3, or 4, wherein the dosage form achieves at least about 60 ng / mL of (S)-varenicline C 最大 .

6. The dosage form of claim 1, 2, 3, 4, or 5, wherein the dosage form achieves at least about 500 ng / mL of (R,R)-hydroxybupropion C 最大 .

7. The dosage form of claim 1, 2, 3, 4, 5, or 6, wherein the dosage form achieves an (S)-bupropion AUC of at least about 400 ng-hr / mL when administered to a human in need thereof. 0-12 .

8. The dosage form of claim 1, 2, 3, 4, 5, 6, or 7, wherein the dosage form achieves an (R,R)-hydroxybupropione AUC of at least about 7000 ng-hr / mL when administered to a human in need thereof. 0-12 .

9. The dosage form of claim 1, 2, 3, 4, 5, 6, 7, or 8, wherein the dosage form provides sustained release of the (S)-bupropion.

10. The dosage form of claim 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the dosage form is well-tolerated when administered to a human.

11. The dosage form of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein the dosage form is used to treat a condition treatable with racemic bupropion in a human in need thereof.

12. The dosage form of claim 11, wherein the human has a condition treatable by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dosing frequency; and orally administering a dosage form containing a second amount of at least 95% enantiomeric purity of (S)-bupropion at the first dosing frequency to achieve the same therapeutic effect as would be achieved by administering the reference dosage form at the first dosing frequency; wherein the first dosing frequency is once a day or twice a day; and wherein the second amount is from about 40% to about 60% of the first amount.

13. The dosage form of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the dosage form is used to treat a central nervous system (CNS) disorder.

14. The dosage form of claim 13, wherein the CNS disorder comprises depression.

15. The dosage form of claim 13, wherein the CNS disorder comprises treatment-resistant depression.

16. The dosage form of claim 13, wherein the CNS disorder comprises an addictive disorder.

17. The dosage form of claim 13, wherein the CNS disorder comprises nicotine addiction.

18. The dosage form of claim 13, wherein the CNS disorder comprises alcohol addiction.

19. The dosage form of claim 13, wherein the CNS disorder comprises attention deficit / hyperactivity disorder.

20. The dosage form of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, wherein the dosage form is used to reduce pain in a human in need thereof. ​

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