Dosage form comprising bupropion and dextromethorphan

Abstract

To provide methods for administering erythrohydroxybupropion or a prodrug thereof in conjunction with dextromethorphan to a human being.SOLUTION: Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and erythrohydroxybupropion or a prodrug of erythrohydroxybupropion are disclosed.SELECTED DRAWING: None

Description

Summary of the Invention

Means for Solving the Problems

[0001] Some embodiments include co - administering erythrohydroxybupropion or a prodrug thereof with dextromethorphan to a human, wherein the erythrohydroxybupropion or a prodrug thereof is administered in an amount that results in an AUC of dextromethorphan of at least about 40 ng·hour / mL 0-12 and includes a method for increasing the plasma concentration of dextromethorphan in a human.

[0002] Some embodiments include co - administering erythrohydroxybupropion or a prodrug thereof with dextromethorphan to a human, wherein the erythrohydroxybupropion or a prodrug thereof is administered in an amount that results in a C of dextromethorphan of at least about 6 ng / mL 最大 and includes a method for increasing the plasma concentration of dextromethorphan in a human.

[0003] Some embodiments include co - administering erythrohydroxybupropion or a prodrug thereof with dextromethorphan to a human, wherein the erythrohydroxybupropion or a prodrug thereof is administered in an amount that results in a C of dextromethorphan of at least about 5 ng / mL over a period between two separate and consecutive administrations of dextromethorphan 平均 and includes a method for increasing the plasma concentration of dextromethorphan in a human.

[0004] Some embodiments include administering threohydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is in the high - metabolizer group of dextromethorphan and dextromethorphan is present in the human body simultaneously with threohydroxybupropion, and includes a method for increasing the metabolic life of dextromethorphan.

[0005] Some embodiments include co-administering to a human patient in need of treatment with dextromethorphan, threohydroxybupropion or a prodrug thereof, wherein the human patient is at risk of experiencing an adverse event as a result of treatment with dextromethorphan, a method of reducing adverse events associated with treatment with dextromethorphan.

[0006] Some embodiments include an oral sustained release delivery system for dextromethorphan, comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, dextromethorphan, and a water-soluble vehicle.

[0007] Some embodiments include a method of reducing the number of administrations of dextromethorphan that can be administered without loss of efficacy, comprising orally administering to a human in need of treatment with dextromethorphan an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds.

[0008] Some embodiments include co-administering to a human in need of treatment with dextromethorphan, threohydroxybupropion or a prodrug thereof, and dextromethorphan, wherein the threohydroxybupropion or a prodrug thereof is administered on the first day of at least 2 days of treatment with dextromethorphan, and a method of reducing the dextromethorphan plasma concentration, wherein a reduction in the dextromethorphan plasma concentration occurs on the first day when the threohydroxybupropion or a prodrug thereof and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without the threohydroxybupropion or a prodrug thereof.

[0009] Some embodiments include co-administering hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, administering the hydroxybupropion or prodrug thereof on the first day of at least 2 days of treatment with dextromethorphan, and a reduction in the plasma concentration of dextromethorphan occurring on the first day when the hydroxybupropion or prodrug thereof and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without the hydroxybupropion or prodrug thereof, and include a method of reducing the plasma concentration of dextromethorphan.

[0010] Some embodiments include co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, administering the bupropion on the first day of at least 2 days of treatment with dextromethorphan, and a reduction in the plasma concentration of dextromethorphan occurring on the first day when the bupropion and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without the bupropion, and include a method of reducing the plasma concentration of dextromethorphan.

[0011] Some embodiments include co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, administering the erythrohydroxybupropion or prodrug thereof on the first day of at least 2 days of treatment with dextromethorphan, and a reduction in the plasma concentration of dextromethorphan occurring on the first day when the erythrohydroxybupropion or prodrug thereof and dextromethorphan are co-administered, as compared to the same amount of dextromethorphan administered without the erythrohydroxybupropion or prodrug thereof, and include a method of reducing the plasma concentration of dextromethorphan.

[0012] Some embodiments include co - administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, and on the 8th day, administering the same amount of dextromethorphan without bupropion for 8 consecutive days, which results in a lower plasma concentration of dextrorphan than would be achieved by administering the same amount of dextromethorphan without bupropion for 8 consecutive days, including a method for reducing the plasma concentration of dextromethorphan.

[0013] Some embodiments include co - administering hydroxybupropion or its prodrug and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, and on the 8th day, administering the same amount of dextromethorphan without hydroxybupropion or its prodrug for 8 consecutive days, which results in a lower plasma concentration of dextrorphan than would be achieved by administering the same amount of dextromethorphan without hydroxybupropion or its prodrug for 8 consecutive days, including a method for reducing the plasma concentration of dextromethorphan.

[0014] Some embodiments include co - administering erythrohydroxybupropion or its prodrug and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, and on the 8th day, administering the same amount of dextromethorphan without erythrohydroxybupropion or its prodrug for 8 consecutive days, which results in a lower plasma concentration of dextrorphan than would be achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or its prodrug for 8 consecutive days, including a method for reducing the plasma concentration of dextromethorphan.

[0015] Some embodiments include co-administering to a human in need thereof L-threo-hydroxybupropion or a prodrug thereof and dextromethorphan for at least 8 consecutive days, and on day 8, administering the same amount of dextromethorphan without L-threo-hydroxybupropion or a prodrug thereof for 8 consecutive days, wherein the plasma concentration of dextrorphan is lower than the plasma concentration of dextrorphan that would have been achieved by administering the same amount of dextromethorphan for 8 consecutive days. The method includes reducing the plasma concentration of dextrorphan.

[0016] Antidepressant compounds such as bupropion, hydroxybupropion, erythro-hydroxybupropion, L-threo-hydroxybupropion, or metabolites, or prodrugs of any of these compounds, can be used to improve therapeutic properties such as the treatment of neuropathy of dextromethorphan. Bupropion, hydroxybupropion, erythro-hydroxybupropion, L-threo-hydroxybupropion, or metabolites, or prodrugs of any of these compounds, can be effective in inhibiting or reducing the metabolites of dextromethorphan in some humans, regardless of stereochemistry. This can be achieved by co-administering bupropion, hydroxybupropion, erythro-hydroxybupropion, L-threo-hydroxybupropion, or metabolites, or prodrugs of any of these compounds with dextromethorphan.

[0017] Some embodiments include a method of treating neuropathy that includes administering an antidepressant and dextromethorphan to a human in need thereof, wherein the human is a high metabolizer of dextromethorphan.

[0018] Some embodiments include a method of increasing the plasma concentration of dextromethorphan in a human in need thereof, wherein the human is a high metabolizer of dextromethorphan, and includes co-administering dextromethorphan and bupropion to the human.

[0019] Some embodiments include a method of inhibiting the metabolites of dextromethorphan, including administering bupropion to a human, the human being in the high-metabolism group of dextromethorphan, and dextromethorphan being present in the human body simultaneously with bupropion.

[0020] Some embodiments include a method of increasing the metabolite lifespan of dextromethorphan, including administering bupropion to a human in need of treatment with dextromethorphan, the human being in the high-metabolism group of dextromethorphan, and dextromethorphan being present in the human body simultaneously with bupropion.

[0021] Some embodiments include a method of correcting the high metabolites of dextromethorphan, including administering bupropion to a human in need thereof.

[0022] Some embodiments include a method of improving the antitussive properties of dextromethorphan, including administering bupropion in combination with the administration of dextromethorphan to a human in need of cough treatment.

[0023] Some embodiments include a method of treating cough, including administering a combination of bupropion and dextromethorphan to a human in need thereof.

[0024] Some embodiments include a method of treating neuropathy, including administering bupropion and dextromethorphan to a human in need thereof, and bupropion and dextromethorphan are administered at least once a day for 8 days.

[0025] Some embodiments include a method of treating neuropathy, including administering from about 150 mg / day to about 300 mg / day of bupropion and from about 15 mg / day to about 60 mg / day of dextromethorphan to a human in need thereof.

[0026] Some embodiments include a method of increasing the dextromethorphan plasma concentration in a human in need of treatment with dextromethorphan, the human being in the high metabolizer group of dextromethorphan, and comprising co-administering hydroxybupropion or a prodrug thereof to the human together with dextromethorphan.

[0027] Some embodiments include a method of increasing the dextromethorphan plasma concentration in a human in need of treatment with dextromethorphan, the human being in the high metabolizer group of dextromethorphan, and comprising co-administering erythrohydroxybupropion or a prodrug thereof to the human together with dextromethorphan.

[0028] Some embodiments include a method of increasing the dextromethorphan plasma concentration in a human in need of treatment with dextromethorphan, the human being in the high metabolizer group of dextromethorphan, and comprising co-administering threohydroxybupropion or a prodrug thereof to the human together with dextromethorphan.

[0029] Some embodiments include a method of inhibiting the metabolites of dextromethorphan, comprising administering bupropion to a human, the human being in the high metabolizer group of dextromethorphan, and dextromethorphan being present in the human body simultaneously with bupropion.

[0030] Some embodiments include a method of inhibiting the metabolites of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof to a human, the human being in the high metabolizer group of dextromethorphan, and dextromethorphan being present in the human body simultaneously with hydroxybupropion.

[0031] Some embodiments include methods of inhibiting metabolites of dextromethorphan, including administering to a human erythrohydroxybupropion or a prodrug thereof, where the human is in the high metabolizer group of dextromethorphan, and dextromethorphan is present in the human body concurrently with erythrohydroxybupropion.

[0032] Some embodiments include methods of inhibiting metabolites of dextromethorphan, including administering to a human threohydroxybupropion or a prodrug thereof, where the human is in the high metabolizer group of dextromethorphan, and dextromethorphan is present in the human body concurrently with threohydroxybupropion.

[0033] Some embodiments include methods of increasing the metabolic lifespan of dextromethorphan, including administering to a human in need of treatment with dextromethorphan hydroxybupropion or a prodrug thereof, where the human is in the high metabolizer group of dextromethorphan, and dextromethorphan is present in the human body concurrently with hydroxybupropion.

[0034] Some embodiments include methods of increasing the metabolic lifespan of dextromethorphan, including administering to a human in need of treatment with dextromethorphan erythrohydroxybupropion or a prodrug thereof, where the human is in the high metabolizer group of dextromethorphan, and dextromethorphan is present in the human body concurrently with erythrohydroxybupropion.

[0035] Some embodiments include methods of increasing dextrorphan plasma concentration that include co-administering bupropion and dextrorphan to a human in need of treatment with dextrorphan, wherein bupropion is administered on day 1 of at least 2 days (at least 2 days of co-administration) of co-administration of dextrorphan and bupropion, and the increase in dextrorphan plasma concentration occurs on day 1 when bupropion and dextrorphan are co-administered, as compared to administration of the same amount of dextrorphan without bupropion.

[0036] Some embodiments include methods of increasing dextrorphan plasma concentration that include co-administering hydroxybupropion, or a prodrug thereof, and dextrorphan to a human in need of treatment with dextrorphan, wherein hydroxybupropion or a prodrug thereof is administered on day 1 of at least 2 days of co-administration of dextrorphan and hydroxybupropion or a prodrug thereof, and the increase in dextrorphan plasma concentration occurs on day 1 when hydroxybupropion or a prodrug thereof and dextrorphan are co-administered, as compared to administration of the same amount of dextrorphan without hydroxybupropion or a prodrug thereof.

[0037] Some embodiments include methods of increasing dextrorphan plasma concentration that include co-administering erythrohydroxybupropion, or a prodrug thereof, and dextrorphan to a human in need of treatment with dextrorphan, wherein erythrohydroxybupropion or a prodrug thereof is administered on day 1 of at least 2 days of co-administration of dextrorphan and erythrohydroxybupropion or a prodrug thereof, and the increase in dextrorphan plasma concentration occurs on day 1 when erythrohydroxybupropion or a prodrug thereof and dextrorphan are co-administered, as compared to administration of the same amount of dextrorphan without erythrohydroxybupropion or a prodrug thereof.

[0038] Some embodiments include a method of increasing the dextromethorphan plasma concentration comprising co-administering levo-hydroxybupropion, or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the levo-hydroxybupropion or a prodrug thereof is administered on the first day of at least 2 days of co-administration of dextromethorphan and hydroxybupropion or a prodrug thereof, and the increase in the dextromethorphan plasma concentration occurs on the first day on which levo-hydroxybupropion or a prodrug thereof and dextromethorphan are co-administered, as compared to administration of the same amount of dextromethorphan without levo-hydroxybupropion or a prodrug thereof.

[0039] Some embodiments include a method of increasing the dextromethorphan plasma concentration comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on the fifth day, the dextromethorphan plasma concentration is higher than the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan administered without bupropion for 5 consecutive days.

[0040] Some embodiments include a method of increasing the dextromethorphan plasma concentration comprising co-administering hydroxybupropion, or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on the fifth day, the dextromethorphan plasma concentration is higher than the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof for 5 consecutive days.

[0041] Some embodiments include methods of increasing dextromethorphan plasma concentration by co-administering erythrohydroxybupropion, or a prodrug thereof and dextromethorphan, to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan administered without erythrohydroxybupropion or a prodrug thereof for 5 consecutive days.

[0042] Some embodiments include methods of increasing dextromethorphan plasma concentration by co-administering threohydroxybupropion, or a prodrug thereof and dextromethorphan, to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan administered without threohydroxybupropion or a prodrug thereof for 5 consecutive days.

[0043] Some embodiments include methods of increasing dextromethorphan plasma concentration by co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan administered without bupropion for 6 consecutive days.

[0044] Some embodiments include a method of increasing dextromethorphan plasma concentration by co-administering hydroxybupropion, or a prodrug thereof and dextromethorphan, to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof for 6 consecutive days.

[0045] Some embodiments include a method of increasing dextromethorphan plasma concentration by co-administering erythrohydroxybupropion, or a prodrug thereof and dextromethorphan, to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof for 6 consecutive days.

[0046] Some embodiments include a method of increasing dextromethorphan plasma concentration by co-administering threohydroxybupropion, or a prodrug thereof and dextromethorphan, to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma concentration is higher compared to the dextromethorphan plasma concentration achieved by administering the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof for 6 consecutive days.

[0047] Some embodiments include a method of reducing the trough effect of dextromethorphan, which involves co-administering bupropion with dextromethorphan to a human in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of bupropion with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without bupropion.

[0048] Some embodiments include a method of reducing the trough effect of dextromethorphan, which involves co-administering hydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

[0049] Some embodiments include a method of reducing the trough effect of dextromethorphan, which involves co-administering erythrohydroxybupropion, or a prodrug thereof, with dextromethorphan to a human patient in need of treatment with dextromethorphan, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

[0050] Some embodiments include a method of reducing the trough effect of dextromethorphan in a human patient in need of treatment with dextromethorphan, the method comprising co-administering dextromethorphan with threohydroxybupropion, or a prodrug thereof, wherein the dextromethorphan has a plasma concentration 12 hours after co-administration of threohydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma concentration achieved by administration of the same amount of dextromethorphan without threohydroxybupropion or a prodrug thereof.

[0051] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan in a human patient in need of dextromethorphan treatment, the method comprising co-administering bupropion and dextromethorphan to the human patient, wherein the human patient is at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0052] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan in a human patient in need of dextromethorphan treatment, the method comprising co-administering hydroxybupropion, or a prodrug thereof and dextromethorphan to the human patient, wherein the human patient is at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0053] Some embodiments include a method of reducing adverse events associated with treatment with dextromethorphan in a human patient in need of dextromethorphan treatment, the method comprising co-administering erythrohydroxybupropion, or a prodrug thereof and dextromethorphan to the human patient, wherein the human patient is at risk of experiencing adverse events such as those resulting from treatment with dextromethorphan.

[0054] Some embodiments include methods of reducing adverse events associated with treatment with bupropion, including co-administering dextromethorphan and bupropion to a human patient in need of bupropion treatment, where the human patient is at risk of experiencing the same adverse events as the treatment outcome with bupropion.

[0055] Some embodiments include methods of correcting for high metabolites of dextromethorphan, including administering to a human in need of hydroxybupropion, or a prodrug thereof.

[0056] Some embodiments include methods of correcting for high metabolites of dextromethorphan, including administering to a human in need of erythrohydroxybupropion, or a prodrug thereof.

[0057] Some embodiments include methods of correcting for high metabolites of dextromethorphan, including administering to a human in need of threohydroxybupropion, or a prodrug thereof.

[0058] Some embodiments include methods of improving the antitussive properties of dextromethorphan, including administering bupropion in combination with administering dextromethorphan to a human in need of treatment of a cough.

[0059] Some embodiments include methods of improving the antitussive properties of dextromethorphan, including administering hydroxybupropion, or a prodrug thereof, in combination with administering dextromethorphan to a human in need of treatment of a cough.

[0060] Some embodiments include methods of improving the antitussive properties of dextromethorphan, including administering erythrohydroxybupropion, or a prodrug thereof, in combination with administering dextromethorphan to a human in need of treatment of a cough.

[0061] Some embodiments include a method of improving the antitussive properties of dextromethorphan, comprising administering to a human in need thereof levo-hydroxypropionic acid, or a prodrug thereof, in combination with the administration of dextromethorphan.

[0062] Some embodiments include a method of treating a cough, comprising administering to a human in need thereof a combination of hydroxypropionic acid, or a prodrug thereof, and dextromethorphan.

[0063] Some embodiments include a method of treating a cough, comprising administering to a human in need thereof a combination of erythro-hydroxypropionic acid, or a prodrug thereof, and dextromethorphan.

[0064] Some embodiments include a method of treating a cough, comprising administering to a human in need thereof a combination of threo-hydroxypropionic acid, or a prodrug thereof, and dextromethorphan.

[0065] Some embodiments include a method of treating neuropathy, comprising administering to a human in need thereof bupropion and dextromethorphan, wherein bupropion and dextromethorphan are administered once daily for at least 8 days.

[0066] Some embodiments include a method of treating neuropathy, comprising administering to a human in need thereof hydroxypropionic acid, or a prodrug thereof, and dextromethorphan, wherein bupropion and dextromethorphan are administered once daily for at least 8 days.

[0067] Some embodiments include a method of treating neuropathy, comprising administering to a human in need thereof erythro-hydroxypropionic acid, or a prodrug thereof, and dextromethorphan, wherein bupropion and dextromethorphan are administered once daily for at least 8 days.

[0068] Some embodiments include a method of treating neuropathy that involves administering to a human in need thereof threohydroxybupropion, or a prodrug and dextromethorphan thereof, wherein bupropion and dextromethorphan are administered once daily for at least 8 days.

[0069] Some embodiments include a pharmaceutical composition, dosage form, or medicament comprising a therapeutically effective amount of dextrotromethorphan, an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds, and a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0070]

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DETAILED DESCRIPTION OF THE INVENTION

[0071] Some embodiments include a method of treating neuropathy comprising administering to a person in need of treatment for neuropathy a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds.

[0072] Some embodiments include methods of enhancing the therapeutic properties of dextromethorphan in the treatment of neuropathy, including co-administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds.

[0073] Some embodiments include methods of increasing the plasma concentration of dextromethorphan in humans who are in the high-metabolism group of dextromethorphan, including co-administering an antidepressant compound such as bupropion and dextromethorphan to a human.

[0074] Some embodiments include methods of inhibiting the metabolites of dextromethorphan, including administering an antidepressant compound such as bupropion to a human, where the human is in the high-metabolism group of dextromethorphan and dextromethorphan is present in the human body simultaneously with the antidepressant.

[0075] Some embodiments include methods of increasing the elimination half-life (T 1 / 2 ) of dextromethorphan, including methods of increasing the metabolite lifetime of dextromethorphan. These embodiments may include administering an antidepressant compound such as bupropion to a human, where the human is in the high-metabolism group of dextromethorphan and dextromethorphan is present in the human body simultaneously with the antidepressant compound.

[0076] Some embodiments include methods of correcting the high metabolites of dextromethorphan, including administering an antidepressant compound such as bupropion to a human in need of such correction, such as a human in need of treatment for pain.

[0077] Some embodiments include methods of improving the therapeutic properties of dextromethorphan in the treatment of neuropathy, including administering an antidepressant compound such as bupropion in combination with the administration of dextromethorphan to a human in need of treatment for neuropathy.

[0078] Some embodiments include methods of treating neuropathy that involve administering to a human in need of treatment for neuropathy a combination of an antidepressant compound, such as bupropion, and dextromethorphan.

[0079] Co - administration of dextromethorphan and an antidepressant compound, such as bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a prodrug of an antidepressant compound, occurs one or more times continuously for 1 day, or for 2, 3, 4, 5, 6, 7, 8, 14, 30, 60, 90 days, or more. In some embodiments, the co - administration is at least daily for at least 2 consecutive days.

[0080] Dextromethorphan has the following structure.

Chemical formula

[0081] Dextromethorphan is used as a cough suppressant. According to the labeling requirements for FDA dextromethorphan products under the OTC monograph [21 CFR 341.74], dextromethorphan should be administered 6 times a day (every 4 hours), 4 times a day (every 6 hours), or 3 times a day (every 8 hours).

[0082] Dextromethorphan is metabolized at ultra-high speed in the human liver. This ultra-high-speed hepatic metabolism can limit systemic drug exposure in individuals who are in the high-metabolism group. Humans can be 1) those in the high-metabolism group of dextromethorphan - humans who metabolize dextromethorphan at ultra-high speed, 2) those in the low-metabolism group of dextromethorphan - humans who metabolize dextromethorphan only slightly, or 3) those in the intermediate-metabolism group of dextromethorphan - humans whose metabolism of dextromethorphan is somewhere between that of the high-metabolism group and the low-metabolism group. The high-metabolism group of dextromethorphan can also be the ultra-high-metabolism group. The high-metabolism group of dextromethorphan is a significant portion of the population. For example, dextromethorphan can be metabolized to dextrorphan.

[0083] When the same oral dose of dextromethorphan is administered, the plasma concentration of dextromethorphan is significantly higher in the low-metabolism group or the intermediate-metabolism group compared to the high-metabolism group of dextromethorphan. The low plasma concentration of dextromethorphan can limit the clinical usefulness of dextromethorphan as a single agent for the high-metabolism group and, in some cases, for intermediate metabolism. Some antidepressants such as bupropion can inhibit the metabolism of dextromethorphan and thus improve its therapeutic effect. Similarly, antidepressants can allow dextrorphan to be administered at a lower frequency, such as once a day instead of twice a day, once a day instead of three times a day, once a day instead of four times a day, twice a day instead of three times a day, or twice a day instead of four times a day, without losing the therapeutic effect.

[0084] Co-administration of dextromethorphan or dextromorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds may enhance the mechanism of action or pharmacological properties of dextromethorphan and dextromorphan. The mechanisms of action of dextromethorphan and dextromorphan can include sigma-1 agonist and NMDA antagonist properties, calcium channel blockade, muscarinic binding, serotonin transporter (5HTT) inhibition, and mu receptor potentiation.

[0085] Some embodiments include co-administration of dextromethorphan or dextromorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds to activate, antagonize, or modulate a sigma-1 receptor or an NMDA receptor, block a calcium channel, bind to a muscarinic receptor, inhibit a serotonin transporter (5HTT), or potentiate a mu receptor.

[0086] Pharmacological properties of dextromethorphan and dextrorphan can include NMDA high affinity site, NMDR-2A, and functional NMDR-2B receptor antagonism, sigma-1 stimulation, putative mTOR activation (by sigma-1 stimulation, mu enhancement, beta-adrenergic receptor stimulation, and 5HTT inhibition), putative AMPA receptor trafficking (by mTOR activation, PCP antagonism, sigma-1 stimulation, beta stimulation, mu enhancement, and 5HTT inhibition), and dendritic spine formation, spindle formation, synapse formation, NMDA antagonism and neuron survival by sigma-1 and mTOR signaling. Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds to bind to, activate, antagonize, stimulate, activate, inhibit, affect the trafficking of, or modulate an NMDA high affinity site, NMDR-2A, functional NMDR-2B receptor, sigma-1 receptor, putative mTOR receptor (such as by stimulation of sigma-1, enhancement of mu receptor, stimulation of beta-adrenergic receptor, or inhibition of 5HTT), or putative AMPA receptor (such as by activation of mTOR, antagonism of PCP activity, stimulation of sigma-1 receptor, stimulation of beta-adrenergic receptor, enhancement of mu receptor, or inhibition of 5HTT). Some embodiments include co-administration of dextromethorphan or dextrorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds to cause, increase, reduce, or modulate dendritic spine formation, spindle formation, or synapse formation.Some embodiments include co - administration of dextromethorphan or dextropropoxyphene with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to cause, increase, reduce, or modulate neuron survival via NMDA antagonism and / or sigma - 1 and / or mTOR signaling.

[0087] The pharmacological properties of dextromethorphan and dextropropoxyphene can include 5HTT and norepinephrine transporter inhibition, sigma - 1 stimulation, NMDA and PCP antagonism, and, if present, serotonin 5HT1b / d receptor stimulation. Some embodiments include co - administration of dextromethorphan or dextropropoxyphene with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, to bind to, activate, antagonize, stimulate, activate, inhibit, affect the transport of, or modulate 5HTT and / or norepinephrine transporter, sigma - 1 receptor, NMDA and / or PCP receptor, and / or to stimulate serotonin 5HT1b / d receptor.

[0088] Additional properties of dextromethorphan and dextrofan may include antagonism of presynaptic alpha-2 adrenergic receptors if present, or postsynaptic alpha-2 stimulation, beta stimulation, and possible muscarinic and mu antagonism. Some embodiments include co-administration of dextromethorphan or dextrofan, which binds to, activates, antagonizes, stimulates, activates, inhibits, affects the transport of, or regulates a presynaptic alpha-2 adrenergic receptor, a postsynaptic alpha-2 receptor, a beta adrenergic receptor, a muscarinic receptor, or a mu receptor, with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. Dextromethorphan and dextrofan can be glial cell regulators. Some embodiments include co-administration of dextromethorphan or dextrofan, which regulates glial cells, with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0089] Pain or other neuropathy can be treated by a method comprising administering to a person in need of treatment of pain or other neuropathy a therapeutically effective amount of dextrofan and a therapeutically effective amount of an antidepressant compound such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0090] Examples of neurological disorders that can be treated with, or treated with enhanced efficacy by, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, mood disorders, mental disorders, brain function disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headache.

[0091] Mood disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, depression, major depression, treatment-resistant depression and treatment-resistant bipolar depression, bipolar disorder including cyclothymia, seasonal affective disorder, mood disorder, mania, anxiety disorder, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH) including hyperactivity, attention deficit / hyperactivity disorder (AD / HD), bipolar and manic states, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance intoxication or abuse, nicotine intoxication, psychological dysfunction, factitious disorder, and emotional lability.

[0092] Depression can be manifested by mood changes, intense feelings of sadness, despair, mental retardation, decreased concentration, pessimistic worry, agitation, and self-abasement. Physical symptoms of depression include insomnia, loss of appetite, weight loss, reduced energy and libido, and abnormal hormonal circadian rhythms.

[0093] Mental disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, anxiety disorders including phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, and post-traumatic stress disorder (PTSD), mania, bipolar disorder, hypomania, unipolar depression, depression, stress disorders, somatic symptom disorders, personality disorders, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypal tendencies, aggression, aggression in Alzheimer's disease, agitation, and agitation in Alzheimer's disease.

[0094] Substance use disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, drug dependence on cocaine, intoxication, stimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine use disorder includes all known forms of nicotine use disorder such as cigarette smoking, chewing tobacco, and / or pipe smoking, as well as smokeless tobacco use disorder.

[0095] Brain function disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, senile dementia, Alzheimer's dementia, memory loss, amnesia / amnesia syndrome, epilepsy, disturbance of consciousness, coma, decreased attention, language disorder, vocal tremor, Parkinson's disease, Lennox-Gastaut syndrome, autism, attention deficit hyperactivity disorder, and disorders including intellectual disabilities such as schizophrenia. Brain function disorders also include, but are not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, etc., and those caused by cerebrovascular diseases with symptoms including disturbance of consciousness, senile dementia, coma, decreased attention, and language disorder.

[0096] Movement disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, akathisia, akinesia, associated movements, athetoid movements, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless legs syndrome (RLS), tremor, essential tremor, and Tourette syndrome, and Wilson's disease.

[0097] Dementia that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds includes, but is not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, dementia with Lewy bodies, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0098] Motor neuron diseases that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds includes, but is not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal muscular atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0099] Neurodegenerative diseases that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar muscular atrophy, Friedreich'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 dystrophy, Charcot-Marie-Tooth (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0100] Seizure disorders that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, epileptic seizures, nonepileptic seizures, epilepsy, febrile convulsions, simple partial seizures, Jacksonian seizures, complex partial seizures, and partial seizures including, but not limited to, continuous partial epilepsy, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms, and status epilepticus.

[0101] Headache types that can be treated by a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, migraine, tension, and cluster headache.

[0102] Other neurological disorders that can be treated by combination with dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds include Rett syndrome, autism, tinnitus, disturbance of consciousness, sexual dysfunction, intractable cough, narcolepsy, fainting spells, abductor spastic dysphonia, adductor spastic dysphonia, muscle tension dysphonia, and vocal tremor, including but not limited to uncontrolled laryngeal muscle spasm-induced voice disorders, diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity, abdominal pressure urinary incontinence, urge urinary incontinence, and fecal incontinence, including but not limited to incontinence, and erectile dysfunction.

[0103] In some embodiments, the combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used for the treatment of pain, arthralgia, pain associated with sickle cell disease, mood regulation disorders, depression (including treatment-resistant depression), disorders associated with memory and dementia, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0104] In some embodiments, the combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used for the treatment of treatment-resistant depression.

[0105] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used for the treatment of allodynia.

[0106] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used for the treatment of treatment - refractory hyperalgesia.

[0107] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds can be used for the treatment of dermatitis.

[0108] The pain - relieving properties of dextromethorphan can be enhanced by a method comprising co - administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0109] The pain - relieving properties of bupropion can be enhanced by a method comprising co - administering dextromethorphan together with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0110] In some embodiments, ketamine or other NMDA receptor antagonists can be administered with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0111] In some embodiments, dextromethorphan and quinidine can be co-administered with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0112] These methods can be used to treat or provide relief from any type of 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, etc.

[0113] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds with dextromethorphan can be used to treat or reduce an inflammation or inflammatory condition such as Crohn's disease, including pain associated with the inflammation.

[0114] In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of these compounds with dextromethorphan can be used in the treatment of psoriasis, cancer, viral infections, or as adjuvant therapy for multiple myeloma.

[0115] Examples of skeletal pain include low back pain (i.e., lumbosacral pain), primary dysmenorrhea, and pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spondyloarthritis including ankylosing spondylitis, pain associated with vertebral crush fractures, fibrous dysplasia, osteogenesis imperfecta, Paget's disease of bone, transient osteoporosis, transient osteoporosis of the hip, etc.

[0116] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be orally administered to relieve skeletal pain including low back pain, pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, erosive osteoarthritis, seronegative (non-rheumatoid-like) arthropathy, non-articular rheumatism, periarticular disorders, axial spondyloarthritis including ankylosing spondylitis, Paget's disease, fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip, vertebral crush fractures, osteoporosis, etc.

[0117] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be administered to relieve inflammatory pain including skeletal pain, arthritic pain, and complex regional pain syndrome.

[0118] Arthritis refers to inflammatory joint diseases that can be associated with pain. Examples of arthritic pain include osteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, seronegative (non-rheumatoid-like) arthropathy, non-articular rheumatism, periarticular disorders, neuropathic arthropathy including Charcot's foot, axial spondyloarthritis including ankylosing spondylitis, pain associated with SAPHO syndrome.

[0119] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be used for the treatment of chronic skeletal pain.

[0120] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be administered to alleviate complex regional pain syndrome type I (CRPS-I), complex regional pain syndrome type II (CRPS-II), CRPS-NOS, or other types of CRPS, such as complex regional pain syndrome. CRPS is a type of inflammatory pain. CRPS can also have a neuropathic component. Complex regional pain syndrome is a debilitating pain syndrome. It is characterized by severe pain in the limbs that can be accompanied by edema, autonomic, motor, and sensory changes.

[0121] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be administered orally to alleviate neuropathic pain.

[0122] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, central pain, etc. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central pain in multiple sclerosis, HIV-related neuropathy, radiation or chemotherapy-related neuropathy, etc.

[0123] In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion can be administered orally to alleviate fibromyalgia.

[0124] The term "treating" or "treatment" includes any activity of diagnosing, curing, alleviating, treating, or preventing a disease in a human or other animal, or otherwise affecting the structure or any function of the body of a human or other animal.

[0125] Any antidepressant can be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. The dextromethorphan and the antidepressant compound can be administered in separate compositions or dosage forms, or in a single composition or dosage form containing both.

[0126] Antidepressant compositions that can be co-administered with dextromethorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloromipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyindaneamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tesofensine, brasofensine, moclobemide, rasagiline, nialamide, iproniazid, iproclozide, tropoxone, butriptyline, dosulepin, dibenzepin, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, etc., or any metabolite or prodrug of these compounds, or any pharmaceutically acceptable salt of these compounds.

[0127] Bupropion has the following structure (shown in the form of bupropion hydrochloride).

Chemical formula

[0128] The combination of dextromethorphan and bupropion can provide a higher effect such as greater pain relief than can be achieved by administering either component alone. In the high-metabolism group, dextromethorphan can be rapidly and extensively metabolized, resulting in low systemic exposure even at high doses. Bupropion, in addition to having antidepressant and analgesic properties, is an inhibitor of dextromethorphan metabolism. Bupropion is a dopamine and norepinephrine reuptake inhibitor. It can also be a nicotinic acetylcholine receptor antagonist, which can regulate cytokines associated with inflammatory diseases. Bupropion can affect the concentrations of tumor necrosis factor-alpha and interferon-gamma. Metabolites of bupropion, including hydroxybupropion, threohydroxybupropion (also known as threohydrobupropion or threedihydrobupropion), and erythrohydroxybupropion (also known as erythrohydrobupropion or erythrodihydrobupropion), are also inhibitors of dextromethorphan metabolism. Thus, bupropion, including forms of bupropion that are rapidly converted in the body (e.g., salts, hydrates, solvates, polymorphs, etc.), is a prodrug of propion, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. Prodrugs of bupropion can include N-methylbupropion and N-benzylbupropion.

[0129] As described above, this inhibition can increase the plasma concentration of dextromethorphan, resulting in additive or synergistic effects such as relief of neuropathy, including pain, depression, smoking cessation, etc. Thus, inhibition of dextromethorphan metabolism is just one of many potential benefits of the combination, but co-administration of bupropion and dextromethorphan can thereby enhance the effectiveness of bupropion in many individuals. Co-administration of bupropion and dextromethorphan can enhance the analgesic properties of bupropion in many individuals. Co-administration of bupropion and dextromethorphan can also enhance the antidepressant properties of bupropion in many individuals, including an earlier onset of action.

[0130] Another potential benefit of the co - administration of dextromethorphan and bupropion is that it may be useful in reducing the likelihood of adverse events such as such somnolence associated with treatment with dextromethorphan. This can be useful, for example, in human patients at risk of experiencing adverse events as a result of treatment with dextromethorphan.

[0131] Another potential advantage of the co - administration of dextromethorphan and bupropion is that it may be useful in reducing the likelihood of adverse events such as seizures associated with treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds. This can be useful, for example, in human patients at risk of experiencing adverse events as a result of treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds.

[0132] With respect to dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of these compounds, co - administration can reduce central nervous system adverse events, gastrointestinal events, or other types of adverse events associated with any of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, nervousness, dizziness, insomnia, unsteadiness, tremors, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased hypersensitivity or excitability, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, lethargy, impaired coordination, fatigue, well - being, hypersensitivity, insomnia, sleep disturbances, epileptic seizures, excitability, states such as tension, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, and extrapyramidal symptoms such as oculogyric crisis, torticollis, excessive excitability, increased muscle tone, ataxia, and tongue protrusion.

[0133] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, flatulence, peptic ulcer with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, stomach fullness, dyspepsia, fullness, hyperacidity, thirst, gastrointestinal disorders, and stomach pain.

[0134] Co - administration of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds can be administered in a single dosage form, or they can be administered in two separate dosage forms. Further, the two compounds can be administered simultaneously, but this is not essential. The compounds can be administered at different times as long as both are present in the human body simultaneously for at least a portion of the time during which co - administration therapy is being carried out.

[0135] In some embodiments, co - administration consisting of a combination of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan results in both bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan, which contribute to the pain - relieving properties of the combination. For example, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone or dextromethorphan alone, the combination can improve pain - relieving properties, including a potentially earlier onset of action.

[0136] In some embodiments, the combination may provide at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 100%, up to about 500%, or up to 1000%, from about 0.5% to about 1000%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, from about 100% to about 110%, from about 110% to about 120%, from about 120% to about 130%, from about 130% to about 140%, from about 140% to about 150%, from about 150% to about 160%, from about 160% to about 170%, from about 170% to about 180%, from about 180% to about 190%, from about 190% to about 200%, or any amount of pain relief within any range bounded by any of these values, or any amount of pain relief between any of these values, in improving pain relief properties as compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds alone.

[0137] In some embodiments, the combination may provide at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 100%, up to about 500%, or up to 1000%, from about 0.5% to about 1000%, from about 10% to about 20%, from about 20% to about 30%, from about 30% to about 40%, from about 40% to about 50%, from about 50% to about 60%, from about 60% to about 70%, from about 70% to about 80%, from about 80% to about 90%, from about 90% to about 100%, from about 100% to about 110%, from about 110% to about 120%, from about 120% to about 130%, from about 130% to about 140%, from about 140% to about 150%, from about 150% to about 160%, from about 160% to about 170%, from about 170% to about 180%, from about 180% to about 190%, from about 190% to about 200%, or any amount of pain relief within any range bounded by any of these values, or any amount of pain relief between any of these values, in improving pain relief properties as compared to dextromethorphan alone.

[0138] Unless otherwise indicated, references to compounds described herein such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion by structure, name, or any other means include pharmaceutically acceptable salts, alternative solid forms such as polymorphs, solvates, hydrates, tautomers, deuterated derivatives such as deuterated dextromethorphan, and any chemical species that can rapidly convert to the compounds described herein under the conditions under which the compound is used as described herein.

[0139] Examples of deuterated dextromethorphan include, but are not limited to, those shown below.

Chemical formula

[0140] The dosage form or composition can be a formulation or mixture of dextromethorphan with a compound that inhibits the metabolism of dextromethorphan, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds, either alone or within a vehicle. For example, dextromethorphan and bupropion can be dispersed in each other within a vehicle or can be dispersed together within a vehicle. The dispersion contains a mixture of solid materials, and the small individual particles are dispersed among each other in a manner that can occur when two powders of two different drugs, which are substantially one compound, are formulated with a solid vehicle material, and the formulation is carried out in solid form. In some embodiments, dextromethorphan and bupropion can be substantially uniformly dispersed within the composition or dosage form. Alternatively, dextromethorphan and bupropion can be in separate domains or phases within the composition or dosage form. For example, one drug can be in a coating and 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.

[0141] Some embodiments include the administration of a tablet comprising bupropion in a dosage form that provides sustained release and dextromethorphan in a dosage form that provides immediate release. There are various ways to achieve sustained release of bupropion, but in some embodiments, bupropion is combined with hydroxypropylmethylcellulose. For example, particles of bupropion hydrochloride can be formulated with microcrystalline cellulose and hydroxypropylmethylcellulose (such as METHOCEL®) to form a blend powder mixture. This can be combined with immediate release dextromethorphan in a single tablet.

[0142] Dextromethorphan and / or an antidepressant such as bupropion, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, or a non-bupropion antidepressant (collectively referred to herein for convenience as "therapeutic compounds") can be combined with a pharmaceutical carrier selected based on, for example, the selected route of administration and standard pharmaceutical practice as described in Remington’s Pharmaceutical Sciences, 2005. The relative proportions of the active ingredient and the carrier can be determined, for example, by the solubility and chemical nature of the compound, the selected route of administration, and standard pharmaceutical practice.

[0143] The therapeutic compounds can be administered by any means that results in contact of the active agent with the desired site or sites of action (one or more) within the patient's body. The compounds can be administered by any conventional means that can be used in conjunction with a medicament, either as an individual therapeutic agent or as part of a combination of therapeutic agents. For example, they can be administered as the sole active agent in a pharmaceutical composition, or they can be used in combination with other therapeutically active ingredients.

[0144] The therapeutic compound can be administered to a human patient in various forms suitable for the selected route of administration, for example, orally or parenterally. In this regard, parenteral administration includes administration by the following routes. That is, intravenous, intramuscular, subcutaneous, intraocular, intra-synovial, transdermal, ocular, sublingual and buccal including trans-epithelial; local administration including ophthalmic, dermal, ocular, rectal and nasal inhalation via ventilation, aerosol and rectal systemic.

[0145] The ratio of dextromethorphan to bupropion can vary. In some embodiments, the weight ratio of dextromethorphan to bupropion is from 0.1 to about 10, from about 0.1 to about 2, from about 0.2 to about 1, from about 0.1 to about 0.5, from about 0.1 to about 0.3, from about 0.2 to about 0.4, from about 0.3 to about 0.5, from about 0.5 to about 0.7, from about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio within a range bounded by any of these values, or any ratio between any of these values. A ratio of 0.1 indicates that the weight of dextromethorphan is 1 / 10 of that of bupropion. A ratio of 10 indicates that the weight of dextromethorphan is 10 times that of bupropion.

[0146] The amount of dextromethorphan in the therapeutic composition can vary. For example, some liquid compositions can contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% to about 10% (w / v), from about 0.001% (w / v) to about 1% (w / v), from about 0.1% (w / v) to about 0.5% (w / v), from about 1% (w / v) to about 3% (w / v), from about 3% (w / v) to about 5% (w / v), from about 5% (w / v) to about 7% (w / v), from about 7% (w / v) to about 10% (w / v), from about 10% (w / v) to about 15% (w / v), from about 15% (w / v) to about 20% (w / v), from about 20% (w / v) to about 30% (w / v), from about 30% (w / v) to about 40% (w / v), or from about 40% (w / v) to about 50% (w / v) of dextromethorphan.

[0147] Some liquid dosage forms can contain from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, from about 50 mg to about 200 mg, from about 50 mg to about 70 mg, from about 20 mg to about 50 mg, from about 30 mg to about 60 mg, from about 40 mg to about 50 mg, from about 40 mg to about 42 mg, from about 42 mg to about 44 mg, from about 44 mg to about 46 mg, from about 46 mg to about 48 mg, from about 48 mg to about 50 mg, from about 80 mg to about 100 mg, from about 110 mg to about 130 mg, from about 170 mg to about 190 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan in a range bounded by any of these values, or any amount of dextromethorphan between any of these values.

[0148] Some solid compositions can contain 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%, from about 10% (w / w) to about 30% (w / w), from about 10% (w / w) to about 20% (w / w), from about 20% (w / w) to about 30% (w / w), from about 30% (w / w) to about 50% (w / w), from about 30% (w / w) to about 40% (w / w), from about 40% (w / w) to about 50% (w / w), from about 50% (w / w) to about 80% (w / w), from about 50% (w / w) to about 60% (w / w), from about 70% (w / w) to about 80% (w / w), or from about 80% (w / w) to about 90% (w / w) of dextromethorphan.

[0149] Some solid dosage forms can contain from about 10 mg to about 500 mg, from about 30 mg to about 350 mg, from about 20 mg to about 50 mg, from about 30 mg to about 60 mg, from about 40 mg to about 50 mg, from about 40 mg to about 42 mg, from about 42 mg to about 44 mg, from about 44 mg to about 46 mg, from about 46 mg to about 48 mg, from about 48 mg to about 50 mg, from about 50 mg to about 200 mg, from about 50 mg to about 70 mg, from about 80 mg to about 100 mg, from about 110 mg to about 130 mg, from about 170 mg to about 190 mg, about 60 mg, about 90 mg, about 120 mg, or about 180 mg of dextromethorphan, or any amount of dextromethorphan within a range bounded by any of these values, or any amount of dextromethorphan between any of these values.

[0150] The amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds in a therapeutic composition can vary. When an increase in the plasma concentration of dextromethorphan is desired, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds should be administered in an amount that increases the plasma concentration of dextromethorphan. For example, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds can be administered on day 8 in an amount that results in a plasma concentration of dextromethorphan in humans that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or any metabolite or prodrug of any of these compounds.

[0151] In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds is, on day 8, at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, or at least about 80 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. The area under the curve (AUC 0-12 ) or the mean plasma concentration in humans at 12 hours after administration (C 平均 ) can be administered to humans in an amount of dextromethorphan that provides.

[0152] 最大 ) In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds is, on day 8, at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of dextromethorphan administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds. The maximum plasma concentration (C

[0153] can be administered to humans in an amount of dextromethorphan that provides.For co - administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds, an increase in dextromethorphan plasma concentration can occur on the first day of administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on the first day of administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds can be at least about 1.5 - 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 6 - fold, at least about 7 - fold, at least about 8 - fold, at least about 9 - fold, or at least about 10 - fold the level that can be achieved with administration of the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0154] In some embodiments, the dextromethorphan AUC on the first day of administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds can be at least 2 - fold the AUC that can be achieved with administration of the same amount of dextromethorphan without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0155] In some embodiments, the dextromethorphan AUC on the first day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds is administered 0-12 is at least about 15 ng·hour / mL, at least about 17 ng·hour / mL, at least about 19 ng·hour / mL, at least about 20 ng·hour / mL, at least about 22 ng·hour / mL, at least about 23 ng·hour / mL, at least about 24 ng·hour / mL, at least about 25 ng·hour / mL, at least about 26 ng·hour / mL, at least about 27 ng·hour / mL, at least about 28 ng·hour / mL, at least about 29 ng·hour / mL, at least about 30 ng·hour / mL, at least about 31 ng·hour / mL, at least about 32 ng·hour / mL, at least about 33 ng·hour / mL, at least about 34 ng·hour / mL, at least about 35 ng·hour / mL, at least about 36 ng·hour / mL, at least about 37 ng·hour / mL, at least about 38 ng·hour / mL, at least about 39 ng·hour / mL, at least about 40 ng·hour / mL, at least about 41 ng·hour / mL, at least about 42 ng·hour / mL, at least about 43 ng·hour / mL, at least about 44 ng·hour / mL, at least about 45 ng·hour / mL, at least about 46 ng·hour / mL, at least about 47 ng·hour / mL, at least about 48 ng·hour / mL, at least about 49 ng·hour / mL, at least about 50 ng·hour / mL, at least about 51 ng·hour / mL, at least about 52 ng·hour / mL, at least about 53 ng·hour / mL, at least about 54 ng·hour / mL, at least about 55 ng·hour / mL, at least about 56 ng·hour / mL, at least about 56.7 ng·hour / mL, and can be up to 10,000 ng·hour / mL.

[0156] In some embodiments, the dextromethorphan AUC on the eighth day that bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds is administered0-12 is at least about 40 ng·hour / mL, at least about 50 ng·hour / mL, at least about 60 ng·hour / mL, at least about 70 ng·hour / mL, at least about 80 ng·hour / mL, at least about 90 ng·hour / mL, at least about 100 ng·hour / mL, at least about 150 ng·hour / mL, at least about 200 ng·hour / mL, at least about 250 ng·hour / mL, at least about 300 ng·hour / mL, at least about 350 ng·hour / mL, at least about 400 ng·hour / mL, at least about 450 ng·hour / mL, at least about 500 ng·hour / mL, at least about 550 ng·hour / mL, at least about 600 ng·hour / mL, at least about 650 ng·hour / mL, at least about 700 ng·hour / mL, at least about 750 ng·hour / mL, at least about 800 ng·hour / mL, at least about 850 ng·hour / mL, at least about 900 ng·hour / mL, at least about 950 ng·hour / mL, at least about 1000 ng·hour / mL, at least about 1050 ng·hour / mL, at least about 1100 ng·hour / mL, at least about 1150 ng·hour / mL, at least about 1200 ng·hour / mL, at least about 1250 ng·hour / mL, at least about 1300 ng·hour / mL, at least about 1350 ng·hour / mL, at least about 1400 ng·hour / mL, at least about 1450 ng·hour / mL, at least about 1500 ng·hour / mL, at least about 1550 ng·hour / mL, at least about 1600 ng·hour / mL, at least about 1625 ng·hour / mL, at least about 1650 ng·hour / mL, at least about 1675 ng·hour / mL, or at least about 1686.3 ng·hour / mL, and in some embodiments can be up to about 50,000 ng·hour / mL.

[0157] In some embodiments, the dextromethorphan AUC on day 8 of administration of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds 0-24is at least about 50 ng·hour / mL, at least about 75 ng·hour / mL, at least about 100 ng·hour / mL, at least about 200 ng·hour / mL, at least about 300 ng·hour / mL, at least about 400 ng·hour / mL, at least about 500 ng·hour / mL, at least about 600 ng·hour / mL, at least about 700 ng·hour / mL, at least about 800 ng·hour / mL, at least about 900 ng·hour / mL, at least about 1000 ng·hour / mL, at least about 1100 ng·hour / mL, at least about 1200 ng·hour / mL, at least about 1300 ng·hour / mL, at least about 1400 ng·hour / mL, at least about 1500 ng·hour / mL, at least about 1600 ng·hour / mL, at least about 1700 ng·hour / mL, at least about 1800 ng·hour / mL, at least about 1900 ng·hour / mL, at least about 2000 ng·hour / mL, at least about 2100 ng·hour / mL, at least about 2200 ng·hour / mL, at least about 2300 ng·hour / mL, at least about 2400 ng·hour / mL, at least about 2500 ng·hour / mL, at least about 2600 ng·hour / mL, at least about 2700 ng·hour / mL, at least about 2800 ng·hour / mL, at least about 1850 ng·hour / mL, at least about 2900 ng·hour / mL, at least about 2950 ng·hour / mL, or at least about 2975.3 ng·hour / mL, and in some embodiments can be up to about 100,000 ng·hour / mL.

[0158] In some embodiments, the dextromethorphan AUC on day 8 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 0-infis at least about 75 ng·hour / mL, at least about 100 ng·hour / mL, at least about 200 ng·hour / mL, at least about 300 ng·hour / mL, at least about 400 ng·hour / mL, at least about 500 ng·hour / mL, at least about 600 ng·hour / mL, at least about 700 ng·hour / mL, at least about 800 ng·hour / mL, at least about 900 ng·hour / mL, at least about 1000 ng·hour / mL, at least about 1100 ng·hour / mL, at least about 1200 ng·hour / mL, at least about 1300 ng·hour / mL, at least about 1400 ng·hour / mL, at least about 1500 ng·hour / mL, at least about 1600 ng·hour / mL, at least about 1700 ng·hour / mL, at least about 1800 ng·hour / mL, at least about 1900 ng·hour / mL, at least about 2000 ng·hour / mL, at least about 2100 ng·hour / mL, at least about 2200 ng·hour / mL, at least about 2300 ng·hour / mL, at least about 2400 ng·hour / mL, at least about 2500 ng·hour / mL, at least about 2600 ng·hour / mL, at least about 2700 ng·hour / mL, at least about 2800 ng·hour / mL, at least about 2900 ng·hour / mL, at least about 3000 ng·hour / mL, at least about 3100 ng·hour / mL, at least about 3200 ng·hour / mL, at least about 3300 ng·hour / mL, at least about 3400 ng·hour / mL, at least about 3500 ng·hour / mL, at least about 3600 ng·hour / mL, at least about 3700 ng·hour / mL, at least about 3800 ng·hour / mL, at least about 3900 ng·hour / mL, at least about 4000 ng·hour / mL, at least about 4100 ng·hour / mL, at least about 4200 ng·hour / mL, at least about 4300 ng·hour / mL, at least about 4400 ng·hour / mL, at least about 4500 ng·hour / mL, at least about 4600 ng·hour / mL, at least about 4700 ng·hour / mL, at least about 4800 ng·hour / mL, at least about 4900 ng·hour / mL, at least about 5000 ng·hour / mL, at least about 5100 ng·hour / mL, at least about 5200 ng·hour / mL,At least about 5300 ng·hour / mL, at least about 5400 ng·hour / mL, at least about 5500 ng·hour / mL, at least about 5600 ng·hour / mL, at least about 5700 ng·hour / mL, at least about 5800 ng·hour / mL, at least about 5900 ng·hour / mL, at least about 6000 ng·hour / mL, at least about 6100 ng·hour / mL, at least about 6200 ng·hour / mL, at least about 6300 ng·hour / mL, at least about 6400 ng·hour / mL, at least about 6500 ng·hour / mL, at least about 6600 ng·hour / mL, at least about 6700 ng·hour / mL, at least about 6800 ng·hour / mL, at least about 6900 ng·hour / mL, at least about 7000 ng·hour / mL, at least about 7100 ng·hour / mL, at least about 7150 ng·hour / mL, at least about 7200 ng·hour / mL, or at least about 7237.3 ng·hour / mL, and in some embodiments, can be up to about 100,000 ng·hour / mL.

[0159] In some embodiments, the dextromethorphan C on the first day on which bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最大 can be achieved with the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. 最大 can be at least twice that of.

[0160] In some embodiments, the dextromethorphan C on the first day on which bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最大is at least about 1.0 ng / mL, at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 2.5 ng / mL, at least about 3.0 ng / mL, at least about 3.1 ng / mL, at least about 3.2 ng / mL, at least about 3.3 ng / mL, at least about 3.4 ng / mL, at least about 3.5 ng / mL, at least about 3.6 ng / mL, at least about 3.7 ng / mL, at least about 3.8 ng / mL, at least about 3.9 ng / mL, at least about 4.0 ng / mL, at least about 4.1 ng / mL, at least about 4.2 ng / mL, at least about 4.3 ng / mL, at least about 4.4 ng / mL, at least about 4.5 ng / mL, at least about 4.6 ng / mL, at least about 4.7 ng / mL, at least about 4.8 ng / mL, at least about 4.9 ng / mL, at least about 5.0 ng / mL, at least about 5.1 ng / mL, at least about 5.2 ng / mL, at least about 5.3 ng / mL, at least about 5.4 ng / mL, at least about 5.5 ng / mL, at least about 5.6 ng / mL, at least about 5.7 ng / mL, at least about 5.7 ng / mL, at least about 5.8 ng / mL, at least about 5.9 ng / mL, at least about 6.0 ng / mL, at least about 6.1 ng / mL, at least about 6.2 ng / mL, at least about 6.3 ng / mL, at least about 6.4 ng / mL, at least about 6.5 ng / mL, at least about 6.6 ng / mL, at least about 6.7 ng / mL, at least about 6.8 ng / mL, at least about 6.9 ng / mL, at least about 7.0 ng / mL, at least about 7.1 ng / mL, at least about 7.2 ng / mL, at least about 7.3 ng / mL, at least about 7.4 ng / mL, at least about 7.5 ng / mL, at least about 7.6 ng / mL, at least about 7.7 ng / mL, at least about 7.8 ng / mL, at least about 7.9 ng / mL, at least about 8.0 ng / mL, at least about 8.1 ng / mL, at least about 8.2 ng / mL, at least about 8.3 ng / mL, at least about 8.4 ng / mL, at least about 8.5 ng / mL, at least about 8.6 ng / mL, or at least about 8.7 ng / mL, and in some embodiments can be up to about 1000 ng·hour / mL.

[0161] In some embodiments, on day 8, dextromethorphan C is administered with bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds 最大 is at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 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 135 ng / mL, at least about 140 ng / mL, at least about 145 ng / mL, at least about 150 ng / mL, at least about 155 ng / mL, or at least about 158.1 ng / mL and, in some embodiments, can be up to about 10,000 ng / mL.

[0162] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds is at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 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 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL over the period between two separate and consecutive administrations of dextromethorphan, and in some embodiments up to about 10,000 ng / mL of dextromethorphan C 平均 is administered in an amount that provides. For example, if dextromethorphan is administered at 8:00 am and 8:00 pm on day 1 and not administered between 8:00 am and 8:00 pm on day 1, the period between two separate and consecutive administrations of dextromethorphan is from immediately after 8:00 am on day 1 to immediately before 8:00 pm on day 1.

[0163] In some embodiments, the dextromethorphan C on day 8 on which bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any metabolite or prodrug of these compounds is administered 平均is at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 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 135 ng / mL, at least about 140 ng / mL, or at least about 140.5 ng / mL, and in some embodiments can be up to about 10,000 ng / mL. The above C 平均 value can be for the period between two separate and consecutive administrations of dextromethorphan, or if dextromethorphan is administered only once on day 8, C 平均 can be for 12 hours after the first administration of dextromethorphan.

[0164] In some embodiments, the dextromethorphan trough concentration on day 1 (e.g., plasma concentration 12 hours after administration; "C 最小Also referred to as ") can be at least twice the trough level that can be achieved with the same dose of dextromethorphan without metabolites or prodrugs of bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or any of these compounds.

[0165] In some embodiments, the dextromethorphan C on the first day when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最小 can be at least about 0.8 ng / mL, at least about 0.9 ng / mL, at least about 1.0 ng / mL, at least about 1.1 ng / mL, at least about 1.2 ng / mL, at least about 1.3 ng / mL, at least about 1.4 ng / mL, at least about 1.5 ng / mL, at least about 1.6 ng / mL, at least about 1.7 ng / mL, at least about 1.8 ng / mL, at least about 1.9 ng / mL, at least about 2.0 ng / mL, at least about 2.1 ng / mL, at least about 2.2 ng / mL, at least about 2.3 ng / mL, at least about 2.4 ng / mL, at least about 2.5 ng / mL, or at least about 2.5 ng / mL and can be up to about 100 ng / mL.

[0166] In some embodiments, the dextromethorphan C on the fifth day when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最小is at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, at least about 20 ng / mL, at least about 25 mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, or at least about 80.9 ng / mL and can be up to about 10,000 ng / mL.

[0167] In some embodiments, dextromethorphan C on day 6 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最小can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 ng / mL, at least about 90 ng / mL, at least about 95 ng / mL, at least about 100 ng / mL, or at least about 102.2 ng / mL, and can be up to about 10,000 ng / mL.

[0168] In some embodiments, dextromethorphan C on day 7 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最小is at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 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, or at least about 110.6 ng / mL and can be up to about 10,000 ng / mL.

[0169] In some embodiments, dextromethorphan C on day 8 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered 最小can be at least about 1.5 ng / mL, at least about 2.0 ng / mL, at least about 3.0 ng / mL, at least about 4.0 ng / mL, at least about 5.0 ng / mL, at least about 6.0 ng / mL, at least about 7.0 ng / mL, at least about 8.0 ng / mL, at least about 9.0 ng / mL, at least about 10 ng / mL, at least about 15 ng / mL, 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, at least about 45 ng / mL, at least about 50 ng / mL, at least about 55 ng / mL, at least about 60 ng / mL, at least about 65 ng / mL, at least about 70 ng / mL, at least about 75 ng / mL, at least about 80 ng / mL, at least about 85 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, or at least about 119.3 ng / mL, and can be up to about 10,000 ng / mL.

[0170] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is administered on Day 1 of at least 2 days of treatment with dextromethorphan, and the reduction in dextromethorphan plasma concentration occurs on Day 1 when bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered, compared to the same amount of dextromethorphan administered without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the plasma concentration of dextromethorphan on Day 1 can be reduced by at least 5% compared to the dextromethorphan plasma concentration that can be achieved by administration of the same amount of dextromethorphan without bupropion.

[0171] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds is co-administered to a human in need of treatment with dextromethorphan for at least 5 consecutive days, and the dextromethorphan plasma concentration on day 5 is higher than the dextromethorphan plasma concentration that can be achieved with the same amount of administration for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on day 5 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) is at least 5 times, at least 10 times, at least 20 times, at least 40 times, at least 50 times, at least 60 times, at least 65 times, or up to about 500 times the level that can be achieved with the same amount of administration of dextromethorphan for 5 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0172] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 6 consecutive days, and the dextromethorphan plasma concentration on day 6 is higher than the dextromethorphan plasma concentration achievable with the same amount of dextromethorphan administered for 6 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on day 6 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 75-fold, or up to about 500-fold the level achievable with the same amount of dextromethorphan administered for 6 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0173] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 7 consecutive days, and the dextromethorphan plasma concentration on day 7 is higher than the dextromethorphan plasma concentration achievable with the same amount of dextromethorphan administered for 7 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on day 7 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) is at least 5-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 50-fold, at least 70-fold, at least 80-fold, at least 90-fold, or up to about 500-fold the level achievable with the same amount of dextromethorphan administered for 7 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0174] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 8 consecutive days, and on day 8, dextromethorphan has, for example, at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration, at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma concentration achievable with the same amount of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0175] In some embodiments, bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered to a human in need of treatment with dextromethorphan for at least 8 consecutive days, and the dextromethorphan plasma concentration on day 8 is lower than the dextromethorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the dextromethorphan plasma concentration on day 8 (e.g., at 0 hours, 1 hour, 3 hours, 6 hours, or 12 hours after administration) can be reduced by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to the dextromethorphan plasma concentration that can be achieved with the same amount of dextromethorphan administered for 8 consecutive days without bupropion, hydroxybupropion, threohydroxybupropion, erythrohydroxybupropion, or a metabolite or prodrug of any of these compounds.

[0176] In some embodiments, bupropion is administered to a human in an amount that results in an AUC of bupropion in the human of at least about 100 ng·hour / mL, at least about 200 ng·hour / mL, at least about 500 ng·hour / mL, at least about 600 ng·hour / mL, at least about 700 ng·hour / mL, at least about 800 ng·hour / mL, at least about 900 ng·hour / mL, at least about 1,000 ng·hour / mL, at least about 1,200 ng·hour / mL, at least 1,600 ng·hour / mL, or up to about 15,000 ng·hour / mL on day 8. 0-12 It can be administered to a human in an amount that provides.

[0177] In some embodiments, bupropion is administered to a human in an amount that results in a C of bupropion in the human of at least about 10 ng / mL, at least about 20 ng / mL, at least about 40 ng / mL, at least about 50 ng / mL, at least about 60 ng / mL, at least about 70 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least 120 ng / mL, or up to about 1,500 ng / mL on day 8. 平均 It can be administered to a human in an amount that provides.

[0178] In some embodiments, bupropion is administered to a human in an amount that results in a C of bupropion in the human of at least about 10 ng / mL, at least about 20 ng / mL, at least about 50 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 110 ng / mL, at least about 120 ng / mL, at least about 130 ng / mL, at least about 140 ng / mL, at least 200 ng / mL, or up to about 1,500 ng / mL on day 8. 最大 It can be administered to a human in an amount that provides.

[0179] Some liquid compositions can contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% to about 10% (w / v), from about 1% (w / v) to about 3% (w / v), from about 3% (w / v) to about 5% (w / v), from about 5% (w / v) to about 7% (w / v), from about 5% (w / v) to about 15% (w / v), from about 7% (w / v) to about 10% (w / v), from about 10% (w / v) to about 15% (w / v), from about 15% (w / v) to about 20% (w / v), from about 20% (w / v) to about 30% (w / v), from about 30% (w / v) to about 40% (w / v), or from about 40% (w / v) to about 50% (w / v) of bupropion, or any amount of bupropion within the range bounded by any of these values, or any amount of bupropion between any of these values.

[0180] Some liquid dosage forms can contain from about 10 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 10 mg to about 50 mg, from about 50 mg to about 100 mg, from about 40 mg to about 90 mg, from about 200 mg to about 300 mg, from about 70 mg to about 95 mg, from about 100 mg to about 200 mg, from about 105 mg to about 200 mg, from about 110 mg to about 140 mg, from about 180 mg to about 220 mg, from about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion in a range bounded by any of these values, or any amount of bupropion between any of these values.

[0181] Some solid compositions can contain 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%, from about 10% (w / w) to about 30% (w / w), from about 10% (w / w) to about 20% (w / w), from about 20% (w / w) to about 30% (w / w), from about 30% (w / w) to about 50% (w / w), from about 30% (w / w) to about 40% (w / w), from about 40% (w / w) to about 50% (w / w), from about 50% (w / w) to about 80% (w / w), from about 50% (w / w) to about 60% (w / w), from about 70% (w / w) to about 80% (w / w), or from about 80% (w / w) to about 90% (w / w) of bupropion, or any amount of bupropion in a range bounded by any of these values, or any amount of bupropion between any of these values.

[0182] Some solid dosage forms may contain from about 10 mg to about 1000 mg, from about 50 mg to about 1000 mg, from about 10 mg to about 50 mg, from about 50 mg to about 100 mg, from about 40 mg to about 90 mg, from about 200 mg to about 300 mg, from about 70 mg to about 95 mg, from about 100 mg to about 200 mg, from about 105 mg to about 200 mg, from about 110 mg to about 140 mg, from about 50 mg to about 150 mg, from about 180 mg to about 220 mg, from about 280 mg to about 320 mg, about 200 mg, about 150 mg, or about 300 mg of bupropion, or any amount of bupropion within a range bounded by any of these values, or any amount of bupropion between any of these values.

[0183] In some embodiments, bupropion is administered in a dose that provides a bupropion plasma concentration of from about 0.1 μM to about 10 μM, from about 0.1 μM to about 5 μM, from about 0.2 μM to about 3 μM, from 0.1 μM to about 1 μM, from about 0.2 μM to about 2 μM, from 1 μM to about 10 μM, from about 1 μM to about 5 μM, from about 2 μM to about 3 μM, or from about 2.8 μM to about 3 μM, from about 1.5 μM to about 2 μM, from about 4.5 μM to about 5 μM, from about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration within a range bounded by any of these values, or any plasma concentration between any of these values.

[0184] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered in a dose that provides a hydroxybupropion plasma concentration of from 0.1 μM to about 10 μM, from about 0.1 μM to about 5 μM, from about 0.2 μM to about 3 μM, from 0.1 μM to about 1 μM, from about 0.2 μM to about 2 μM, from 1 μM to about 10 μM, from about 1 μM to about 5 μM, from about 2 μM to about 3 μM, or from about 2.8 μM to about 3 μM, from about 1.5 μM to about 2 μM, from about 4.5 μM to about 5 μM, from about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration within a range bounded by any of these values, or any plasma concentration between any of these values.

[0185] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has an AUC of hydroxybupropion in humans that, on day 8, is at least about 3,000 ng·hour / mL, at least about 7,000 ng·hour / mL, at least about 10,000 ng·hour / mL, at least about 15,000 ng·hour / mL, at least about 20,000 ng·hour / mL, at least about 30,000 ng·hour / mL, with an upper limit of about 50,000 ng·hour / mL, an upper limit of about 150,000 ng·hour / mL, or any AUC within a range bounded by any of these values, or any AUC between any of these values. 0-12 It can be administered to humans in an amount that provides this.

[0186] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion has a C of hydroxybupropion in humans that, on day 8, is at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, with an upper limit of about 10,000 ng / mL, an upper limit of about 50,000 ng / mL, or any C within a range bounded by any of these values, 最大 or any C between any of these values. 最大 It can be administered to humans in an amount that provides this C of hydroxybupropion in humans. 最大 It can be administered to humans in an amount that provides this.

[0187] In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion is administered to a human in an amount that results in a C of hydroxybupropion in the human of at least about 200 ng / mL, at least about 300 ng / mL, at least about 700 ng / mL, at least about 1,000 ng / mL, at least about 1,500 ng / mL, at least about 2,000 ng / mL, at least about 4,000 ng / mL, with an upper limit of about 10,000 ng / mL, an upper limit of about 50,000 ng / mL, or any C within a range bounded by any of these values. 平均 or any C between any of these values 平均 resulting in a C of hydroxybupropion in a human 平均 can be administered to a human.

[0188] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is administered at a dose that results in a plasma concentration of threohydroxybupropion of from about 0.1 μM to about 10 μM, from about 0.1 μM to about 5 μM, from about 0.2 μM to about 3 μM, from 0.1 μM to about 1 μM, from about 0.2 μM to about 2 μM, from 1 μM to about 10 μM, from about 1 μM to about 5 μM, from about 2 μM to about 3 μM, or from about 2.8 μM to about 3 μM, from about 1.5 μM to about 2 μM, from about 4.5 μM to about 5 μM, from about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration within a range bounded by any of these values, or any plasma concentration between any of these values.

[0189] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is administered to a human in an amount that results in an AUC of threohydroxybupropion in humans that is at least about 1,000 ng·hour / mL, at least about 2,000 ng·hour / mL, at least about 4,000 ng·hour / mL, at least about 5,000 ng·hour / mL, at least about 8,000 ng·hour / mL, up to about 10,000 ng·hour / mL, up to about 40,000 ng·hour / mL, or any AUC within a range bounded by any of these values, or any AUC between any of these values, on day 8. 0-12 and can be administered to a human in an amount that provides such.

[0190] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is a C of threohydroxybupropion in humans that is at least about 100 ng / mL, at least about 200 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C within a range bounded by any of these values 最大 or any C between any of these values 最大 on day 8. 最大 and can be administered to a human in an amount that provides such.

[0191] In some embodiments, bupropion, threohydroxybupropion, or a prodrug of threohydroxybupropion is a C of threohydroxybupropion in humans that is at least about 100 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 600 ng / mL, at least about 800 ng / mL, up to about 2,000 ng / mL, up to about 10,000 ng / mL, or any C within a range bounded by any of these values 平均 or any C between any of these values 平均 on day 8. 平均It can be administered to humans in an amount that provides

[0192] In some embodiments, bupropion, erythro-hydroxybupropion, or a prodrug of erythro-hydroxybupropion is administered in a dose that provides an erythro-hydroxybupropion plasma concentration of from about 0.1 μM to about 10 μM, from about 0.1 μM to about 5 μM, from about 0.2 μM to about 3 μM, from 0.1 μM to about 1 μM, from about 0.2 μM to about 2 μM, from 1 μM to about 10 μM, from about 1 μM to about 5 μM, from about 2 μM to about 3 μM, or from about 2.8 μM to about 3 μM, from about 1.5 μM to about 2 μM, from about 4.5 μM to about 5 μM, from about 2.5 μM to about 3 μM, about 1.8 μM, about 4.8 μM, about 2.9 μM, about 2.8 μM, or any plasma concentration within a range bounded by any of these values, or a dose that provides any plasma concentration between any of these values.

[0193] In some embodiments, bupropion, erythro-hydroxybupropion, or a prodrug of erythro-hydroxybupropion is the AUC of erythro-hydroxybupropion in humans that is at least about 200 ng·h / mL, at least about 400 ng·h / mL, at least about 700 ng·h / mL, at least about 1,000 ng·h / mL, at least about 1,500 ng·h / mL, at least about 3,000 ng·h / mL, with an upper limit of about 5,000 ng·h / mL, an upper limit of about 30,000 ng·h / mL, or any AUC within a range bounded by any of these values, or any AUC between any of these values, on day 8. 0-12 It can be administered to humans in an amount that provides

[0194] In some embodiments, bupropion, erythro-hydroxybupropion, or a prodrug of erythro-hydroxybupropion is at least about 30 ng / mL, at least about 60 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, up to about 1,000 ng / mL, or any C within a range bounded by any of these values on day 8 最大 or any C between any of these values 最大 of erythro-hydroxybupropion in a human, which results in a C 最大 of erythro-hydroxybupropion in a human, can be administered to a human in an amount that provides.

[0195] In some embodiments, bupropion, erythro-hydroxybupropion, or a prodrug of erythro-hydroxybupropion is at least about 20 ng / mL, at least about 30 ng / mL, at least about 50 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, up to about 1,000 ng / mL, up to about 5,000 ng / mL, any C within a range bounded by any of these values 平均 or any C between any of these values 平均 of erythro-hydroxybupropion in a human, which results in a C 平均 of erythro-hydroxybupropion in a human, can be administered to a human in an amount that provides.

[0196] For compositions containing dextromethorphan and bupropion, some liquids can contain from about 0.0001% (w / v) to about 50% (w / v), from about 0.01% (w / v) to about 20% (w / v), from about 0.01% to about 10% (w / v), from about 1% (w / v) to about 3% (w / v), from about 3% (w / v) to about 5% (w / v), from about 5% (w / v) to about 7% (w / v), from about 5% (w / v) to about 15% (w / v), from about 7% (w / v) to about 10% (w / v), from about 10% (w / v) to about 15% (w / v), from about 15% (w / v) to about 20% (w / v), from about 20% (w / v) to about 30% (w / v), from about 30% (w / v) to about 40% (w / v), from about 40% (w / v) to about 50% (w / v) of combined dextromethorphan and bupropion, or any amount within the ranges bounded by any of these values, or any amount between any of these values. Some solid compositions can contain 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%, from about 10% (w / w) to about 30% (w / w), from about 10% (w / w) to about 20% (w / w), from about 20% (w / w) to about 30% (w / w), from about 30% (w / w) to about 50% (w / w), from about 30% (w / w) to about 40% (w / w), from about 40% (w / w) to about 50% (w / w), from about 50% (w / w) to about 80% (w / w), from about 50% (w / w) to about 60% (w / w), from about 70% (w / w) to about 80% (w / w), from about 80% (w / w) to about 90% (w / w) of combined dextromethorphan and bupropion, or any amount within the ranges bounded by any of these values, or any amount between any of these values. In some embodiments, the weight ratio of dextromethorphan to bupropion in a single composition or dosage form can be from about 0.1 to about 2, from about 0.2 to about 1, from about 0.1 to about 0.3, from about 0.2 to about 0.4, from about 0.3 to about 0.5, from about 0.5 to about 0.7, from about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any value within the ranges bounded by any of these values, or any value between any of these values.

[0197] The therapeutically effective amount of a therapeutic compound can vary depending on the circumstances. For example, the daily dose of dextromethorphan can, in some instances, range from about 0.1 mg to about 1000 mg, from about 40 mg to about 1000 mg, from about 20 mg to about 600 mg, from about 60 mg to about 700 mg, from about 100 mg to about 400 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, from about 45 mg to about 50 mg, from about 50 mg to about 55 mg, from about 55 mg to about 60 mg, from about 20 mg to about 60 mg, from about 60 mg to about 100 mg, from about 100 mg to about 200 mg, from about 100 mg to about 140 mg, from about 160 mg to about 200 mg, from about 200 mg to about 300 mg, from about 220 mg to about 260 mg, from about 300 mg to about 400 mg, from about 340 mg to about 380 mg, from about 400 mg to about 500 mg, from about 500 mg to about 600 mg, from about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 180 mg, about 240 mg, about 360 mg, or a daily dose within a range bounded by any of these values, or any daily dose between any of these values. Dextromethorphan can be administered once daily, or twice daily or every 12 hours, three times daily, four times daily, or six times daily in an amount that is about half, one-third, one-fourth, or one-sixth of the respective daily dose.

[0198] The daily dose of bupropion, in some examples, can be in the range of about 10 mg to about 1000 mg, about 50 mg to about 600 mg, about 100 mg to about 2000 mg, about 50 mg to about 100 mg, about 70 mg to about 95 mg, about 100 mg to about 200 mg, about 105 mg to about 200 mg, about 100 mg to about 150 mg, about 150 mg to about 300 mg, about 150 mg to about 200 mg, about 200 mg to about 250 mg, about 250 mg to about 300 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 600 mg, about 360 mg to about 440 mg, about 560 mg to about 640 mg, or about 500 mg to about 600 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 600 mg, or a daily dose within the range bounded by any of these values, or any daily dose between any of these values. Bupropion can be administered once daily; or in approximately half or one-third of each daily dose, twice daily or every 12 hours, or three times daily.

[0199] In some embodiments, 1) bupropion of about 50 mg / day to about 100 mg / day, about 100 mg / day to about 150 mg / day, about 150 mg / day to about 300 mg / day, about 150 mg / day to about 200 mg / day, about 200 mg / day to about 250 mg / day, about 250 mg / day to about 300 mg / day, or about 300 mg / day to about 500 mg / day, and / or 2) dextromethorphan of about 15 mg / day to about 60 mg / day, about 15 mg / day to about 30 mg / day, about 30 mg / day to about 45 mg / day, about 45 mg / day to about 60 mg / day, about 60 mg / day to about 100 mg / day, about 80 mg / day to about 110 mg / day, about 100 mg / day to about 150 mg / day, or about 100 mg / day to about 300 mg / day is administered to a human in need thereof.

[0200] In some embodiments, humans are administered bupropion at about 150 mg / day and dextromethorphan at about 30 mg / day, bupropion at about 150 mg / day and dextromethorphan at about 60 mg / day, bupropion at about 150 mg / day and dextromethorphan at about 90 mg / day, bupropion at about 150 mg / day and dextromethorphan at about 120 mg / day, bupropion at about 200 mg / day and dextromethorphan at about 30 mg / day, bupropion at about 200 mg / day and dextromethorphan at about 60 mg / day, bupropion at about 200 mg / day and dextromethorphan at about 90 mg / day, bupropion at about 200 mg / day and dextromethorphan at about 120 mg / day, bupropion at about 300 mg / day and dextromethorphan at about 30 mg / day, bupropion at about 300 mg / day and dextromethorphan at about 60 mg / day, bupropion at about 300 mg / day and dextromethorphan at about 90 mg / day, or bupropion at about 300 mg / day and dextromethorphan at about 120 mg / day.

[0201] In some embodiments, humans are administered bupropion at about 100 mg / day and dextromethorphan at about 15 mg / day for 1, 2, or 3 days, followed by bupropion at about 200 mg / day and dextromethorphan at about 30 mg / day. In some embodiments, humans are administered bupropion at about 100 mg / day and dextromethorphan at about 30 mg / day for 1, 2, or 3 days, followed by bupropion at about 200 mg / day and dextromethorphan at about 60 mg / day.

[0202] In some embodiments, bupropion at about 75 mg / day and dextromethorphan at about 15 mg / day are administered to a human for 1, 2, or 3 days, followed by bupropion at about 150 mg / day and dextromethorphan at about 30 mg / day. In some embodiments, bupropion at about 75 mg / day and dextromethorphan at about 30 mg / day are administered to a human for 1, 2, or 3 days, followed by bupropion at about 150 mg / day and dextromethorphan at about 60 mg / day.

[0203] Antidepressant compounds such as bupropion can be administered only as needed to treat neurological conditions such as pain, depression or cough. In some embodiments, antidepressant compositions such as bupropion and dextromethorphan are administered at least once a day, such as once or twice a day, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0204] The therapeutic compounds can be formulated for oral administration, for example, together with an inert diluent or an edible carrier. Alternatively, they may be enclosed in hard or soft shell gelatin capsules, compressed in tablets, or directly incorporated into the food of a diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of oral ingestion tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc.

[0205] Tablets, troches, pills, capsules, etc. may also contain one or more of the following: namely, binders such as tragacanth gum, acacia, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch, potato starch, alginic acid, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, or flavoring agents such as peppermint, wintergreen oil or cherry flavor. When the unit dosage form is a capsule, it may contain a liquid carrier in addition to the materials of the above types. Various other materials may be present as coating agents, 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, methyl and propyl parabens as preservatives, dyes, and flavors such as cherry or orange flavor. It may be desired that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts used.

[0206] A composition or dosage form may be liquid or may contain a solid phase dispersed in a liquid.

[0207] Therapeutic compounds can be formulated for parenteral or intraperitoneal administration. Solutions of the active compound, such as the free base or a pharmaceutically acceptable salt, can be prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also have oils dispersed in or among glycerol, liquid polyethylene glycols and mixtures thereof. Under normal storage and use conditions, these formulations may contain preservatives to prevent the growth of microorganisms.

[0208] Particularly intended embodiments (Embodiment 1) A method of treating pain or neuropathy comprising administering to a person in need a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound. (Embodiment 2) A method for treating pain, comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan. (Embodiment 3) A method for enhancing the pain-relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound. (Embodiment 4) A method for increasing the plasma concentration of dextromethorphan in a human who is a high metabolizer of dextromethorphan, comprising co-administering an antidepressant compound to a human receiving treatment with dextromethorphan. (Embodiment 5) A method for inhibiting the metabolism of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a high metabolizer of dextromethorphan and dextromethorphan is present in the human body simultaneously with the antidepressant compound. (Embodiment 6) A method for increasing the metabolic life of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a high metabolizer of dextromethorphan and dextromethorphan is present in the human body simultaneously with the antidepressant compound. (Embodiment 7) A method for correcting high metabolic products of dextromethorphan, comprising administering an antidepressant compound to a human in need thereof. (Embodiment 8) A method for improving the pain-relieving properties of dextromethorphan, comprising administering an antidepressant compound together with dextromethorphan to a human in need of treatment for pain. (Embodiment 9) A method for improving the antitussive properties of dextromethorphan, comprising administering an antidepressant compound together with dextromethorphan to a human in need of treatment for cough. (Embodiment 10) A method for treating cough, comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan. (Embodiment 11) A method for improving the therapeutic properties of dextromethorphan, which comprises administering an antidepressant compound together with dextromethorphan to a human in need of treatment for neuropathy. (Embodiment 12) A method for treating neuropathy, which comprises administering a combination of an antidepressant compound and dextromethorphan to a human in need thereof. (Embodiment 13) A method for treating neuropathy, which comprises administering an antidepressant compound and dextromethorphan to a human in need thereof, wherein the human is a high metabolizer group of dextromethorphan. (Embodiment 14) The method according to any one of the preceding embodiments, for example, Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms. (Embodiment 15) A pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient. (Embodiment 16) An oral dosage form comprising at least 20 mg of dextromethorphan and an effective amount of an antidepressant compound for inhibiting the metabolism of dextromethorphan in a human who is a high metabolizer group of dextromethorphan. (Embodiment 17) The oral dosage form according to Embodiment 16, wherein about 30 mg to about 350 mg of dextromethorphan is present in the dosage form. (Embodiment 18) The oral dosage form according to Embodiment 16 or 17, wherein about 100 mg to about 400 mg of bupropion is present in the dosage form. (Embodiment 19) The oral dosage form according to Embodiment 16, 17, or 18, which comprises an amount of bupropion that provides a bupropion plasma concentration of about 0.1 μM to about 10 μM when the oral dosage form is administered to a human. (Embodiment 20) The oral dosage form according to embodiment 19, when administered to a human, comprising an amount of bupropion that provides a bupropion plasma concentration of from about 0.1 μM to about 2 μM. (Embodiment 21) Bupropion is administered in an amount that provides a bupropion plasma concentration of from about 0.1 μM to about 10 μM, according to any of the preceding embodiments, such as the method according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. (Embodiment 22) Bupropion is administered in an amount that provides a bupropion plasma concentration of from about 0.3 μM to about 1 μM, according to any of the preceding embodiments, such as the method according to embodiment 21. (Embodiment 23) The antidepressant compound is bupropion or a metabolite thereof, according to any of the preceding embodiments, such as the method, composition, or dosage form according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17. (Embodiment 24) The antidepressant compound is bupropion, according to any of the preceding embodiments, such as the method, composition, or dosage form according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17. (Embodiment 25) The antidepressant compound is clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloromipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, oxyindanamine, benactyzine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, or a pharmaceutically acceptable salt thereof, according to any of the preceding embodiments, such as the method, composition, or dosage form according to embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17. (Embodiment 26) The dextromethorphan is administered to the human for the treatment of cough by the method according to any of the preceding embodiments, for example, embodiments 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 21, 22, 23, 24, or 25. (Embodiment 27) A method for treating neuropathy, comprising administering to a human in need thereof from about 150 mg / day to about 300 mg / day of bupropion and from about 30 mg / day to about 120 mg / day of dextromethorphan. (Embodiment 28) A method for treating neuropathy, comprising administering to a human in need thereof bupropion and dextromethorphan, wherein the bupropion and dextromethorphan are administered at least once a day for at least 8 days. (Embodiment 29) Bupropion is administered to the human in need thereof at least once a day for at least 8 days by the method according to any of the preceding embodiments, for example, embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, or 27. (Embodiment 30) Dextromethorphan is administered to the human in need thereof at least once a day for at least 8 days by the method according to any of the preceding embodiments, for example, embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, or 28. (Embodiment 31) Bupropion is administered on the 8th day in an amount that provides a plasma concentration of dextromethorphan in the human that is at least 10 times the plasma concentration of dextromethorphan administered without bupropion on the same amount by the method according to any of the preceding embodiments, for example, embodiments 28, 29, or 30. (Embodiment 32) Bupropion, on the 8th day, provides an AUC of hydroxybupropion that is at least about 3000 ng·hour / mL 0-12The method according to any of the preceding embodiments, such as embodiment 28, 29, 30, or 31, administered in an amount that provides (Embodiment 33) Bupropion has an AUC of erythro-hydroxybupropion of at least about 400 ng·hour / mL on day 8 0-12 The method according to any of the preceding embodiments, such as embodiment 28, 29, 30, 31, or 32, administered in an amount that provides (Embodiment 34) Bupropion has an AUC of threo-hydroxybupropion of at least about 2000 ng·hour / mL on day 8 0-12 The method according to any of the preceding embodiments, such as embodiment 28, 29, 30, 31, 32, or 33, administered in an amount that provides (Embodiment 35) The mass ratio of dextromethorphan to bupropion is from about 0.1 to about 0.5, according to any of the preceding embodiments, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, or 34, method, composition, or dosage form. (Embodiment 36) The human is a high metabolizer group of dextromethorphan, according to any of the preceding embodiments, such as embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, method. (Embodiment 37) About 150 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human, according to any of the preceding embodiments, such as embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, method. (Embodiment 38) The method according to any of the preceding embodiments, such as Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 150 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human. (Embodiment 39) The method according to any of the preceding embodiments, such as Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan are administered to the human. (Embodiment 40) The method according to any of the preceding embodiments, such as Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 100 mg / day of bupropion and about 15 mg / day of dextromethorphan are administered to the human for about 1 to about 3 days, followed by about 200 mg / day of bupropion and about 30 mg / day of dextromethorphan. (Embodiment 41) The method according to any of the preceding embodiments, such as Embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein about 200 mg / day of bupropion and about 60 mg / day of dextromethorphan are administered to the human. (Embodiment 42) The human is administered bupropion at about 100 mg / day and dextromethorphan at about 30 mg / day for about 1 to about 3 days, followed by bupropion at about 200 mg / day and dextromethorphan at about 60 mg / day, in any of the preceding embodiments, for example, the method described in embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36. (Embodiment 43) Dextromethorphan is administered to the human for the treatment of pain, in any of the preceding embodiments, for example, the method described in embodiments 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42. (Embodiment 44) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, post-pain, cancer pain, arthralgia, lumbosacral pain, musculoskeletal pain, pain in central multiple sclerosis, nociceptive pain, or neuropathic pain. (Embodiment 45) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain. (Embodiment 46) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, postoperative pain. (Embodiment 47) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, cancer pain. (Embodiment 48) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, arthralgia. (Embodiment 49) The pain includes lumbosacral pain, by the method described in embodiment 43. (Embodiment 50) The pain includes, in any of the preceding embodiments, for example, the method described in embodiment 43, musculoskeletal pain. (Embodiment 51) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, including neuropathic pain. (Embodiment 52) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, including nociceptive pain. (Embodiment 53) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, including chronic musculoskeletal pain. (Embodiment 54) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with rheumatoid arthritis. (Embodiment 55) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with juvenile idiopathic arthritis. (Embodiment 56) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with osteoarthritis. (Embodiment 57) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with axial spondyloarthritis. (Embodiment 58) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with ankylosing spondylitis. (Embodiment 59) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with diabetic peripheral neuropathy. (Embodiment 60) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with postherpetic neuralgia. (Embodiment 61) The pain is any of the methods described in any of the preceding embodiments, for example, Embodiment 43, associated with trigeminal neuralgia. (Embodiment 62) The pain is associated with monoradiculopathies in any of the preceding embodiments, for example, Embodiment 43. (Embodiment 63) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to phantom limb pain. (Embodiment 64) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to central pain. (Embodiment 65) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which includes cancer-related pain. (Embodiment 66) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to lumbar nerve root compression. (Embodiment 67) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to spinal cord injury. (Embodiment 68) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to post-stroke pain. (Embodiment 69) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to the pain of central multiple sclerosis. (Embodiment 70) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to HIV-related neuropathy. (Embodiment 71) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to radiation therapy-related neuropathy. (Embodiment 72) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to chemotherapy-related neuropathy. (Embodiment 73) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which includes toothache. (Embodiment 74) The pain is the method described in any of the preceding embodiments, for example, Embodiment 43, which is related to primary dysmenorrhea. (Embodiment 75) Any of the preceding embodiments, for example, the methods of embodiments 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74, wherein 90 mg / day of dextromethorphan is administered to the human. (Embodiment 76) Any of the preceding embodiments, for example, the method of embodiment 75, wherein 45 mg of dextromethorphan is administered to the human twice a day. (Embodiment 77) Any of the preceding embodiments, for example, the method of embodiment 75 or 76, wherein 150 mg / day of bupropion is administered to the human. (Embodiment 78) Any of the preceding embodiments, for example, the method of embodiment 75 or 76, wherein 180 mg / day of bupropion is administered to the human. (Embodiment 79) Any of the preceding embodiments, for example, the method of embodiment 75 or 76, wherein 200 mg / day of bupropion is administered to the human. (Embodiment 80) Any of the preceding embodiments, for example, the method of claim 123 or 124, wherein 300 mg / day of bupropion is administered to the human. (Embodiment 81) Co-administering to a human dextromethorphan with threohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrug thereof, wherein the threohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrug thereof results in an AUC of dextromethorphan that is at least about 40 ng·hour / mL 0-12A method for increasing the plasma concentration of dextromethorphan in humans, administered in an amount that results in (Embodiment 82) The AUC of the dextromethorphan 0-12 is at least about 50 ng·hour / mL, the method according to any previous embodiment, for example, Embodiment 81. (Embodiment 83) The human being is in need of treatment with dextromethorphan, the method according to any previous embodiment, for example, Embodiment 81 or 82. (Embodiment 84) The human being is a high metabolizer of dextromethorphan, the method according to any previous embodiment, for example, Embodiment 81, 82 or 83. (Embodiment 85) L-threohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion, or their prodrugs, and dextromethorphan are administered to the human being at least daily for at least 8 days, the method according to any previous embodiment, for example, Embodiment 81, 82, 83 or 84. (Embodiment 86) The AUC of the dextromethorphan on the 8th day 0-12 is at least about 100 ng·hour / mL, the method according to any previous embodiment, for example, Embodiment 85. (Embodiment 87) The AUC of the dextromethorphan on the 8th day 0-12 is at least about 400 ng·hour / mL, the method according to any previous embodiment, for example, Embodiment 85 or 86. (Embodiment 88) The AUC of the dextromethorphan on the 8th day 0-12 is at least about 800 ng·hour / mL, the method according to any previous embodiment, for example, Embodiment 85, 86 or 87. (Embodiment 89) The AUC of the dextromethorphan on the 8th day 0-12is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87 or 88, that is at least about 1500 ng·hour / mL. (Embodiment 90) The AUC of the dextromethorphan on day 8 0-24 is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88 or 89, that is at least about 100 ng·hour / mL. (Embodiment 91) The AUC of the dextromethorphan on day 8 0-24 is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88, 89 or 90, that is at least about 1500 ng·hour / mL. (Embodiment 92) The AUC of the dextromethorphan on day 8 0-24 is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88, 89, 90 or 91, that is at least about 2900 ng·hour / mL. (Embodiment 93) The AUC of the dextromethorphan on day 8 0-inf is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88, 89, 90, 91 or 92, that is at least about 100 ng·hour / mL. (Actual situation form 94) The AUC of the dextromethorphan on day 8 0-inf is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88, 89, 90, 91, 92 or 93, that is at least about 1500 ng·hour / mL. (Embodiment 95) The AUC of the dextromethorphan on day 8 0-inf is a method according to any of the preceding embodiments, such as embodiments 85, 86, 87, 88, 89, 90, 91, 92, 93 or 94, that is at least about 3500 ng·hour / mL. (Embodiment 96) The AUC of the dextromethorphan on day 8 0-infis a method according to any of the preceding embodiments, for example embodiments 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 or 95, which is at least about 5000 ng·hour / mL. (Embodiment 97) Comprising co-administering to a human treohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion or a prodrug thereof with dextromethorphan, wherein the treohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion or a prodrug thereof is administered in an amount that results in a C 最大 of dextromethorphan in the human plasma concentration increasing method, which is at least about 6 ng / mL. (Embodiment 98) The method according to any of the preceding embodiments, for example embodiment 97, wherein the human is in need of treatment with dextromethorphan. (Embodiment 99) The method according to any of the preceding embodiments, for example embodiment 97 or 98, wherein the human is a high metabolizer of dextromethorphan. (Embodiment 100) The method according to any of the preceding embodiments, for example embodiment 97, 98 or 99, wherein the treohydroxybupropion, hydroxybupropion, erythrohydroxybupropion, bupropion, or a prodrug thereof, and dextromethorphan are administered to the human at least daily for at least 8 days. (Embodiment 101) The C 最大 of dextromethorphan on day 8 is at least about 20 ng / mL according to any of the preceding embodiments, for example embodiment 100. (Embodiment 102) The C 最大 of dextromethorphan on day 8 is at least about 60 ng / mL according to any of the preceding embodiments, for example embodiment 100 or 101. (Embodiment 103) On the 8th day, the C of the dextromethorphan 最大 is at least about 120 ng / mL, by the method described in any of the previous embodiments, such as Embodiment 100, 101 or 102. (Embodiment 104) Co-administering to a human treohydroxybutyric acid, hydroxybutyric acid, erythrohydroxybutyric acid, butyric acid or a prodrug thereof with dextromethorphan, wherein the treohydroxybutyric acid, hydroxybutyric acid, erythrohydroxybutyric acid, butyric acid or a prodrug thereof is present at least about 5 ng / mL over a 12-hour period after a single dose, the method for increasing the plasma concentration of dextromethorphan in a human that results in a C of dextromethorphan 平均 administered in an amount that results in. (Embodiment 105) The human is a method according to any of the previous embodiments, such as Embodiment 104, in need of treatment with dextromethorphan. (Embodiment 106) The human is a method according to any of the previous embodiments, such as Embodiment 104 or 105, in the high metabolizer group of dextromethorphan. (Embodiment 107) Treohydroxybutyric acid, hydroxybutyric acid, erythrohydroxybutyric acid, butyric acid, or a prodrug thereof, and dextromethorphan are administered to the human at least daily for at least 8 days, by the method described in any of the previous embodiments, such as Embodiment 104, 105 or 106. (Embodiment 108) On the 8th day, the C of the dextromethorphan 平均 is at least about 20 ng / mL, by the method described in any of the previous embodiments, such as Embodiment 107. (Embodiment 109) On the 8th day, the C of the dextromethorphan 平均 is at least about 70 ng / mL, by the method described in any of the previous embodiments, such as Embodiment 107 or 108. (Embodiment 110) C of the dextromethorphan on the 8th day 平均 is at least about 120 ng / mL, the method according to any of the preceding embodiments, for example, Embodiment 107, 108 or 109. (Embodiment 111) Co-administering to a human bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds with dextromethorphan, wherein the bupropion or its prodrug is administered in an amount that results in an AUC of dextromethorphan that is at least about 40 ng·hour / mL 0-12 A method for increasing the plasma concentration of dextromethorphan in a human. (Embodiment 112) The AUC of the dextromethorphan 0-12 is at least about 50 ng·hour / mL, the method according to any of the preceding embodiments, for example, Embodiment 111. (Embodiment 113) The human is in need of treatment with dextromethorphan, the method according to any of the preceding embodiments, for example, Embodiment 111 or 112. (Embodiment 114) The human is a high metabolizer of dextromethorphan, the method according to any of the preceding embodiments, for example, Embodiment 111, 112 or 113. (Embodiment 115) Bupropion or its prodrug is co-administered with dextromethorphan to the human at least daily for at least 2 consecutive days, the method according to any of the preceding embodiments, for example, Embodiment 111, 112, 113 or 114. (Embodiment 116) Administering bupropion, or its prodrug, and dextromethorphan to the human at least daily for at least 8 days, the method according to any of the preceding embodiments, for example, Embodiment 115. (Embodiment 117) The AUC of the dextromethorphan on the 8th day 0-12is at least about 100 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 118) The AUC of dextromethorphan on day 8 0-12 is at least about 800 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 119) The AUC of dextromethorphan on day 8 0-12 is at least about 1500 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 120) The AUC of dextromethorphan on day 8 0-24 is at least about 100 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 121) The AUC of dextromethorphan on day 8 0-24 is at least about 1500 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 122) The AUC of dextromethorphan on day 8 0-inf is at least about 100 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 123) The AUC of dextromethorphan on day 8 0-inf is at least about 3500 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 124) The AUC of dextromethorphan on day 8 0-inf is at least about 5000 ng·hour / mL, any of the preceding embodiments, for example, the method described in Embodiment 116. (Embodiment 125) A method for increasing the plasma concentration of dextromethorphan in a human, comprising co-administering to the human bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds with dextromethorphan, wherein the bupropion or its prodrug is administered in an amount that results in a C 最大 of dextromethorphan of at least about 6 ng / mL. (Embodiment 126) The method according to any preceding embodiment, for example, the method according to Embodiment 125, wherein the human is in need of treatment with dextromethorphan. (Embodiment 127) The method according to any preceding embodiment, for example, the method according to Embodiment 125 or 126, wherein the human is a high metabolizer of dextromethorphan. (Embodiment 128) The method according to any preceding embodiment, for example, the method according to Embodiment 126, 127 or 128, wherein the bupropion or its prodrug is co-administered with dextromethorphan at least daily for at least 2 consecutive days. (Embodiment 129) The method according to any preceding embodiment, for example, the method according to Embodiment 128, wherein bupropion, or a prodrug thereof, and dextromethorphan are co-administered to the human at least daily for at least 8 days. (Embodiment 130) The C 最大 of dextromethorphan on the 8th day is at least about 10 ng / mL, according to any preceding embodiment, for example, the method according to Embodiment 129. (Embodiment 131) The C 最大 of dextromethorphan on the 8th day is at least about 60 ng / mL, according to any preceding embodiment, for example, the method according to Embodiment 129. (Embodiment 132) The C 最大 of dextromethorphan on the 8th day is at least about 120 ng / mL, according to any preceding embodiment, for example, the method according to Embodiment 129. (Embodiment 133) Co-administering to a human bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug of any of these compounds with dextromethorphan, wherein the bupropion or its prodrug is at least about 5 ng / mL of dextromethorphan C 平均 for a period between two separate and consecutive administrations of dextromethorphan, in an amount that results in an increased plasma concentration of dextromethorphan in the human. (Embodiment 134) The bupropion or its prodrug is administered in an amount that results in at least about 60 ng / mL of dextromethorphan C 平均 for a period between two separate and consecutive administrations of dextromethorphan, in any of the embodiments, for example, the method according to Embodiment 134. (Embodiment 135) The human is in need of treatment with dextromethorphan, in any of the preceding embodiments, for example, the method according to Embodiment 134. (Embodiment 136) The human is a high metabolizer of dextromethorphan, in any of the preceding embodiments, for example, the method according to Embodiment 134 or 135. (Embodiment 137) The bupropion or its prodrug is co-administered with dextromethorphan at least daily for at least two consecutive days, in any of the preceding embodiments, for example, the method according to Embodiment 134, 135 or 136. (Embodiment 138) The bupropion, or its prodrug, and dextromethorphan are administered to the human at least daily for at least eight days, in any of the preceding embodiments, for example, the method according to Embodiment 137. (Embodiment 139) The C 平均 of dextromethorphan on the eighth day is at least about 8 ng / mL, said C 平均is for the period between two separate administrations and continuous administrations of dextromethorphan, or, when dextromethorphan is administered only once on the 8th day, said C 平均 is for 12 hours after the first administration of dextromethorphan on the 8th day, any of the preceding embodiments, for example, the method described in Embodiment 138. (Embodiment 140) The C of said dextromethorphan on the 8th day 平均 is at least about 120 ng / mL, said C 平均 is for the period between two separate administrations and continuous administrations of dextromethorphan, or, when dextromethorphan is administered only once on the 8th day, said C 平均 is for 12 hours after the first administration of dextromethorphan on the 8th day, any of the preceding embodiments, for example, the method described in Embodiment 138.

[0209] The following documents are hereby incorporated by reference in their entirety: U.S. Provisional Patent Application No. 61 / 900,354; PCT Application No. PCT / US2014 / 64184; U.S. Patent Application No. 14 / 554,947; U.S. Patent Application No. 14 / 554,988; U.S. Patent Application No. 14 / 550,618; and U.S. Patent Application No. 14 / 555,085; U.S. Patent Application No. 14 / 602,177; U.S. Patent Application No. 14 / 604,397.

Examples

[0210] Example 1 As shown in Table 1 below, 15 human subjects were randomly selected into one of two treatment groups that received dextromethorphan (DM) alone or DM in combination with bupropion.

Table 1

[0211] All subjects were in the high (including ultra-rapid) metabolizer group of dextromethorphan as determined by CYP2D6 gene testing. Dextromethorphan was administered at 12-hour intervals for 1 to 8 days, with the morning dose on day 8 being the last. Bupropion was administered once a day at 12-hour intervals for 1 to 3 days, with the morning dose on day 8 being the last.

[0212] Plasma samples were collected for the determination of the concentrations of dextromethorphan, total dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion on days 1 and 8. Plasma samples for the determination of the trough concentration of dextromethorphan were obtained approximately 12 hours after dosing on days 1, 5, 6, and 8.

[0213] The concentrations of dextromethorphan, total dextromethorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were measured using LC-MS / MS. Pharmacokinetic parameters were calculated.

[0214] The phenotype of the dextromethorphan metabolic state was determined by calculating the dextromethorphan / dextromethorphan metabolic rate as described in Jurica et al., Journal of Clinical Pharmacy and Therapeutics, 2012, 37, 486 - 490. Plasma concentrations of dextromethorphan and dextromethorphan 3 hours after dosing were used with a dextromethorphan / dextromethorphan ratio of 0.3 or greater, indicating a poor metabolizer phenotype.

[0215] Results As shown in Figure 1 and Table 2, the plasma concentration of dextromethorphan increased significantly with bupropion administration.

Table 2-1

[0216] As shown in FIGS. 2 to 4, the AUC of dextromethorphan increased considerably with the administration of bupropion. As shown in FIG. 5 and Table 2A, the administration of bupropion with dextromethorphan resulted in an increase in the AUC of each mean dextromethorphan on the 8th day compared to the administration of dextromethorphan alone 0-12 , AUC 0-24 , and AUC 0-inf resulted in an increase of approximately 60-fold, 80-fold, and 175-fold, respectively. As shown in FIG. 6 and Table 2B, the increase in dextromethorphan AUC occurred as early as on the 1st day (about 3 times the increase in AUC 0-12 ).

Table 2-2

Table 2-3

[0217] As shown in FIG. 7 and Tables 2A and 3, the trough plasma concentration of dextromethorphan (also called "minimum mean plasma concentration" or "C 最小 ") increased considerably with the administration of bupropion. The administration of bupropion with dextromethorphan resulted in an increase of approximately 105-fold in the mean trough plasma concentration of dextromethorphan on the 8th day compared to the administration of dextromethorphan alone

[0218] As shown in Table 2A, the mean plasma concentration of dextromethorphan (C 平均 ) on the 8th day increased approximately 60-fold with the administration of bupropion compared to the administration of dextromethorphan alone. The maximum mean plasma concentration (C 最大 ) also increased considerably, as shown in FIG. 8 and Table 2A

Table 3

[0219] The T 最大 and elimination half-life (T1 / 2el ) increased significantly with bupropion administration on day 8. Administration of bupropion with dextromethorphan resulted in an average T of 3.6 hours compared to 2.3 hours for dextromethorphan alone. 最大 ) with dextromethorphan resulted in an average T of 27.7 hours compared to 6.6 hours for dextromethorphan alone. 1 / 2el )

[0220] As shown in Figure 9 and Table 4, the plasma concentration of dextromethorphan was significantly reduced with bupropion administration.

Table 4

[0221] As shown in Figures 10 - 11, there was a decrease of approximately 78% in the C of mean dextromethorphan, and a decrease of approximately 55% in the AUC of mean dextromethorphan on day 8 with bupropion administration. 最大 and a decrease of approximately 55% in the AUC of mean dextromethorphan on day 8 with bupropion administration. 0-12 )

[0222] Determination of the phenotype of the dextromethorphan metabolic state showed that none of the subjects in any treatment had low metabolism on day 1. However, on day 8, 100% of the subjects treated with bupropion were converted to the low - metabolism group state compared to 0% of the subjects treated with dextromethorphan alone. The mean plasma dextromethorphan / dextromorphan metabolic rate increased from 0.01 on day 1 to 0.71 on day 8 with bupropion administration. The mean rate in the group administered DM alone was 0.00 on day 1 and remained unchanged on day 8.

[0223] On day 8, the mean plasma concentrations of bupropion, hydroxybupropion, erythro - hydroxybupropion, and threo - hydroxybupropion were at least 10 ng / mL, 200 ng / mL, 20 ng / mL, and 100 ng / mL respectively after bupropion administration.

[0224] As used in this section, the term "fold change" or "fold increase" refers to the ratio of the value of bupropion to the dextromethorphan for the same value of dextromethorphan alone (i.e., the value of bupropion with dextromethorphan divided by the same value of dextromethorphan alone).

[0225] Example 2 The ability of various antidepressant compounds to inhibit the metabolism of dextromethorphan was examined using human liver microsomes. Each antidepressant compound was prepared in duplicate at seven increasing concentrations (0.1 - 100 μM) in the presence of dextromethorphan (5 μM) at 37 °C and incubated with human liver microsomes (0.5 mg / mL). The assay was performed in the presence of 2 mM NADPH in 100 mM potassium phosphate (pH 7.4) containing 5 mM magnesium chloride in a final volume of 200 μl of assay.

[0226] After optimal incubation at 37 °C, methanol containing an internal standard was added to stop the reaction for analytical quantification. The quenched samples were incubated at 4 °C for 10 minutes and centrifuged at 4 °C for 10 minutes. The supernatant was removed, and the metabolites of dextromethorphan (dextrorphan) were analyzed by LC - MS / MS. Using the degree of reduction in metabolite formation compared to the vehicle control, the IC 50 value (the test concentration that causes 50% inhibition of dextromethorphan metabolism) was calculated for each antidepressant compound, and the lower the IC 50 the higher the potency was indicated.

[0227] The results are summarized in Table 5 below, and the corresponding potencies are shown in Figure 12.

Table 5

[0228] Unless otherwise indicated, all numbers expressing quantities of ingredients, molecular weights, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about” as well as the indicated exact value. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0229] The terms “a,” “an,” “the,” and similar referents used in the context of describing the invention (especially in the context of the appended claims) are to be construed to cover both the singular and the plural unless otherwise indicated or clearly contradicted by the context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is merely intended to better illustrate the invention and is not a limitation on the scope of the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0230] The grouping of alternative elements or embodiments disclosed herein should not be construed as a limitation. Members of each group may be referred to individually, or in any combination with other members of that group or other elements found herein, and may be claimed. For convenience and / or patentability reasons, it is anticipated that one or more members of a group may be included in, or deleted from, the group. When such inclusion or deletion occurs, the specification is to be regarded as including the modified group and thus to satisfy the written description requirements of all Markush groups used in the appended claims.

[0231] This specification describes certain embodiments, including the best mode known to the inventors of carrying out the invention. It will of course be apparent to those skilled in the art that variations of these described embodiments will become apparent upon reading the above description. The inventors expect those skilled in the art to appropriately use such variations, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the claims are intended to cover all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Further, unless otherwise indicated herein or clearly contradicted by context, any combination of the above elements in all possible variations is contemplated.

[0232] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be used are within the scope of the claims. Accordingly, by way of example and not limitation, other embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not precisely limited to the embodiments as shown and described.

[0233] (Appendix) (Appendix 1) A method for increasing the plasma concentration of dextromethorphan in a human, comprising co-administering erythrohydroxybupropion or a prodrug thereof with dextromethorphan to the human.

[0234] (Appendix 2) A method for increasing the plasma concentration of dextromethorphan in a human, comprising co-administering bupropion or a prodrug thereof with dextromethorphan to the human.

[0235] (Appendix 3) A method for increasing the plasma concentration of dextromethorphan in a human, comprising co-administering hydroxybupropion or a prodrug thereof with dextromethorphan to the human.

[0236] (Appendix 4) A method for increasing the plasma concentration of dextromethorphan in a human, comprising co-administering to the human a threohydroxypropionic acid or a prodrug thereof together with dextromethorphan.

[0237] (Appendix 5) The AUC of dextromethorphan that is at least about 40 ng·h / mL 0-12 The method according to Appendix 1, 2, 3 or 4, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof is administered in an amount that provides the AUC.

[0238] (Appendix 6) The AUC of the dextromethorphan 0-12 is at least about 50 ng·h / mL, the method according to Appendix 5.

[0239] (Appendix 7) The C of dextromethorphan that is at least about 6 ng / mL 最大 The method according to Appendix 1, 2, 3, 4, 5 or 6, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof is administered in an amount that provides the C.

[0240] (Appendix 8) The C of dextromethorphan that is at least about 5 ng / mL over a period between two separate and consecutive administrations of dextromethorphan 平均 The method according to Appendix 1, 2, 3, 4, 5, 6 or 7, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof is administered in an amount that provides the C.

[0241] (Appendix 9) The C of dextromethorphan that is at least about 60 ng / mL over a period between two separate and consecutive administrations of dextromethorphan 平均The method according to appendix 8, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof is administered in an amount that provides

[0242] (Appendix 10) The method according to appendix 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof is co-administered with dextromethorphan at least daily for at least 2 consecutive days.

[0243] (Appendix 11) The method according to appendix 10, wherein bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a prodrug thereof, and dextromethorphan are co-administered to a human at least daily for at least 8 days.

[0244] (Appendix 12) The C 平均 of dextromethorphan on the 8th day is at least about 8 ng / mL, wherein the C 平均 is for the period between two separate and consecutive administrations of dextromethorphan, or, when dextromethorphan is administered only once on the 8th day, the C 平均 is for 12 hours after the first administration of dextromethorphan on the 8th day. The method according to appendix 11.

[0245] (Appendix 13) The C 平均 of dextromethorphan on the 8th day is at least about 30 ng / mL. The method according to appendix 12.

[0246] (Appendix 14) The AUC 0-12 of dextromethorphan on the 8th day is at least about 100 ng·hour / mL. The method according to appendix 11, 12, or 13.

[0247] (Appendix 15) The AUC of the dextrometorphan on the 8th day 0-12 is at least about 400 ng·hour / mL, according to the method described in Appendix 14.

[0248] (Appendix 16) The AUC of the dextrometorphan on the 8th day 0-12 is at least about 700 ng·hour / mL, according to the method described in Appendix 14.

[0249] (Appendix 17) The AUC of the dextrometorphan on the 8th day 0-12 is at least about 800 ng·hour / mL, according to the method described in Appendix 14.

[0250] (Appendix 18) The AUC of the dextrometorphan on the 8th day 0-24 is at least about 100 ng·hour / mL, according to the method described in Appendix 11, 12, 13, 14, 15, 16 or 17.

[0251] (Appendix 19) The AUC of the dextrometorphan on the 8th day 0-24 is at least about 1000 ng·hour / mL, according to the method described in Appendix 18.

[0252] (Appendix 20) The AUC of the dextrometorphan on the 8th day 0-inf is at least about 100 ng·hour / mL, according to the method described in Appendix 11, 12, 13, 14, 15, 16, 17, 18 or 19.

[0253] (Appendix 21) The AUC of the dextrometorphan on the 8th day 0-inf is at least about 2000 ng·hour / mL, according to the method described in Appendix 20.

[0254] (Appendix 22) The AUC of the dextrometorphan on the 8th day0-inf is the method described in Supplementary Note 20 that is at least about 3000 ng·hour / mL.

[0255] (Supplementary Note 23) C of the dextromethorphan on the 8th day 最大 is the method described in Supplementary Notes 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 that is at least about 10 ng / mL.

[0256] (Supplementary Note 24) C of the dextromethorphan on the 8th day 最大 is the method described in Supplementary Note 23 that is at least about 60 ng / mL.

[0257] (Supplementary Note 25) C of the dextromethorphan on the 8th day 最大 is the method described in Supplementary Note 23 that is at least about 80 ng / mL.

[0258] (Supplementary Note 26) The human needs treatment with dextromethorphan, by the method described in Supplementary Notes 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.

[0259] (Supplementary Note 27) The human is a high metabolizer of dextromethorphan, by the method described in Supplementary Notes 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.

[0260] (Supplementary Note 28) AUC of the dextromethorphan on the 8th day 0-12 is the method described in Supplementary Note 14 that is at least about 1500 ng·hour / mL.

[0261] (Supplementary Note 29) AUC of the dextromethorphan on the 8th day 0-24The method described in Supplementary Note 18, which is at least about 1500 ng·hour / mL.

[0262] (Supplementary Note 30) The AUC of the dextromethorphan on the 8th day 0-inf The method described in Supplementary Note 20, which is at least about 3500 ng·hour / mL.

[0263] (Supplementary Note 31) The AUC of the dextromethorphan on the 8th day 0-inf The method described in Supplementary Note 20, which is at least about 5000 ng·hour / mL.

[0264] (Supplementary Note 32) The C of the dextromethorphan on the 8th day 最大 The method described in Supplementary Note 23, which is at least about 120 ng / mL.

Claims

1. An approximately 105 mg of bupropion hydrochloride, or a molar equivalent of bupropion in free base form or other salt form, and An approximately 45 mg of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan in free base form or other salt form, and A dosage form containing the same.

2. The dosage form according to claim 1, comprising approximately 105 mg of bupropion hydrochloride and approximately 45 mg of dextromethorphan hydrobromide.

3. The dosage form according to claim 1, wherein the dextromethorphan is formulated for immediate release.

4. The dosage form according to claim 1, wherein the bupropion is formulated for sustained release.

5. The dosage form according to claim 1, which delivers the dextromethorphan and the bupropion systemically to a human.

6. The dosage form according to claim 5, which is orally administered to the human.

7. The dosage form according to claim 5, which is administered to the human once a day.

8. The dosage form according to claim 5, which is administered to the human twice a day.

9. The dosage form according to claim 5, which is administered to the human continuously for at least 8 days.

10. The dosage form according to claim 5, which is administered to the human continuously for at least 14 days.

11. The dosage form according to claim 5, which is administered to the human continuously for at least 30 days.

12. An approximately 210 mg of bupropion hydrochloride, or a molar equivalent of bupropion in free base form or other salt form, and An approximately 90 mg of dextromethorphan hydrobromide, or a molar equivalent of dextromethorphan in free base form or other salt form, and A dosage form containing the same.

13. The dosage form according to claim 12, comprising approximately 210 mg of bupropion hydrochloride and approximately 90 mg of dextromethorphan hydrobromide.

14. The dosage form according to claim 12, wherein the dextromethorphan is formulated for immediate release.

15. The dosage form according to claim 12, wherein the bupropion is formulated for sustained release.

16. The dosage form according to claim 12, which delivers the dextromethorphan and the bupropion systemically to a human.

17. The dosage form according to claim 16, which is orally administered to the human.

18. The dosage form according to claim 16, which is administered to the human once a day.

19. The dosage form according to claim 16, which is administered to the human continuously for at least 8 days.

20. The dosage form according to claim 16, which is administered to the human continuously for at least 14 days.

21. The dosage form according to claim 16, which is administered to the human continuously for at least 30 days.

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