Pharmaceutical composition containing enantiomers of pure bupropion

Abstract

This invention provides a dosage form of bupropion that can be used for the treatment of neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, and the like. [Solution] Described herein are dosage forms of enantiomerically enriched (S)-bupropion or enantiomerically enriched (R)-bupropion. (S)-bupropion or (R)-bupropion may be deuterium enriched or may be in their natural isotopic abundance. These dosage forms can be administered either ingested or fasted to treat conditions such as neurological disorders, to achieve specific pharmacokinetic parameters of bupropion or its metabolites, and / or to increase the plasma concentration of dextromethorphan.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority pursuant to U.S. Provisional Patent Application No. 62 / 634,718 filed on 23 February 2018, 62 / 794,469 filed on 18 January 2019, and 62 / 809,480 filed on 22 February 2019, all of which are incorporated herein by reference in their entirety. [Overview of the project] [Means for solving the problem]

[0002] Described herein are dosage forms of enantiomerically enriched (S)-bupropion or enantiomerically enriched (R)-bupropion. (S)-bupropion or (R)-bupropion may be deuterium-enriched or in their natural isotopic abundance. These dosage forms can be administered either in a fed or fasted state to treat the conditions described herein, to achieve predetermined pharmacokinetic parameters of bupropion or its metabolites, and / or to increase the plasma concentration of dextromethorphan.

[0003] Some embodiments include a method for delivering bupropion or its metabolites into plasma, comprising orally administering to humans at least once daily a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure.

[0004] Some embodiments include a method for delivering bupropion into human plasma, comprising selecting a human patient having a pharmacokinetic profile obtained by orally administering a reference dosage form containing a first amount of racemic bupropion at a first frequency of administration, and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at a first frequency of administration to achieve the same pharmacokinetic profile achieved by administering the reference dosage form at a first frequency of administration, wherein the first frequency of administration is once or twice daily, and the second amount is about 40% to about 60% of the first amount.

[0005] Some embodiments include a method for treating a condition treatable by racemic bupropion, comprising: selecting a human patient having a condition treatable by orally administering a reference dosage form containing a first amount of racemic bupropion at a first frequency of administration; and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at a first frequency of administration to achieve the same therapeutic effect as achieved by administering the reference dosage form at a first frequency of administration, wherein the first frequency of administration is once or twice daily, and the second amount is about 40% to about 60% of the first amount.

[0006] Some embodiments include a method for increasing plasma concentrations of (S)-bupropion and dextromethorphan, comprising co-administering dextromethorphan and at least 90 mg of at least 95% enantiomerically pure (S)-bupropion orally at least once daily to a person requiring treatment with both (S)-bupropion and dextromethorphan, wherein the method involves C max The method achieves a concentration of at least approximately 90 ng / mL in humans, and the C of (R)-bupropion when the same amount of (R)-bupropion is administered to the same human. max Compared to (S)-bupropion C max It has the effect of increasing it by at least three times.

[0007] Some embodiments include orally co-administering to a human who requires treatment with both (R,R)-hydroxybupropion and dextromethorphan, at least once a day, a dextromethorphan and at least 90 mg of at least 95% enantiomerically pure (S)-bupropion, the method of increasing plasma concentrations of (R,R)-hydroxybupropion and dextromethorphan, the method having (R,R)-hydroxybupropion C max achieving at least about 700 ng / mL in humans, the method being the C of ((R,R)-hydroxybupropion when the same amount of (R)-bupropion is administered to the human max compared to the C of (R,R)-hydroxybupropion max has the effect of increasing by at least 3-fold.

[0008] Some embodiments include orally administering at least once a day, to a human who requires treatment with (S)-bupropion, at least 90 mg of at least 95% enantiomerically pure (S)-bupropion, the method of increasing the plasma concentration of (S)-bupropion, the method having (S)-bupropion C min achieving at least about 20 ng / mL, the method being the C of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to the human min compared to the C of (S)-bupropion min has the effect of increasing by at least 3-fold.

[0009] Some embodiments include orally administering at least once a day, to a human who requires treatment with (R,R)-hydroxybupropion, at least 90 mg of at least 95% enantiomerically pure (S)-bupropion, the method of increasing the plasma concentration of (R,R)-hydroxybupropion, by which method the C of (R,R)-hydroxybupropion min becomes at least about 700 ng / mL in humans, the method being the C of (R,R)-hydroxybupropion when the same amount of (R)-bupropion is administered to the human minCompared to (R,R)-hydroxybupropion C min It has the effect of increasing it by at least three times.

[0010] Some embodiments include methods for treating central nervous system (CNS) disorders in humans, comprising administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion and dextromethorphan to humans in a therapeutically effective amount.

[0011] Some embodiments include a method for increasing the plasma concentration of (S)-bupropion while increasing the plasma concentration of dextromethorphan, comprising administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion and dextromethorphan to a person in need of treatment with bupropion.

[0012] Some embodiments include dosage forms containing at least about 95% enantiomerically pure (R)-bupropion and dextromethorphan, and when these dosage forms are administered orally to humans, the plasma concentration of dextromethorphan in humans is enhanced compared to oral administration of a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0013] Some embodiments include a method for increasing the plasma concentration of dextromethorphan in humans, comprising administering to humans a dosage form containing at least about 95% enantiomerically pure (R)-bupropion and dextromethorphan, the dosage form enhancing the plasma concentration of dextromethorphan in humans compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0014] Some embodiments include a method for treating central nervous system (CNS) disorders in humans, comprising administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion in a therapeutically effective amount to a human, wherein the human is not administered dextromethorphan.

[0015] Some embodiments include a method for increasing the plasma concentration of (S)-bupropion, which involves administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion in a therapeutically effective amount and without dextromethorphan to a person in need of treatment with bupropion.

[0016] Some embodiments include a method for increasing the plasma concentration of (S)-bupropion, comprising orally administering an oral dosage form containing at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion to a person requiring treatment with (S)-bupropion and dextromethorphan, thereby increasing the C of (S)-bupropion max The C of (R)-bupropion in the human was at least about 90 ng / mL, and this method is used to determine the C of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to the human. max In comparison, (S)-bupropion's C max It has the effect of increasing at least threefold, and the person is not administered dextromethorphan.

[0017] Some embodiments include a method for increasing the plasma concentration of (R,R)-hydroxybupropion, comprising orally administering an oral dosage form containing at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion to a person requiring treatment with (R,R)-hydroxybupropion and dextromethorphan, thereby increasing the C of (R,R)-hydroxybupropion. max This results in at least approximately 90 ng / mL, and this method determines the C of (R,R)-hydroxybupropion when a dosage form containing the same amount of (R)-bupropion is administered to the person. max In comparison, (R,R)-hydroxybupropion C max It has the effect of increasing at least threefold, and the person is not administered dextromethorphan.

[0018] Some embodiments include an oral dosage form containing (R)-bupropion and dextromethorphan in an enantiomer excess of at least 95%, the dosage form increasing the plasma concentration of dextromethorphan in humans compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0019] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, which, when administered orally to humans daily for at least eight consecutive days, can enhance the plasma concentration of dextromethorphan in humans on day 1 or day 8 to a much greater extent than the reference oral dosage form, the reference oral dosage form containing the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0020] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, wherein the dosage form, when administered orally to a human being daily for at least 8 consecutive days, has an average C1 of dextromethorphan in the human on day 1 compared to that of a reference oral dosage form administered orally to the same human being daily for at least 8 consecutive days. max The reference oral dosage form contains an equal amount of bupropion and an equal amount of dextromethorphan as (S)-bupropion, with an increase of at least 150%.

[0021] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, wherein the dosage form, when administered orally to a human being daily for at least 8 consecutive days, yields the mean C12 of dextromethorphan in the human on day 8 compared to the same human being when administered orally to the same human being daily for at least 8 consecutive days. max The reference oral dosage form contains an equal amount of bupropion and an equal amount of dextromethorphan as (S)-bupropion, with the amount increased by at least 25%.

[0022] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, wherein the dosage form is compared to the mean C1 of dextromethorphan in a human on day 8 when the reference dosage form is administered orally to a human on day 1 for at least 8 consecutive days. max The amount is increased by at least 20 times, and the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0023] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, wherein the dosage form is compared to the mean C1 of dextromethorphan in humans on day 1 when the reference dosage form is administered orally to humans daily for at least 8 consecutive days. max The reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion, with the amount increased by at least 60%.

[0024] Some embodiments include oral dosage forms containing (R)-bupropion and dextromethorphan, wherein the dosage form is compared to the mean C1 of dextromethorphan on day 8 in humans when the reference dosage form is administered orally to humans daily for at least 8 consecutive days. max The reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion, with the amount increased by at least 20%.

[0025] Some embodiments include a method for increasing the plasma concentration of dextromethorphan on day 1 or day 8 to a much greater extent than that of a reference dosage form when administered orally to humans daily for at least 8 consecutive days, comprising orally administering a dosage form containing (R)-bupropion and dextromethorphan, wherein the reference dosage form contains the same amount of bupropion and the same amount of dextromethorphan as (S)-bupropion.

[0026] Some embodiments include methods for treating neuropsychiatric disorders, comprising administering the dosage forms described in any of the preceding paragraphs to a person in need of treatment.

[0027] Some embodiments include methods for treating a cold or cough, which involve administering the dosage forms described in any of the preceding paragraphs to a person in need of treatment.

[0028] Some embodiments include methods for relieving pain, which involve administering the dosage forms described in any of the preceding paragraphs to a person in need of treatment.

[0029] Some embodiments include methods for treating addiction, which involve administering the dosage forms described in any of the preceding paragraphs to a person in need of treatment.

[0030] Some embodiments include a method for treating a person comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a person having a condition treatable with (S)-bupropion, wherein the amount of (S)-bupropion administered is selected from about 20% to about 70% of the amount of racemic bupropion administered to treat the same condition in the same person.

[0031] Some embodiments include a method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion, at least 95% enantiomerically pure, once or twice daily to a person requiring treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the person's plasma, thereby providing a C of (R,R)-hydroxybupropion in the person. max This will be at least approximately 500 ng / mL.

[0032] Some embodiments include a method for treating a human being, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human being in need of treatment with (S)-bupropion, wherein (S)-bupropion is the only active agent used to treat a human being.

[0033] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, once or twice daily.

[0034] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby providing (S)-bupropion C max This will be at least approximately 60 ng / mL.

[0035] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human's plasma.

[0036] Some embodiments include a method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion that is at least 95% enantiomerically pure once or twice daily to a person in need of treatment with (R,R)-hydroxybupropion, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person.

[0037] Some embodiments include a method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion, at least 95% enantiomerically pure, once or twice daily to a person requiring treatment with (R,R)-hydroxybupropion, thereby providing a C of (R,R)-hydroxybupropion in the person. max This will be at least approximately 500 ng / mL.

[0038] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby providing (S)-bupropion C max This will be at least approximately 70 ng / mL.

[0039] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby reducing the AUC of (S)-bupropion. 0-12 This will be at least approximately 600 ng·h / mL.

[0040] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby (R,R)-hydroxybupropion C max This will be at least approximately 800 ng / mL.

[0041] Some embodiments include a method for treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby reducing the AUC of (R,R)-hydroxybupropion. 0-12This will be at least approximately 8,000 ng·h / mL.

[0042] Some embodiments include a method of treating a human being who requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby providing C of erythrohydroxybupropion max This will be at least approximately 90 ng / mL.

[0043] Some embodiments include a method for treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby reducing the AUC of erythrohydroxybupropion. 0-12 This will be at least approximately 1,000 ng·h / mL.

[0044] Some embodiments include a method of treating a human being who requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby treohydroxybupropion C max This will be at least approximately 450 ng / mL.

[0045] Some embodiments include a method of treating a human being that requires treatment with (S)-bupropion, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to the human being, thereby reducing the AUC of threohydroxybupropion. 0-12 This will be at least approximately 5,000 ng·h / mL.

[0046] Some embodiments include dosage forms containing at least 95% enantiomerically pure (S)-bupropion.

[0047] Some embodiments include methods for increasing the plasma concentration of (S)-bupropion or its metabolites, which involve administering any of the dosage forms described herein to a person in need of treatment with bupropion or its metabolites.

[0048] Some embodiments include methods for treating neurological conditions, which involve administering the dosage forms described in any of the preceding paragraphs to a person in need of treatment.

[0049] Some embodiments include a method for increasing the plasma concentration of dextromethorphan, comprising administering a combination of (R)-bupropion and dextromethorphan to a person in need of treatment with dextromethorphan, wherein (R)-bupropion is at least 95% enantiomerically pure.

[0050] Some embodiments include a method for delivering (S)-bupropion into human plasma, which involves orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human.

[0051] Some embodiments include a method for delivering both (R)-bupropion and (S)-bupropion into human plasma, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human, and the C of (R)-bupropion max This is the C content of (R)-bupropion when the same amount of racemic bupropion is administered to humans. max It is within 20% of that.

[0052] Some embodiments include a method for delivering bupropion to human plasma, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human, and the AUC of (R)-bupropion. 0-12 This is the AUC of (R)-bupropion when the same amount of racemic bupropion is administered to humans. 0-12 It is within 20% of that.

[0053] Some embodiments include a method for delivering bupropion into human plasma, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human, and (R,R)-hydroxybupropion C max This refers to the C of (R,R)-hydroxybupropion when the same amount of racemic bupropion is administered to the same person. max It is within 20% of that. [Modes for carrying out the invention]

[0054] Some dosage forms contain enantiomer-rich (S)-bupropion or enantiomerically pure (S)-bupropion. For example, (S)-bupropion may have an enantiomer purity of at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99%, or (nearly) 100%. (S)-bupropion with an enantiomer purity of 99.99% (or enantiomer excess, or 99.99%ee) contains 99.99% (S)-bupropion and 0.005% [[0.01%]] (R)-bupropion. For convenience, any of the above may be referred to as "(S)-bupropion". This type of dosage form may be useful for treating conditions in which an increase in the concentration of (S)-bupropion and / or (R,R)-hydroxybupropion is therapeutically effective, or for conditions in which a person requires treatment with (S)-bupropion and / or (R,R)-hydroxybupropion. Furthermore, for example, an increase in (S)-bupropion concentration or (R,R)-hydroxybupropion concentration by co-administration of (S)-bupropion and dextromethorphan may be useful for increasing bioavailability or increasing the plasma concentration of dextromethorphan. Therefore, co-administration of enantiomer-rich (S)-bupropion or enantiomerically pure (S)-bupropion with dextromethorphan, in the same dosage form or different dosage forms, may be useful for treating conditions that respond to dextromethorphan alone or to a combination of (S)-bupropion and dextromethorphan. However, in some treatments, the combination of dextromethorphan with (S)-bupropion or (R,R)-hydroxybupropion may be undesirable. Therefore, some dosage forms are substantially dextromethorphan-free, and some treatments involve administering (S)-bupropion without co-administration of dextromethorphan.

[0055] Some embodiments are methods for providing a pharmacokinetic equivalent of racemic bupropion to human plasma, comprising selecting a human patient who requires a pharmacokinetic profile obtained by orally administering a reference dosage form containing a first amount of racemic bupropion at a first frequency of administration, and orally administering a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at a first frequency of administration, to achieve the same pharmacokinetic profile achieved by administering the reference dosage form at a first frequency of administration, where the first frequency of administration is once or twice daily, and the second amount is about 20–70%, about 40–60%, about 45–55%, or about 50% of the first amount. For example, if a particular pharmacokinetic profile is achieved by orally administering a dosage form containing 150 mg of racemic bupropion, and the second amount is 40–60% of the first amount, then the second amount is 60–90 mg. Therefore, in this situation, 60-90 mg of (S)-bupropion is administered once daily to achieve a pharmacokinetic profile similar to that achieved by administering 150 mg of racemic bupropion once daily, or 60-90 mg of (S)-bupropion is administered twice daily to achieve a pharmacokinetic profile similar to that achieved by administering 150 mg of racemic bupropion twice daily.

[0056] Some embodiments include a method for treating a condition treatable with racemic bupropion, comprising: selecting a human patient having a condition treatable by oral administration of a reference dosage form containing a first amount of racemic bupropion at a first frequency of administration; and oral administration of a dosage form containing a second amount of (S)-bupropion that is at least 95% enantiomerically pure at a first frequency of administration to achieve the same therapeutic effect as achieved by administering the reference dosage form at a first frequency of administration, wherein the first frequency of administration is once or twice daily, and the second amount is about 40-60%, about 45-55%, or about 50% of the first amount. For example, if a condition is treatable by oral administration of a dosage form containing 150 mg of racemic bupropion, and the second amount is 40-60% of the first amount, then the second amount is 60-90 mg. Therefore, in this situation, the condition is treated by administering 60-90 mg of (S)-bupropion once daily to obtain a similar therapeutic effect to that achieved by administering 150 mg of racemic bupropion once daily, or by administering 60-90 mg of (S)-bupropion twice daily to obtain a similar therapeutic effect to that achieved by administering 150 mg of racemic bupropion twice daily.

[0057] For the purposes of this disclosure, if a dosage form containing enantiomerically pure (S)-bupropion is recognized by the FDA as bioequivalent to a dosage form containing racemic bupropion, the two dosage forms will have similar pharmacokinetic profiles.

[0058] In some embodiments, (S)-bupropion C max , (R)-bupropion C max , (S)-bupropion and (R)-bupropion combined C max , (R,R)-hydroxybupropion C max , (S,S)-hydroxybupropion C max , the combined C of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion max , C of threohydroxybupropion max, C of erythrohydroxybupropion max , (S)-bupropion AUC 0-12 AUC of (R)-bupropion 0-12 The combined AUC of (S)-bupropion and (R)-bupropion. 0-12 AUC of (R,R)-hydroxybupropion 0-12 AUC of (S,S)-hydroxybupropion 0-12 The combined AUC of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion. 0-12 , the AUC of threohydroxybupropion 0-12 , AUC of erythrohydroxybupropion 0-12 or any combination thereof is within 20% of each other. If the value of one dosage form is 1, and the value of the second dosage form is between 0.8 and 1.2, the two dosage forms are considered to be within 20% of each other.

[0059] Some dosage forms contain enantiomer-rich (R)-bupropion or enantiomerically pure (R)-bupropion. For example, (R)-bupropion may have an enantiomer purity of at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.9%, or at least 99.99%, or (nearly) 100%. For convenience, any of the above may be referred to as "(R)-bupropion". This type of dosage form may be useful, for example, in co-administration of (R)-bupropion with dextromethorphan, to increase bioavailability or to increase plasma concentrations of dextromethorphan. Therefore, co-administration of enantiomer-rich (R)-bupropion or enantiomerically pure (R)-bupropion with dextromethorphan, either in a single or separate dosage form, may be useful in treating conditions responsive to dextromethorphan.

[0060] The above dosage forms and methods may be incorporated into methods for reducing adverse events associated with bupropion treatment, methods for increasing plasma concentrations of bupropion, such as increasing the plasma concentration of (S)-bupropion, methods for reducing the amount or frequency of bupropion administration required without loss of efficacy, methods for improving the therapeutic properties of bupropion, methods for reducing the trough effect of bupropion, or other methods.

[0061] The above-described dosage forms and methods relating to dextromethorphan may be incorporated into methods for increasing the plasma concentration of dextromethorphan, increasing the metabolic time of dextromethorphan, reducing adverse events associated with treatment with dextromethorphan, reducing the amount or frequency of administration of dextromethorphan without loss of efficacy, decreasing the plasma concentration of dextromethorphan, improving the therapeutic properties of dextromethorphan, inhibiting the metabolism of dextromethorphan, modifying the high metabolic activity of dextromethorphan, improving the antitussive effect of dextromethorphan, treating cough, reducing the trough effect of dextromethorphan, or other methods.

[0062] Furthermore, the above-described dosage forms and methods can be applied to neurological disorders, central nervous system disorders, psychiatric disorders, neuropsychiatric disorders, and related conditions.

[0063] Administration of enantiomerically enriched (S)-bupropion, enantiomerically enriched (R)-bupropion, and / or dextromethorphan, as described above or elsewhere in this disclosure, may be once or more times daily, for example by oral administration, or over multiple days, such as several consecutive days. For example, enantiomerically enriched (S)-bupropion may be administered alone or in combination with dextromethorphan once or twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days. Alternatively, enantiomerically concentrated (R)-bupropion may be administered alone or in combination with dextromethorphan once or twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days. Patients may fast before and / or after oral administration of dosage forms containing (S)-bupropion or (R)-bupropion and / or dextromethorphan.

[0064] In some embodiments, the above treatment may include administering a dosage form containing (R)-bupropion or (S)-bupropion, alone or in combination with dextromethorphan, once daily for 1, 2, 3, 4, 5, 6, or 7 days, followed by twice-daily treatment. For example, a dosage form containing (R)-bupropion or (S)-bupropion may be administered once daily on days 1, 2, and 3, then twice daily from day 4, and then twice daily for a longer period, such as 2, 3, 4, 5, 6, 7, 8, 9-13, 14, 15-20, 21, 22-27, 28, 29, 30, 31, 32-59, 60, 61-89, 90, or more consecutive days, or for the remainder of the treatment period. Starting with once-daily administration for a short period and then increasing the frequency to twice daily may be useful in reducing the risk of seizures.

[0065] (S)-bupropion has the following structure. [ka]

[0066] Unless otherwise stated, compounds described herein by structure, name, or by other means, such as (S)-bupropione, (R)-bupropione, or dextromethorphan, include pharmaceutically acceptable salts, polymorphs, crystals, solvates, hydrates, or other solid forms, tautomers, deuterium-modified compounds such as deuterium-modified dextromethorphan, or any chemical species that can be rapidly converted to the compounds described herein under the conditions of use as described herein.

[0067] For dosage forms containing enantiomer excess (S)-bupropion, an appropriate amount of (S)-bupropion may be used. In some embodiments, the dosage form may include at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, about 4-90 mg, about 50-100 mg, about 50-150 mg, about 70-95 mg, about 50-70 mg, about 60-80 mg, about 60-90 mg, about 70-80 mg, about 70-74 mg, about 72-76 mg, about 74-76 mg, about 74-78 mg, about 70-90 mg, about 90-110 mg, about 90-120 mg, about 100-200 mg, about 100-140 mg, about 140-160 mg, about 160-200 mg, and about 104-106 mg. g contains approximately 100-110 mg, approximately 110-120 mg, approximately 120-130 mg, approximately 130-140 mg, approximately 140-150 mg, approximately 145-155 mg, approximately 148-152 mg, approximately 150-200 mg, approximately 200-400 mg, approximately 250-350 mg, approximately 280-320 mg, approximately 290-310 mg, approximately 200-250 mg, approximately 250-300 mg, approximately 70 mg, approximately 75 mg, approximately 80 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, approximately 150 mg, approximately 10-50 mg, approximately 50-100 mg, approximately 40-90 mg, approximately 70-95 mg, or approximately 50-150 mg of (S)-bupropion, or any amount in the range between these values. In particular, if the range obtained includes or is close to one or more of the following values ​​for the amount of (S)-bupropion in the dosage form: approximately 50 mg, approximately 60 mg, approximately 75 mg, approximately 90 mg, approximately 105 mg, or approximately 150 mg, then a range of amounts of (S)-Bu obtained by combining either the above ranges or the terminal values ​​is also possible. These are values ​​that are considered to have potentially specific utility. Dosage forms containing the above amounts of (S)-bupropion may be administered once, twice, or three times daily, i.e., one, two, or three times any of the above doses or dose ranges, for example, 180-240 mg per day, which is twice 90-120 mg, or 270-360 mg per day, which is three times 90-120 mg.In particular, if the resulting range includes or is close to one or more of the following values: approximately 150 mg, approximately 210 mg, or approximately 250 mg, then any combination of the above dosage ranges or terminal values, and the resulting daily dose obtained by multiplying the result by 1, 2, or 3, are also possible. These are values ​​that are considered to have potentially specific utility.

[0068] Some of the solid compositions may contain, by weight, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, about 10-30%, about 30-50%, about 50-80%, about 80-95%, about 10-50%, about 30-70%, or about 50-90% (S)-bupropion.

[0069] In some embodiments, the dosage form may contain, or substantially contain, any active agent or drug other than (S)-bupropion. For example, the dosage form may contain any active agent in amounts of less than 10%, less than 5%, less than 1%, or less than 0.1% by weight relative to the weight of (S)-bupropion. In some embodiments, the dosage form may contain, or may not contain, dextromethorphan in amounts of less than 10%, less than 5%, less than 1%, or less than 0.1% by weight relative to the weight of (S)-bupropion. Alternatively, (S)-bupropion may be combined with other compounds such as dextromethorphan in the dosage form.

[0070] Administration of (S)-bupropion results in plasma concentrations of (R)-bupropion obtained by administering the same amount of (R)-bupropion to the same person by at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, approximately 5 to 20 times, at least approximately 10 times, at least approximately 20 times, at least approximately 50 times, and less It may be useful in increasing the plasma concentration of (S)-bupropion by approximately 100 times, at least approximately 150 times, at least approximately 200 times, or more, approximately 10-15 times, approximately 10-25 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 60-70 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0071] In some embodiments, the method involves administering a dosage form containing the same amount of (R)-bupropion to a human, thereby obtaining the AUC of (R)-bupropion. 0-12 Compared to standard AUC 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of (S)-bupropion such as 0-12to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 8 times, at least approximately 10 times, approximately 10 times, at least approximately 15 times, at least approximately 20 times, at least approximately 25 times, at least approximately 50 times, at least approximately 100 times, and at least It has the effect of increasing by approximately 150 times, at least approximately 200 times or more, approximately 10-15 times, approximately 10-25 times, approximately 5-20 times, approximately 20-30 times, approximately 30-40 times, approximately 40-50 times, approximately 50-60 times, approximately 60-70 times, approximately 70-80 times, approximately 80-90 times, approximately 90-100 times, approximately 100-110 times, approximately 110-120 times, approximately 120-130 times, approximately 130-140 times, approximately 140-150 times, approximately 150-160 times, approximately 160-170 times, approximately 170-180 times, approximately 180-190 times, or approximately 190-200 times.

[0072] In some embodiments, the method allows for the use of standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC values ​​for (S)-bupropion, or combinations of (S)-bupropion and (R)-bupropion, such as the above. 0-12This includes at least approximately 300 ng·hr / mL, at least approximately 400 ng·hr / mL, at least approximately 500 ng·hr / mL, at least approximately 600 ng·hr / mL, at least approximately 700 ng·hr / mL, at least approximately 750 ng·hr / mL, at least approximately 800 ng·hr / mL, at least approximately 850 ng·hr / mL, at least approximately 900 ng·hr / mL, at least approximately 950 ng·hr / mL, at least approximately 1,000 ng·hr / mL, and less Both approximately 1,100 ng·hr / mL, at least approximately 1,200 ng·hr / mL, ~ approximately 1,200 ng·hr / mL, ~ approximately 1,300 ng·hr / mL, ~ approximately 1,400 ng·hr / mL, ~ approximately 1,500 ng·hr / mL, ~ approximately 1,600 ng·hr / mL, ~ approximately 1,700 ng·hr / mL, ~ approximately 1,800 ng·hr / mL, approximately 300~400 ng·hr / mL, approximately 400~500 ng·hr / mL, approximately 500~600 ng·hr / mL, approximately 600~ 700ng·hr / mL, approximately 700–800ng·hr / mL, approximately 800–900ng·hr / mL, approximately 900–1,000ng·hr / mL, approximately 1,000–1,100ng·hr / mL, approximately 1,100–1,200ng·h r / mL, approximately 1,200~1,300ng hr / mL, approximately 1,300~1,400ng hr / mL, approximately 1,400~1,500ng hr / mL, approximately 1,500~1,600ng hr / mL, approximately 1,600~1,700ng The ranges are approximately 1,700-1,800 ng·hr / mL, approximately 300-600 ng·hr / mL, approximately 600-900 ng·hr / mL, approximately 900-1,200 ng·hr / mL, approximately 1,200-1,500 ng·hr / mL, approximately 1,500-1,800 ng·hr / mL, approximately 300-800 ng·hr / mL, approximately 800-1,300 ng·hr / mL, approximately 1,300-1,800 ng·hr / mL, or approximately 300-1,800 ng·hr / mL. In particular, the range obtained is AUC. 0-12 The AUC obtained by combining any of the following values: 350 ng·hr / mL, 400 ng·hr / mL, 750 ng·hr / mL, 900 ng·hr / mL, 1,150 ng·hr / mL, or 1,400 ng·hr / mL, or if it includes or is close to one of these values, is calculated using either the above range or the end values.0-12 Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The range of AUC to be considered may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or thereafter.

[0073] In some embodiments, compared to administering a dosage form containing the same amount of (R)-bupropion to humans, standard C max , average C max , middle C max , or individual C max C such as (S)-bupropion max to at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 8 times, approximately 5 to 20 times, at least approximately 10 times, approximately 10 times, at least approximately 20 times, at least approximately 25 times, at least approximately 50 times, at least approximately 100 times, less It has the effect of increasing by at least 150 times, at least 200 times or more, about 10-15 times, about 10-25 times, about 5-20 times, about 20-30 times, about 30-40 times, about 40-50 times, about 50-60 times, about 70-80 times, about 80-90 times, about 90-100 times, about 100-110 times, about 110-120 times, about 120-130 times, about 130-140 times, about 140-150 times, about 150-160 times, about 160-170 times, about 170-180 times, about 180-190 times, or about 190-200 times.

[0074] In some embodiments, by method, the standard C max , average C max , middle C max , or individual C max C such as (S)-bupropion, or a combination of (S)-bupropion and (R)-bupropion. maxThis includes at least approximately 30 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, at least approximately 95 ng / mL, at least approximately 100 ng / mL, at least approximately 105 ng / mL, at least approximately 110 ng / mL, at least approximately 115 ng / mL, at least approximately 120 ng / mL, at least approximately 125 ng / mL, and less than At least about 130 ng / mL, at least about 140 ng / mL, ~ about 130 ng / mL, ~ about 140 ng / mL, ~ about 150 ng / mL, ~ about 160 ng / mL, ~ about 170 ng / mL, ~ about 180 ng / mL, ~ about 190 ng / mL, ~ about 200 ng / mL, ~ about 210 ng / mL, ~ about 220 ng / mL, about 30~40 ng / mL, about 40~50 ng / mL, about 50~60 ng / mL, about 60~70 ng / mL, about 70~80 ng / mL g / mL, approx. 80~90ng / mL, approx. 90~100ng / mL, approx. 100~110ng / mL, approx. 110~120ng / mL, approx. 120~130ng / mL, approx. 130~140ng / mL, approx. 140~150ng / mL, approx. 150~160ng / mL, approx. 160~170ng / mL, approx. 170~180ng / mL, approx. 180~190ng / mL, approx. 190~200ng / mL, approx. 200~210ng / mL, approx. 210~220n The resulting ranges are approximately g / mL, 50-70 ng / mL, 70-90 ng / mL, 30-60 ng / mL, 60-90 ng / mL, 90-120 ng / mL, 120-160 ng / mL, 160-220 ng / mL, 30-90 ng / mL, 90-150 ng / mL, 150-220 ng / mL, 30-110 ng / mL, 130-190 ng / mL, 110-220 ng / mL, or 30-220 ng / mL. In particular, the range obtained is C max The following values ​​for C: include one or more of the following values: 45 ng / mL, 90 ng / mL, 130 ng / mL, 160 ng / mL, or 190 ng / mL, or if close to these, a combination of either the above range or the end values. max Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The target C maxThe range may be seen on the 1st day, 2nd day, 3rd day, 4th day, 5th day, 6th day, 7th day, 8th day, or thereafter.

[0075] In some embodiments, the C of (S)-bupropion, such as standard C min , average C min , median C min , or individual C min etc., is increased by at least about 1.1-fold, at least about 1.2-fold, at least about 1.3-fold, at least about 1.4-fold, at least about 1.5-fold, at least about 1.6-fold, at least about 1.7-fold, at least about 1.8-fold, at least about 1.9-fold, at least about 2-fold, at least about 2.5-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 8-fold, at least about 10-fold, at least about 20-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, about 10 - 15-fold, about 10 - 25-fold, about 5 - 20-fold, about 20 - 30-fold, about 30 - 40-fold, about 40 - 50-fold, about 50 - 60-fold, about 七十-八十倍, about 80 - 90-fold, about 90 - 100-fold, about 100 - 110-fold, about 110 - 120-fold, about 120 - 130-fold, about 130 - 140-fold, about 140 - 150-fold, about 150 - 160-fold, about 160 - 170-fold, about 170 - 180-fold, about 180 - 190-fold, or about 190 - 200-fold, as compared to the case of administering a dosage form containing the same amount of (R)-bupropion to a human.

[0076] In some embodiments, by the method, the C of (S)-bupropion, such as standard C min , average C min , median C min , or individual C min etc., of min It should be noted that in the original text, "七十-八十倍" is likely a typo and should be something like "about 70 - 80-fold" in English. I've translated it as "about 七十-八十倍" for now to show the original text's inaccuracy. You may want to correct that in the source material.​The resulting range is at least about 20 ng / mL, at least about 25 ng / mL, at least about 30 ng / mL, at least about 35 ng / mL, at least about 40 ng / mL, about 20-60 ng / mL, about 25-30 ng / mL, about 30-35 ng / mL, about 35-40 ng / mL, about 30-40 ng / mL, about 40-45 ng / mL, about 45-50 ng / mL, about 30-50 ng / mL, about 40-50 ng / mL, or about 50-60 ng / mL. In particular, the range obtained is C min The following values ​​for C: include one or more of the following values: 20 ng / mL, 30 ng / mL, 40 ng / mL, or 50 ng / mL, or if close to these, a combination of either the above range or the terminal values. min Ranges can also be considered. These are values ​​that are thought to have a potentially specific utility.

[0077] Administration of (S)-bupropion is at least about 1.1 times, at least about 1.5 times, at least about 2 times, at least about 3 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 40 times, at least about 50 times, at least about 100 times, at least about 150 times, at least about 200 times, or more, about 5-10 times, about 5-25 times, compared to administration of a dosage form containing the same amount of (R)-bupropion to humans. It may be useful for increasing the plasma concentration of (R,R)-hydroxybupropion by a factor of 1, 5-20, 20-30, 30-40, 40-50, 50-60, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, or 190-200.

[0078] The administration of (S)-bupropion increases the standard AUC, the mean AUC, the central AUC, or the individual AUC of (R,R)-hydroxybupropion, such as 0-12 , 0-12 , 0-12 , or 0-12 , by at least about 1.1-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, at least about 5-fold, at least about 6-fold, at least about 10-fold, at least about 15-fold, at least about 20-fold, at least about 40-fold, at least about 50-fold, at least about 100-fold, at least about 150-fold, at least about 200-fold, or more, or by about 5-10-fold, about 5-25-fold, about 5-20-fold, about 20-30-fold, about 30-40-fold, about 40-50-fold, about 50-60-fold, about 70-80-fold, about 80-90-fold, about 90-100-fold, about 100-110-fold, about 110-120-fold, about 120-130-fold, about 130-140-fold, about 140-150-fold, about 150-160-fold, about 160-170-fold, about 170-180-fold, or about 190-200-fold, compared to the administration to humans of a dosage form containing the same amount of (R)-bupropion. 0-12 the mean AUC 0-12 the central AUC 0-12 or the individual AUC 0-12 such as the AUC of (R,R)-hydroxybupropion 0-12 may be useful for increasing.

[0079] In some embodiments, the method increases the AUC of (R,R)-hydroxybupropion, or the combined AUC of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion, such as the standard AUC 0-12 , the mean AUC 0-12 , the central AUC 0-12 , or the individual AUC 0-12 . 0-12 the mean AUC 0-12 the central AUC 0-12 or the individual AUC 0-12 such as the AUC of (R,R)-hydroxybupropion, or the combined AUC of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion 0-12This includes at least approximately 1,000 ng·hr / mL, at least approximately 3,000 ng·hr / mL, at least approximately 4,000 ng·hr / mL, at least approximately 6,000 ng·hr / mL, at least approximately 7,000 ng·hr / mL, at least approximately 7,500 ng·hr / mL, at least approximately 8,000 ng·hr / mL, at least approximately 8,500 ng·hr / mL, and at least approximately 9,000 ng· hr / mL, at least about 9,500 ng·hr / mL, at least about 10,000 ng·hr / mL, at least about 12,000 ng·hr / mL, at least about 13,000 ng·hr / mL, about 4,000-6,000 ng·hr / mL, about 6,000-8,000 ng·hr / mL, about 8,000-10,000 ng·hr / mL, about 10,000-12,000 ng·hr / mL, Approximately 12,000~14,000ng·hr / mL, Approximately 14,000~16,000ng·hr / mL, Approximately 16,000~18,000ng·hr / mL, Approximately 18,000~20,000ng·hr / mL, approximately 20,000~22,000ng·hr / mL, approximately 22,000~24,000ng·hr / mL, approximately 4,000~10,000ng·hr / mL, approximately 10,000~16,000ng The ranges are approximately 16,000-24,000 ng·hr / mL, approximately 4,000-24,000 ng·hr / mL, approximately 14,000 ng·hr / mL, approximately 16,000 ng·hr / mL, approximately 18,000 ng·hr / mL, approximately 20,000 ng·hr / mL, approximately 22,000 ng·hr / mL, approximately 24,000 ng·hr / mL, or approximately 30,000 ng·hr / mL. In particular, the range obtained is AUC. 0-12 The AUC obtained by combining any of the following values: 4,000 ng·hr / mL, 5,000 ng·hr / mL, 10,000 ng·hr / mL, 13,400 ng·hr / mL, 16,000 ng·hr / mL, or 22,000 ng·hr / mL, or any of the ranges or end values ​​above, if it includes or is close to one of these values. 0-12Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The range of AUC to be considered may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or thereafter.

[0080] Administration of (S)-bupropion is at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, about 6 times, at least approximately 10 times, at least approximately 20 times, and at least approximately 5 times compared to administration of a dosage form containing the same amount of (R)-bupropion to humans. 0x, at least about 100x, at least about 150x, at least about 200x, or more, about 5-10x, about 10-20x, about 5-20x, about 20-30x, about 30-40x, about 40-50x, about 50-60x, about 70-80x, about 80-90x, about 90-100x, about 100-110x, about 110-120x, about 120-130x, about 130-140x, about 140-150x, about 150-160x, about 160-170x, about 170-180x, about 180-190x, or about 190-200x, Standard C max , average C max , middle C max , or individual C max C of (R,R)-hydroxybupropion, such as max It may be useful in increasing [something].

[0081] In some embodiments, by method, the standard C max , average C max , middle C max , or individual C max C such as (R,R)-hydroxybupropion, or a combination of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion. maxThis includes at least about 90 ng / mL, at least about 150 ng / mL, at least about 200, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, at least about 900 ng / mL, at least about 1,000 ng / mL, at least about 1,100 ng / mL, and at least about 1 ,200ng / mL, at least about 1,300ng / mL, ~about 1,400ng / mL, ~about 1,500ng / mL, ~about 1,600ng / mL, ~about 1,700ng / mL, ~about 1,800ng / mL, ~about 1,900ng / mL, ~about 2,000ng / mL, ~about 2,100ng / mL, ~about 2,200ng / mL, ~about 2,300ng / mL, about 300~400ng / mL, about 400~500ng / mL, about 5 00~600ng / mL, approx. 600~700ng / mL, approx. 700~800ng / mL, approx. 800~900ng / mL, approx. 900~1,000ng / mL, approx. 1,000~1,100ng / mL, approx. 1,10 0~1,200ng / mL, approx. 1,200~1,300ng / mL, approx. 1,300~1,400ng / mL, approx. 1,400~1,500ng / mL, approx. 1,500~1,600ng / mL, approx. 1,600~1, The ranges obtained are approximately 700 ng / mL, 1,700-1,800 ng / mL, 1,800-1,900 ng / mL, 1,900-2,000 ng / mL, 2,000-2,100 ng / mL, 2,100-2,200 ng / mL, 2,200-2,300 ng / mL, 300-800 ng / mL, 800-1,300 ng / mL, 1,300-2,300 ng / mL, or 300-2,300 ng / mL. In particular, the range obtained is C max The following values ​​for C include one or more of the following values: 400 ng / mL, 950 ng / mL, 1,100 ng / mL, 1,250 ng / mL, 1,400 ng / mL, or 2,100 ng / mL, or if close to these, a combination of either the above range or the terminal values. max Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The target C maxThe period may include days 1, 2, 3, 4, 5, 6, 7, 8, or later.

[0082] Administration of (S)-bupropion is at least approximately 1.1 times, at least approximately 1.2 times, at least approximately 1.3 times, at least approximately 1.4 times, at least approximately 1.5 times, at least approximately 1.6 times, at least approximately 1.7 times, at least approximately 1.8 times, at least approximately 1.9 times, at least approximately 2 times, at least approximately 2.5 times, at least approximately 3 times, at least approximately 4 times, at least approximately 5 times, at least approximately 10 times, at least approximately 20 times, at least approximately 50 times, and at least approximately 6 times compared to administration of a dosage form containing the same amount of (R)-bupropion to humans. 0x, at least about 100x, at least about 150x, at least about 200x, or more, about 1-5x, about 5-10x, about 5-20x, about 20-30x, about 30-40x, about 40-50x, about 50-60x, about 60-70x, about 70-80x, about 80-90x, about 90-100x, about 100-110x, about 110-120x, about 120-130x, about 130-140x, about 140-150x, about 150-160x, about 160-170x, about 170-180x, about 180-190x, or about 190-200x, Standard C min , average C min , middle C min , or individual C min C of (R,R)-hydroxybupropion, such as min It may be useful in increasing [something].

[0083] In some embodiments, by method, the standard C min , average C min , middle C min , or individual C min C of (R,R)-hydroxybupropion, such as minThis includes at least approximately 150 ng / mL, at least approximately 200 ng / mL, at least approximately 300 ng / mL, at least approximately 400 ng / mL, at least approximately 500 ng / mL, at least approximately 600 ng / mL, at least approximately 700 ng / mL, at least approximately 800 ng / mL, at least approximately 900 ng / mL, at least approximately 1,000 ng / mL, at least approximately 1,100 ng / mL, at least approximately 1,200 ng / mL, ~approximately 1,300 ng / mL, ~approximately 1,400 ng / mL, ~approximately 1,500 ng / mL, ~approximately 1,600 ng / mL, ~approximately 1,700 ng / mL, ~approximately 1,800 ng / mL, ~approximately 1,900 ng / mL, ~approximately 2,000 ng / mL, ~approximately 2,100 ng / mL, ~approximately 2,200 ng / mL 0ng / mL, ~2,300ng / mL, approximately 200~300ng / mL, approximately 300~400ng / mL, approximately 400~500ng / mL, approximately 500~600ng / mL, approximately 6 00~700ng / mL, approx. 700~800ng / mL, approx. 800~900ng / mL, approx. 900~1,000ng / mL, approx. 1,000~1,100ng / mL, approx. 1,1 The ranges obtained are approximately 00-1,200 ng / mL, approximately 1,200-1,300 ng / mL, approximately 1,300-1,400 ng / mL, approximately 1,400-1,500 ng / mL, approximately 1,500-1,600 ng / mL, approximately 300-700 ng / mL, approximately 700-1,100 ng / mL, approximately 1,100-1,600 ng / mL, or approximately 800-1,200 ng / mL. In particular, the range obtained is C min The following values ​​for C include one or more of the following values: 350 ng / mL, 600 ng / mL, 800 ng / mL, 1,000 ng / mL, 1,200 ng / mL, or 1,400 ng / mL, or if close to these values, a combination of either the above ranges or the end values ​​obtained. min Ranges can also be considered. These are values ​​that are thought to have a potentially specific utility.

[0084] Administration of (S)-bupropion to a human may result in (R,R)-hydroxybupropion accounting for at least 90%, at least 95%, at least 97%, at least 97.2%, at least 97.4%, at least 97.6%, at least 97.8%, or at least 98% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human plasma.

[0085] In some embodiments, the method allows for the use of standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of erythrohydroxybupropion, such as 0-12This includes at least approximately 500 ng·hr / mL, at least approximately 600 ng·hr / mL, at least approximately 800 ng·hr / mL, at least approximately 1,000 ng·hr / mL, at least approximately 1,200 ng·hr / mL, at least approximately 1,400 ng·hr / mL, at least approximately 1,500 ng·hr / mL, at least approximately 1,600 ng·hr / mL, at least approximately 1,800 ng·hr / mL, at least approximately 2,000 ng·hr / mL, and ~approximately 2,6 00ng·hr / mL, ~about 2,800ng·hr / mL, ~about 3,000ng·hr / mL, about 500–600ng·hr / mL, about 600–800ng·hr / mL, about 800–1,000ng·hr / mL, about 1, 000~1,200ng·hr / mL, approximately 1,200~1,400ng·hr / mL, approximately 1,400~1,600ng·hr / mL, approximately 1,600~1,800ng·hr / mL, approximately 1,800~2,000ng·hr / mL, approx. 2,000~2,200ng hr / mL, approx. 2,200~2,400ng hr / mL, approx. 2,400~2,600ng hr / mL, approx. 2,600~2,800ng hr / mL, approx. 2,800~3,000 The ranges obtained are approximately ng·hr / mL, 500-1,000 ng·hr / mL, 1,000-1,500 ng·hr / mL, 1,500-2,000 ng·hr / mL, 2,000-2,500 ng·hr / mL, 2,500-3,000 ng·hr / mL, 500-1,500 ng·hr / mL, 1,500-3,000 ng·hr / mL, 2,000-3,000 ng·hr / mL, or approximately 500-3,000 ng·hr / mL. In particular, the range obtained is AUC. 0-12 The AUC obtained by combining any of the following values: 500 ng·hr / mL, 1,300 ng·hr / mL, 1,500 ng·hr / mL, 1,800 ng·hr / mL, or 2,600 ng·hr / mL, or any of the ranges or end values ​​above, if it includes or is close to one of these values. 0-12Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The range of AUC to be considered may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or thereafter.

[0086] In some embodiments, by method, the standard C max , average C max , middle C max , or individual C max C of erythrohydroxybupropion, such as max This includes at least about 40 ng / mL, at least about 60 ng / mL, at least about 80 ng / mL, at least about 90 ng / mL, at least about 100 ng / mL, at least about 120 ng / mL, at least about 140 ng / mL, at least about 160 ng / mL, at least about 180 ng / mL, at least about 200 ng / mL, ~ about 160 ng / mL, ~ about 180 ng / mL, ~ about 200 ng / mL, ~ about 220 ng / mL, ~ about 240 ng / mL, ~ about 260 ng / mL, ~ about 280 ng / mL, about 40~60 ng / mL, about 60~80 ng / mL, about 80~100 ng / mL, and about 10 0~12 The resulting ranges are 0 ng / mL, approximately 120-140 ng / mL, approximately 140-160 ng / mL, approximately 160-180 ng / mL, approximately 180-200 ng / mL, approximately 200-220 ng / mL, approximately 220-240 ng / mL, approximately 240-260 ng / mL, approximately 260-280 ng / mL, approximately 280-300 ng / mL, approximately 40-100 ng / mL, approximately 100-150 ng / mL, approximately 150-200 ng / mL, approximately 200-250 ng / mL, approximately 250-280 ng / mL, approximately 40-120 ng / mL, approximately 120-200 ng / mL, approximately 200-280 ng / mL, or approximately 40-280 ng / mL. In particular, the range obtained is C max The following values ​​for C: include one or more of the following values: 60 ng / mL, 120 ng / mL, 130 ng / mL, 200 ng / mL, or 240 ng / mL, or if close to these, a combination of either the above range or the end values ​​obtained. maxRanges can also be considered. These are values ​​that are considered to have a potentially specific utility. The target C max The period may include days 1, 2, 3, 4, 5, 6, 7, 8, or later.

[0087] In some embodiments, the method allows for the use of standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of threohydroxybupropion, such as 0-12This includes at least 1,000 ng·hr / mL, at least about 2,000 ng·hr / mL, at least about 3,000 ng·hr / mL, at least about 4,000 ng·hr / mL, at least about 5,000 ng·hr / mL, at least about 6,000 ng·hr / mL, at least about 7,000 ng·hr / mL, at least about 8,000 ng·hr / mL, ~about 8,000 ng·hr / mL, ~about 9,000ng·hr / mL, ~about 10,000ng·hr / mL, ~about 11,000ng·hr / mL, ~about 12,000ng·hr / mL, ~about 13,000ng·hr / mL, ~about 14,00 0ng·hr / mL, ~about 15,000ng·hr / mL, about 2,000–15,000ng·hr / mL, about 2,000–3,000ng·hr / mL, about 3,000–4,000ng·hr / mL , approx. 4,000~5,000ng hr / mL, approx. 5,000~6,000ng hr / mL, approx. 6,000~7,000ng hr / mL, approx. 7,000~8,000ng hr / mL, approx. 8,0 00~9,000ng·hr / mL, approximately 9,000~10,000ng·hr / mL, approximately 10,000~11,000ng·hr / mL, approximately 11,000~12,000ng·hr / mL, approximately 12,0 The ranges obtained are approximately 0-13,000 ng·hr / mL, approximately 13,000-14,000 ng·hr / mL, approximately 14,000-15,000 ng·hr / mL, approximately 2,000-6,000 ng·hr / mL, approximately 6,000-10,000 ng·hr / mL, approximately 10,000-15,000 ng·hr / mL, approximately 2,000-9,000 ng·hr / mL, or approximately 9,000-15,000 ng·hr / mL. In particular, the range obtained is AUC. 0-12 The AUC obtained by combining any of the above ranges or end values ​​is if it includes or is close to one or more of the following values: 3,000 ng·hr / mL, 6,000 ng·hr / mL, 8,000 ng·hr / mL, or 12,000 ng·hr / mL. 0-12 Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The range of AUC to be considered may be observed on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, or thereafter.

[0088] In some embodiments, by method, the standard C max , average C max , middle C max , or individual C max C of threohydroxybupropion, such as max This includes at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 450 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, ~800 ng / mL, ~900 ng / mL, ~1,000 ng / mL, ~1,100 ng / mL, ~1,200 ng / mL, ~1,300 ng / mL, ~1,400 ng / mL, about 200~300 ng / mL, about 300~400 ng / mL, about 400~500 ng / mL, and about 500~600 ng / mL. The ranges obtained are approximately g / mL, 600-700 ng / mL, 700-800 ng / mL, 800-900 ng / mL, 900-1000 ng / mL, 1,000-1,100 ng / mL, 1,100-1,200 ng / mL, 1,200-1,300 ng / mL, 1,300-1,400 ng / mL, 200-500 ng / mL, 500-800 ng / mL, 800-1,100 ng / mL, 1,100-1,400 ng / mL, 200-800 ng / mL, 800-1400 ng / mL, 400-600 ng / mL, or 200-1,400 ng / mL. In particular, the range obtained is C max The following values ​​for C: include one or more of the following values: 300 ng / mL, 500 ng / mL, 600 ng / mL, 900 ng / mL, or 1,200 ng / mL, or if close to these, a combination of either the above range or the end values. max Ranges can also be considered. These are values ​​that are considered to have a potentially specific utility. The target C max The period may include days 1, 2, 3, 4, 5, 6, 7, 8, or later.

[0089] (R)-bupropion has the following structure. [ka]

[0090] For dosage forms containing enantiomer excess (R)-bupropion, an appropriate amount of (R)-bupropion may be used. In some embodiments, the dosage form may contain at least about 80 mg, at least about 90 mg, at least about 100 mg, about 90-110 mg, about 100-200 mg, about 100-150 mg, about 100-140 mg, about 140-160 mg, about 160-200 mg, about 104-106 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 1 The dosage form contains 40–150 mg, approximately 145–155 mg, approximately 148–152 mg, approximately 150–200 mg, approximately 200–400 mg, approximately 250–350 mg, approximately 280–320 mg, approximately 290–310 mg, approximately 200–250 mg, approximately 250–300 mg, approximately 100 mg, approximately 105 mg, approximately 110 mg, or approximately 150 mg of (R)-bupropion, or any amount within the range between these values. Such dosage forms may be administered together with dextromethorphan, which may be administered in a different dosage form from (R)-bupropion or in the same dosage form. The dosage form containing the above amounts of (R)-bupropion may be administered once, twice, or three times daily at a daily dose that is one, two, or three times the above-mentioned dose or dose range.

[0091] In some embodiments, the dosage form may contain, or substantially contain, any active agent or drug other than (R)-bupropion and / or dextromethorphan. For example, the dosage form may contain any active agent in an amount of less than 10%, less than 5%, less than 1%, or less than 0.1% by weight relative to the combined weight of (R)-bupropion and dextromethorphan.

[0092] Some of the solid compositions 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%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), and about 30% (w / w) to about 50% It may contain %(w / w), approximately 30%(w / w) to approximately 40%(w / w), approximately 40%(w / w) to approximately 50%(w / w), approximately 50%(w / w) to approximately 80%(w / w), approximately 50%(w / w) to approximately 60%(w / w), approximately 60%(w / w) to approximately 70%(w / w), approximately 70%(w / w) to approximately 80%(w / w), or approximately 80%(w / w) to approximately 90%(w / w) of (R)-bupropion.

[0093] As described above, depending on the specific treatment needs, dosage forms containing enantiomer-rich (S)-bupropion or enantiomer-rich (R)-bupropion may be administered with dextromethorphan, or may contain dextromethorphan.

[0094] Dextromethorphan has the following structure. [ka]

[0095] Unless otherwise stated, compounds described herein by structure, name, or by other means, such as (S)-bupropione, (R)-bupropione, and / or dextromethorphan, include pharmaceutically acceptable salts, polymorphs, crystals, solvates, hydrates, other solid forms, tautomers, deuterium-modified compounds such as deuterium-modified dextromethorphan, or any chemical species that can be rapidly converted to the compounds described herein under the conditions of use as described herein.

[0096] Dextromethorphan may be deuterium-enriched or may be in its natural isotopic abundance.

[0097] Dextromethorphan is used as a cough suppressant. According to the FDA's labeling requirements for dextromethorphan products based on the OTC monograph [21CFR341.74], dextromethorphan should be administered six times a day (every four hours), four times a day (every six hours), or three times a day (every eight hours).

[0098] Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism can limit systemic drug exposure in individuals with high metabolic activity. Humans can be categorized into three groups: 1) those with high dextromethorphan metabolic activity—those who rapidly metabolize dextromethorphan; 2) those with low dextromethorphan metabolic activity—those who cannot adequately metabolize dextromethorphan; and 3) those with intermediate dextromethorphan metabolic activity—those whose dextromethorphan metabolism falls somewhere between the high and low metabolic activity groups. The high metabolic activity group may also be the ultrarapid metabolism group. Those with high dextromethorphan metabolic activity constitute the majority of the human population. Dextromethorphan (DM) can be metabolized to, for example, dextroorphan (DX). The DM / DX ratio is often used to express the degree of dextromethorphan metabolism. A lower DM / DX ratio indicates a higher degree of dextromethorphan metabolism. Individuals with a DM / DX ratio of less than 0.3 are generally considered to have a phenotype of high metabolic activity.

[0099] When the same dose of oral dextromethorphan is administered, plasma concentrations of dextromethorphan are significantly higher in groups with low or intermediate metabolic activity compared to groups with high metabolic activity. Low plasma concentrations of dextromethorphan may limit the clinical utility of dextromethorphan as a monotherapy for groups with high and possibly intermediate metabolic activity. Several therapeutically active compounds, including antidepressants such as (S)-bupropion or (R)-bupropion, can inhibit the metabolism of dextromethorphan, increasing plasma concentrations and thus improving therapeutic effects. Similarly, (S)-bupropion or (R)-bupropion can reduce the frequency of dextromethorphan administration without compromising therapeutic efficacy, such as reducing it from twice daily to once daily, three times daily to once daily, four times daily to once daily, three times daily to twice daily, and four times daily to twice daily. (S)-bupropion or (R)-bupropion can also reduce the single dose, total dose, or both of the dextromethorphan dose.

[0100] Dosage forms containing dextromethorphan used for this purpose are either administered as an adjunct or combined with (S)-bupropion or (R)-bupropion in a single dosage form, in doses of approximately 1-150 mg, 10-100 mg, 10-50 mg, 20-50 mg, 10-20 mg, 15-25 mg, 20-30 mg, 25-35 mg, 30-40 mg, 35-45 mg, and 30-50 mg. The formulation may contain an appropriate amount of dextromethorphan, such as mg, approximately 40-50 mg, approximately 43-48 mg, approximately 44-46 mg, approximately 50-100 mg, approximately 50-80 mg, approximately 80-100 mg, approximately 85-95 mg, approximately 88-92 mg, approximately 100-150 mg, approximately 30 mg, approximately 45 mg, or approximately 60 mg of dextromethorphan, or any amount of dextromethorphan within the range between these values. Dosage forms containing the above amounts of dextromethorphan may be administered once, twice, or three times daily at a daily dose that is one, two, or three times any of the above doses or dose ranges.

[0101] Some of the solid compositions 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%, about 10% (w / w) to about 30% (w / w), about 10% (w / w) to about 20% (w / w), about 20% (w / w) to about 30% (w / w), and about 30% (w / w) to about 50% It may contain %(w / w), approximately 30%(w / w) to 40%(w / w), approximately 40%(w / w) to 50%(w / w), approximately 50%(w / w) to 80%(w / w), approximately 50%(w / w) to 60%(w / w), approximately 60%(w / w) to 70%(w / w), approximately 70%(w / w) to 80%(w / w), or approximately 80%(w / w) to 90%(w / w) of dextromethorphan.

[0102] (S)-bupropion, (R)-bupropion, and / or dextromethorphan may be combined with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice, for example, as described in Remington's Pharmaceutical Sciences, 2005. The relative ratio of the active ingredient to the carrier can be determined, for example, by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0103] (S)-bupropion, (R)-bupropion, and / or dextromethorphan may be administered to human patients in various forms, such as orally or parenterally, depending on the chosen route of administration. Parenteral administration in this regard includes the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrabursal, transepithelial, including transdermal, ophthalmic, sublingual, oral, topical, including ocular, dermal, ocular, transrectal, and transnasal administration.

[0104] (S)-bupropion, (R)-bupropion, and / or dextromethorphan may be formulated for oral administration, for example, with an inert diluent or with an edible carrier, encapsulated in hard or soft-shell gelatin capsules or tablets, or taken directly into food. For oral therapeutic administration, the active compound may be incorporated into an excipient and used in the form of ingestible tablets, oral tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc.

[0105] Tablets, lozenges, pills, capsules, etc., containing (S)-bupropion, (R)-bupropion, and / or dextromethorphan may contain one or more of the following: binders such as tragacanth gum, acacia, corn starch, and gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, and alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, and saccharin; or flavorings such as peppermint, wintergreen oil, and cherry flavoring. If the dosage form is a capsule, a liquid carrier may be included in addition to the above materials. Various other materials may be present as coatings; for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. Syrups or elixirs may contain the active compound, sucrose as a sweetener, methyl and propylparaben as preservatives, dyes, and flavorings such as cherry or orange flavoring. The materials in the dosage form or pharmaceutical composition should preferably be pharmaceutically pure and substantially nontoxic in the amount used.

[0106] Some compositions or dosage forms may be liquids or may contain a solid phase dispersed in a liquid.

[0107] (S)-bupropion, (R)-bupropion, and / or dextromethorphan may be formulated for parenteral or intraperitoneal administration. Solutions of the active compound as a free base or a pharmaceutically acceptable salt can be prepared by mixing appropriately with a surfactant in water. Dispersions may also have glycerol, liquid polyethylene glycol, and oil dispersed in a mixture thereof. Under normal conditions of storage and use, these preparations may contain preservatives to prevent microbial growth.

[0108] A dosage form or composition containing both (S)-bupropion or (R)-bupropion and dextromethorphan may be a blend or mixture of bupropion and dextromethorphan, either alone or in a solvent. For example, (S)-bupropion or (R)-bupropion and dextromethorphan may be dispersed amongst themselves or together in a solvent. The dispersion may contain a mixture of solid materials in which the individual particles are substantially one compound, but the individual particles are dispersed amongst themselves as can occur when two powders of two different drugs are blended in a solid solvent, and the blending is done in a solid state. In some embodiments, dextromethorphan and (S)-bupropion or (R)-bupropion may be substantially heterogeneously dispersed within the composition or dosage form. Alternatively, dextromethorphan and (S)-bupropion or (R)-bupropion may be present in separate regions or phases within the composition or dosage form. For example, one drug may be located within the coating, while another drug may be located within the core of the coating. For example, one drug may be formulated as a sustained-release agent, while another drug may be formulated as an immediate-release agent.

[0109] Some embodiments involve the administration of tablets containing sustained-release (S)-bupropion or (R)-bupropion and, if present, immediate-release dextromethorphan. While there are many ways in which sustained-release bupropion can be achieved, in some embodiments, (S)-bupropion or (R)-bupropion is combined with hydroxypropyl methylcellulose. For example, particles of (S)-bupropion or (R)-bupropion can be mixed with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., METHOCEL®) to form a blended powder mixture. This can then be combined with immediate-release dextromethorphan into a single tablet.

[0110] By administering a combination of (R)-bupropion and dextromethorphan to a person requiring treatment with dextromethorphan, the concentration of dextromethorphan can be increased compared to the administration of the same amount of (S)-bupropion and the same amount of dextromethorphan. In some embodiments, compared to the administration of the same amount of (S)-bupropion and the same amount of dextromethorphan, the concentration of dextromethorphan can be increased. max , average C max , middle C max , or individual C max Dextromethorphan C max , standard AUC 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12 , standard AUC 0-∞ , average AUC 0-∞ , median AUC 0-∞ , or individual AUC 0-∞ AUC of dextromethorphan such as 0-∞This increases by at least approximately 10%, at least approximately 20%, at least approximately 25%, at least approximately 30%, at least approximately 35%, at least approximately 40%, at least approximately 50%, at least approximately 80%, at least approximately 100%, at least approximately 150%, or at least approximately 200%. This increase is observed on day 1, 2, 3, 4, 5, 6, 7, or 8 of treatment, or thereafter. In some embodiments, this increase is observed on day 1. In some embodiments, this increase is observed on day 8.

[0111] In some embodiments, the combination of (R)-bupropion and dextromethorphan provides a standard AUC 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12For example, from day 1 to 60, the levels are approximately 30-150 ng·hr / mL, approximately 50-100 ng·hr / mL, approximately 80-100 ng·hr / mL, approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, and approximately 500-510 ng· hr / mL, approx. 510~520ng hr / mL, approx. 520~530ng hr / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575~600ng hr / mL, approx. 550~600ng hr / mL, approx. 600~650ng hr / mL, approx. 650~700ng hr / mL , about 700-750ng hr / mL, about 750-800ng hr / mL, about 800-820ng hr / mL, about 820-840ng hr / mL, about 840-850ng hr / mL, about 800~850ng hr / mL, approx. 850~860ng hr / mL, approx. 860~870ng hr / mL, approx. 870~880ng hr / mL, approx. 880~890ng hr / mL, approx. 890 ~900 ng·hr / mL, approximately 850~900 ng·hr / mL, approximately 900~910 ng·hr / mL, approximately 910~930 ng·hr / mL, approximately 930~950 ng·hr / mL, approximately 900~950 ng·hr / mL, approximately 950~1000 ng·hr / mL, approximately 1000 ng·hr / mL~approximately 1300 ng·hr / mL, or any AUC of dextromethorphan in the range between these values. 0-12 This could be the case.

[0112] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On the 5th day, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0113] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 6, the levels were approximately 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, 500-510 ng·hr / mL, 510-520 ng·hr / mL, and 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0114] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 7, the levels were approximately 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, 500-510 ng·hr / mL, 510-520 ng·hr / mL, and 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0115] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On the 8th day, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, approximately 520-530 ng·hr / mL, and approximately 5 30~540ng·hr / mL, approximately 540~560ng·hr / mL, approximately 500~550ng·hr / mL, approximately 550~575ng·hr / mL, approximately 575~600ng·hr / mL, approx. 550~600ng hr / mL, approx. 600~650ng hr / mL, approx. 650~700ng hr / mL, approx. 700~750ng hr / mL, approx. 750~800ng ·hr / mL, approximately 800~820ng·hr / mL, approximately 820~840ng·hr / mL, approximately 840~850ng·hr / mL, approximately 800~850ng·hr / mL, approximately 850~ 860ng·hr / mL, approximately 860~870ng·hr / mL, approximately 870~880ng·hr / mL, approximately 880~890ng·hr / mL, approximately 890~900ng·hr / mL, approximately The AUC of any dextromethorphan in the range of 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, approximately 1000 ng·hr / mL to approximately 1300 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0116] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 9, the levels were approximately 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, 500-510 ng·hr / mL, 510-520 ng·hr / mL, and 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0117] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 10, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng· hr / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 57 5~600ng·hr / mL, approximately 550~600ng·hr / mL, approximately 600~650ng·hr / mL, approximately 650~700ng·hr / mL, approximately 700~750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0118] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 11, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng· hr / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 57 5~600ng·hr / mL, approximately 550~600ng·hr / mL, approximately 600~650ng·hr / mL, approximately 650~700ng·hr / mL, approximately 700~750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0119] In some embodiments, a combination of (R)-bupropion and dextromethorphan is used as standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxFor example, on days 1-60, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 2-20 ng / mL, 5-10 ng / mL, approximately 10-15 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, and approximately 5 0~55ng / mL, approx. 55~58ng / mL, approx. 58~60ng / mL, approx. 55~60ng / mL, approx. 60~65ng / mL, approx. 65~70ng / mL, approx. 70~75 ng / mL, approximately 75~80ng / mL, approximately 80~82ng / mL, approximately 82~84ng / mL, approximately 84~85ng / mL, approximately 80~85ng / mL, approximately 85~86ng / mL Approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, approximately 100-110 ng / mL, or any C in the range between these values. max This could be the case.

[0120] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 5, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0121] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 6, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0122] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 7, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0123] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 8, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, and approximately 55-58 ng / mL. L, approximately 58-60 ng / mL, approximately 55-60 ng / mL, approximately 60-65 ng / mL, approximately 65-70 ng / mL, approximately 70-75 ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, approximately 100-110 ng / mL, or any C in the range between these values. max This could be the case.

[0124] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 9, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0125] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 10, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0126] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (R)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 11, the levels were at least approximately 10 ng / mL, at least approximately 20 ng / mL, at least approximately 30 ng / mL, at least approximately 40 ng / mL, at least approximately 50 ng / mL, at least approximately 60 ng / mL, at least approximately 70 ng / mL, at least approximately 80 ng / mL, at least approximately 90 ng / mL, approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55 ~58 ng / mL, approximately 58~60 ng / mL, approximately 55~60 ng / mL, approximately 60~65 ng / mL, approximately 65~70 ng / mL, approximately 70~75 ng / mL, approximately 75~80 ng / mL, approximately 80~82 ng / mL, approximately 82~84 ng / mL, approximately 84~85 ng / mL, approximately 80~85 ng / mL, approximately 85~86 ng / mL, approximately 86~87 ng / mL, approximately 87~88 ng / mL, approximately 88~89 ng / mL, approximately 89~90 ng / mL, approximately 85~90 ng / mL, approximately 90~91 ng / mL, approximately 91~93 ng / mL, approximately 93~95 ng / mL, approximately 90~95 ng / mL, approximately 95~100 ng / mL, or any range between these values. max This could be the case.

[0127] The dextromethorphan variation index value FI(%) can be calculated using the following equation.

number

[0128] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan daily and approximately 50-150 mg of (R)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 8 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values.

[0129] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan daily and approximately 50-150 mg of (R)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 9 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values.

[0130] In some embodiments, a combination of (R)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan daily and approximately 50-150 mg of (R)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 10 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values.

[0131] Administering a combination of (R)-bupropion and dextromethorphan to a person requiring dextromethorphan therapy can increase the concentration of dextromethorphan compared to administering the same amount of (S)-bupropion and the same amount of dextromethorphan. However, administering the combination of (S)-bupropion and dextromethorphan can increase the plasma concentration of dextromethorphan compared to administering dextromethorphan without (S)-bupropion.

[0132] In some embodiments, administering a combination of R)-bupropion and dextromethorphan to a person requiring treatment with dextromethorphan can increase the concentration of dextromethorphan compared to administering the same amount of racemic bupropion and dextromethorphan combination. In some embodiments, such an increase may be significant or substantial.

[0133] In some embodiments, the combination of (S)-bupropion and dextromethorphan allows for standard AUC 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12For example, from day 1 to 60, the levels are approximately 10-50 ng·hr / mL, 20-40 ng·hr / mL, 30-100 ng·hr / mL, 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, and 500-510 ng ·hr / mL, approx. 510~520ng · hr / mL, approx. 520~530ng · hr / mL, approx. 530~540ng · hr / mL, approx. 540~560ng · hr / mL, approx. 500~550ng · hr / mL, approx. 550~575ng hr / mL, approx. 575~600ng hr / mL, approx. 550~600ng hr / mL, approx. 600~650ng hr / mL, approx. 650~700ng hr / mL, approx. 700~750ng hr / mL, approx. 750~800ng hr / mL, approx. 800~820ng hr / mL, approx. 820~840ng hr / mL, approx. 840~850ng hr / mL, approx. 800~850ng hr / mL, approx. 850~860ng hr / mL, approx. 860~870ng hr / mL, approx. 870~880ng hr / mL, approx. 880~890ng hr / m AUC of any dextromethorphan in the range of L, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, approximately 1000-1100 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0134] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On the 5th day, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0135] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On the sixth day, the AUC of dextromethorphan can be about 400 - 425 ng·hr / mL, about 425 - 450 ng·hr / mL, about 400 - 450 ng·hr / mL, about 450 - 475 ng·hr / mL, about 475 - 500 ng·hr / mL, about 450 - 500 ng·hr / mL, about 500 - 510 ng·hr / mL, about 510 - 520 ng·hr / mL, about 520 - 530 ng·hr / mL, about 530 - 540 ng·hr / mL, about 540 - 560 ng·hr / mL, about 500 - 550 ng·hr / mL, about 550 - 575 ng·hr / mL, about 575 - 600 ng·hr / mL, about 550 - 600 ng·hr / mL, about 600 - 650 ng·hr / mL, about 650 - 700 ng·hr / mL, about 700 - 750 ng·hr / mL, about 750 - 800 ng·hr / mL, about 800 - 820 ng·hr / mL, about 820 - 840 ng·hr / mL, about 840 - 850 ng·hr / mL, about 800 - 850 ng·hr / mL, about 850 - 860 ng·hr / mL, about 860 - 870 ng·hr / mL, about 870 - 880 ng·hr / mL, about 880 - 890 ng·hr / mL, about 890 - 900 ng·hr / mL, about 850 - 900 ng·hr / mL, about 900 - 910 ng·hr / mL, about 910 - 930 ng·hr / mL, about 930 - 950 ng·hr / mL, about 900 - 950 ng·hr / mL, about 950 - 1000 ng·hr / mL, or any range between these values 0-12 can be obtained.

[0136] In some embodiments, the combination of (S)-bupropion and dextromethorphan, such as administration of about 30 - 60 mg of dextromethorphan twice a day and about 50 - 150 mg of (S)-bupropion twice a day, results in the standard AUC 0-12 , the mean AUC 0-12 , the central AUC 0-12 , or the individual AUC 0-12 such as the AUC of dextromethorphan 0-12On day 7, the levels were approximately 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, 500-510 ng·hr / mL, 510-520 ng·hr / mL, and 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0137] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On the 8th day, the AUC of dextromethorphan can be about 400 - 425 ng·hr / mL, about 425 - 450 ng·hr / mL, about 400 - 450 ng·hr / mL, about 450 - 475 ng·hr / mL, about 475 - 500 ng·hr / mL, about 450 - 500 ng·hr / mL, about 500 - 510 ng·hr / mL, about 510 - 520 ng·hr / mL, about 520 - 530 ng·hr / mL, about 530 - 540 ng·hr / mL, about 540 - 560 ng·hr / mL, about 500 - 550 ng·hr / mL, about 550 - 575 ng·hr / mL, about 575 - 600 ng·hr / mL, about 550 - 600 ng·hr / mL, about 600 - 650 ng·hr / mL, about 650 - 700 ng·hr / mL, about 700 - 750 ng·hr / mL, about 750 - 800 ng·hr / mL, about 800 - 820 ng·hr / mL, about 820 - 840 ng·hr / mL, about 840 - 850 ng·hr / mL, about 800 - 850 ng·hr / mL, about 850 - 860 ng·hr / mL, about 860 - 870 ng·hr / mL, about 870 - 880 ng·hr / mL, about 880 - 890 ng·hr / mL, about 890 - 900 ng·hr / mL, about 850 - 900 ng·hr / mL, about 900 - 910 ng·hr / mL, about 910 - 930 ng·hr / mL, about 930 - 950 ng·hr / mL, about 900 - 950 ng·hr / mL, about 950 - 1000 ng·hr / mL, about 1000 - 1100 ng·hr / mL, or any range between these values 0-12 can result.

[0138] In some embodiments, a combination of (S)-bupropion and dextromethorphan, such as administration of about 30 - 60 mg of dextromethorphan twice daily and about 50 - 150 mg of (S)-bupropion twice daily, results in a standard AUC 0-12 , mean AUC 0-12 , central AUC 0-12 , or individual AUC 0-12 such as the AUC of dextromethorphan 0-12On day 9, the levels were approximately 400-425 ng·hr / mL, 425-450 ng·hr / mL, 400-450 ng·hr / mL, 450-475 ng·hr / mL, 475-500 ng·hr / mL, 450-500 ng·hr / mL, 500-510 ng·hr / mL, 510-520 ng·hr / mL, and 520-530 ng·hr / mL. r / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 575 ~600ng·hr / mL, approximately 550–600ng·hr / mL, approximately 600–650ng·hr / mL, approximately 650–700ng·hr / mL, approximately 700–750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0139] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 10, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng· hr / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 57 5~600ng·hr / mL, approximately 550~600ng·hr / mL, approximately 600~650ng·hr / mL, approximately 650~700ng·hr / mL, approximately 700~750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0140] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, results in a standard AUC. 0-12 , average AUC 0-12 , median AUC 0-12 , or individual AUC 0-12 AUC of dextromethorphan such as 0-12On day 11, the levels were approximately 400-425 ng·hr / mL, approximately 425-450 ng·hr / mL, approximately 400-450 ng·hr / mL, approximately 450-475 ng·hr / mL, approximately 475-500 ng·hr / mL, approximately 450-500 ng·hr / mL, approximately 500-510 ng·hr / mL, approximately 510-520 ng·hr / mL, and approximately 520-530 ng· hr / mL, approx. 530~540ng hr / mL, approx. 540~560ng hr / mL, approx. 500~550ng hr / mL, approx. 550~575ng hr / mL, approx. 57 5~600ng·hr / mL, approximately 550~600ng·hr / mL, approximately 600~650ng·hr / mL, approximately 650~700ng·hr / mL, approximately 700~750ng·hr AUC of any dextromethorphan in the range between these values, approximately 750-800 ng·hr / mL, approximately 800-820 ng·hr / mL, approximately 820-840 ng·hr / mL, approximately 840-850 ng·hr / mL, approximately 800-850 ng·hr / mL, approximately 850-860 ng·hr / mL, approximately 860-870 ng·hr / mL, approximately 870-880 ng·hr / mL, approximately 880-890 ng·hr / mL, approximately 890-900 ng·hr / mL, approximately 850-900 ng·hr / mL, approximately 900-910 ng·hr / mL, approximately 910-930 ng·hr / mL, approximately 930-950 ng·hr / mL, approximately 900-950 ng·hr / mL, approximately 950-1000 ng·hr / mL, or any range between these values. 0-12 This could be the case.

[0141] In some embodiments, a combination of (S)-bupropion and dextromethorphan is used as standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxFor example, on days 1-60, the levels are approximately 1-10 ng / mL, 2-5 ng / mL, 5-10 ng / mL, 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, and 65-7 0 ng / mL, approximately 70-75 ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, approximately 100-110 ng / mL, or any C in the range between these values. max This could be the case.

[0142] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn the 5th day, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0143] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 6, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0144] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 7, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0145] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 8, the levels were approximately 40-43 ng / mL, approximately 43-45 ng / mL, approximately 40-45 ng / mL, approximately 45-48 ng / mL, approximately 48-50 ng / mL, approximately 45-50 ng / mL, approximately 50-51 ng / mL, approximately 51-52 ng / mL, approximately 52-53 ng / mL, approximately 53-54 ng / mL, approximately 54-56 ng / mL, approximately 50-55 ng / mL, approximately 55-58 ng / mL, approximately 58-60 ng / mL, approximately 55-60 ng / mL, approximately 60-65 ng / mL, approximately 65-70 ng / mL, approximately 70-75 ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, approximately 100-110 ng / mL, or any range between these values. max This could be the case.

[0146] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 9, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0147] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 10, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0148] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, is used to achieve standard C max , average C max , middle C max , or individual C max Dextromethorphan C maxOn day 11, the levels were approximately 40-43 ng / mL, 43-45 ng / mL, 40-45 ng / mL, 45-48 ng / mL, 48-50 ng / mL, 45-50 ng / mL, 50-51 ng / mL, 51-52 ng / mL, 52-53 ng / mL, 53-54 ng / mL, 54-56 ng / mL, 50-55 ng / mL, 55-58 ng / mL, 58-60 ng / mL, 55-60 ng / mL, 60-65 ng / mL, 65-70 ng / mL, and 70-75 ng / mL. ng / mL, approximately 75-80 ng / mL, approximately 80-82 ng / mL, approximately 82-84 ng / mL, approximately 84-85 ng / mL, approximately 80-85 ng / mL, approximately 85-86 ng / mL, approximately 86-87 ng / mL, approximately 87-88 ng / mL, approximately 88-89 ng / mL, approximately 89-90 ng / mL, approximately 85-90 ng / mL, approximately 90-91 ng / mL, approximately 91-93 ng / mL, approximately 93-95 ng / mL, approximately 90-95 ng / mL, approximately 95-100 ng / mL, or any range between these values. max This could be the case.

[0149] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan twice daily and approximately 50-150 mg of (S)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 8 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values, such as standard FI(%), mean FI(%), median FI(%), or individual FI(%).

[0150] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan daily and approximately 50-150 mg of (S)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 9 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values.

[0151] In some embodiments, a combination of (S)-bupropion and dextromethorphan, for example, administration of approximately 30-60 mg of dextromethorphan daily and approximately 50-150 mg of (S)-bupropion twice daily, can result in a dextromethorphan FI(%) on day 10 being less than 100%, less than 50%, less than 40%, less than 30%, approximately 20-50%, approximately 20-40%, approximately 20-30%, or any FI(%) in the range between these values.

[0152] Examples of neurological or central nervous system disorders that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, affective disorders, psychiatric disorders, brain dysfunction, motor disorders, dementia, motor neuron diseases, neurodegenerative diseases, seizure disorders, and headaches.

[0153] Examples of affective disorders that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, (R,R)-hydroxybupropion, and / or dextromethorphan include, but are not limited to, depression, major depressive disorder, treatment-resistant depression, treatment-resistant bipolar depression, bipolar disorder including cyclothymic disorder, seasonal affective disorder, mood disorders, and chronic depression (dysthymia). This includes psychotic depression, postpartum depression, premenstrual dysphoric disorder (PMDD), situational depression, atypical depression, mania, anxiety disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), attention deficit / hyperactivity disorder (ADHD), bipolar disorder and manic episodes, obsessive-compulsive disorder, bulimia nervosa, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, addiction disorders, drug addiction or abuse, nicotine addiction, psychogenic dysfunction, emotional dysregulation, and emotional instability.

[0154] Depression can manifest as depressive symptoms. These symptoms include psychological changes such as mood swings, intense sadness, feelings of hopelessness, mental sluggishness, difficulty concentrating, pessimistic worry, restlessness, anxiety, irritability, guilt, anger, feelings of worthlessness, reckless behavior, suicidal thoughts or attempts, and / or self-deprecation. Physical symptoms of depression include insomnia, loss of appetite, decreased appetite, weight loss, weight gain, decreased energy and libido, fatigue, restlessness, pain, distress, headaches, seizures, digestive problems, and / or circadian rhythm disturbances of hormones.

[0155] Some patients may have an inadequate or no response to treatment, even after drug therapy such as antidepressants. Treatment-resistant depression (TRD), or treatment-refractory depression, is generally a condition associated with patients who have failed to respond to treatment with at least two different antidepressants. Part of the diagnosis of TRD is that the patient has shown an inadequate response to antidepressant treatment after appropriate doses and a proper course. TRD can be more difficult to treat due to comorbidities such as other medical or psychological disorders, such as drug / alcohol abuse or eating disorders, or due to misdiagnosis of TRD. Some TRD patients have shown an inadequate response to trials of one, two, three, or more appropriate antidepressants, or have shown an inadequate response to one, two, three, or more prior antidepressant treatments. In some embodiments, a patient treated for treatment-resistant depression has failed to respond to treatment with at least one, two, three, four, five, six, seven, eight, nine, ten, or more antidepressants.

[0156] Measures of therapeutic effects that may be improved by increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan include, but are not limited to, the Montgomery-Asberg Depression Rating Scale (MADRS), the Brief Quality of Life Pleasure and Satisfaction Questionnaire, the Range of Functional Impairment Tools, the Sheehan Disorder Scale, the Patient Assessment Inventory for Side Effects (PRISE), the Columbia Suicide Severity Rating Scale (C-SSRS), the Brief Depressive Symptom Scale, Self-Report (QID(S)-SR), the Clinical Global Impression Scale (CGI), the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), the 17-item Hamilton Depression Rating Scale (HAM-D17), and the Massachusetts General Hospital Antidepressant Response Questionnaire (MGH ATRQ), 16-item self-report brief depressive symptom scale (QID(S)-SR16), Sheehan's disorder scale (SDS), Clinical Global Impression Scale for Severity (CGI-S), Impression Assessment of Change with Treatment (CGI-C), EuroQOL 5-point scale (EQ-5D-5L), Patient's Global Impression of Change (PGIC), 7-item Generalized Anxiety Disorder (GAD-7), Global Impression Scale for Improvement (CGI-I), Sheehan's disorder scale (SDS), 16-item self-report brief depressive symptom scale These include the Symptom Scale (QID(S)-SR16), Hamilton Anxiety Scale (HAM-A), Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), CPQF-Cognitive Subscale (items 4-7), Brief Psychiatric Symptom Rating Scale (BPRS), etc., the Digital Substitution Test (DSST), Ray's Auditory Language Learning Scale (RAVLT), Trailmaking Test (TMT), Stroop Color Naming Test (STROOP), Simple Reaction Time (SRT), Choice Reaction Time, etc.

[0157] Patients who may benefit from the treatments described herein include pediatric patients such as those under approximately 18 years of age, approximately 0–5 years, approximately 5–10 years, approximately 10–12 years, or approximately 12–18 years; adult patients such as those approximately 18–65 years, approximately 18–30 years, approximately 30–50 years, or approximately 50–65 years; and elderly patients such as those over 65 years, approximately 65–75 years, 75–90 years, or over 90 years.

[0158] (S)-bupropion increased bioavailability or increased plasma concentration, (R,R)-hydroxybupropion increased bioavailability or increased plasma concentration, and / or dextromethorphan increased bioavailability or increased plasma concentration for the treatment of TRD can result in at least about a 5%, at least about a 10%, at least about a 20%, at least about a 30%, at least about a 40%, at least about a 50%, at least about a 60%, at least about a 70%, at least about a 80%, at least about a 90%, about a 100% reduction, or a reduction of any percentage between any of these values, in depressive symptoms.

[0159] (S)-bupropion increased bioavailability or increased plasma concentration, (R,R)-hydroxybupropion increased bioavailability or increased plasma concentration, and / or dextromethorphan increased bioavailability or increased plasma concentration can be used to treat, but are not limited to, anxiety disorders such as phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD); mood disorders such as mania, bipolar disorder, hypomania, unipolar depression, depression, stress disorder, somatic symptom disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizotypal disorder, aggression, aggression in Alzheimer's disease, excitability, and excitability in Alzheimer's disease.

[0160] Excitability associated with Alzheimer's disease occurs with the progression of the disease. The restlessness itself may manifest as inappropriate words, emotions, and / or physical behaviors. Inappropriate behaviors may include, but are not limited to, muttering, inappropriate emotional reactions, demands for attention, threats, irritability, dissatisfaction, screaming, repetition of questions, mood swings, verbal abuse, obscenities, physical outbursts, emotional distress, restlessness, shredding, sleep disorders, delusions, hallucinations, pacing, wandering, searching, scavenging, repetitive physical movements, hoarding, shadowing, hitting, scratching, biting, combativeness, hyperactivity, and / or kicking.

[0161] In some embodiments, treatment of Alzheimer's disease-related agitation by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan may result in a reduction of agitation-related symptoms by at least 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 100%, or any percentage reduction between any of these values.

[0162] Measures of the therapeutic effect of agitation that may be improved by increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan include, but are not limited to, all items of the Neuropsychiatric Inventory-Clinical (NPI-C) Rating Scale, the agitation item of the Neuropsychiatric Inventory-Clinical (NPI-C) Rating Scale, the Cohen-Mansfield Agitation Rating Scale (CMAI), the Cornell Dementia Scale for Depression (CSDD), and the Neuropsychiatric Symptom Assessment (NPI-C). The assessment included items related to agitation / aggression, concomitant medications (frequency of concomitant medication use), individual items of the Activities of Daily Living (ADC(S)-ADL) assessment of the Alzheimer's Disease Collaborative Study (NPI), and the NIP-C apathy item, NPI agitation / aggression, and the total NPI score (range of 0-144) including caregiver burden, and the modified Alzheimer's Disease Collaborative Study's impression of overall clinical change agitation (mADC(S)-CGIC). This may include agitation, patient's overall impression of change (PGIC) (caregiver assessment), dementia quality of life (DEMQOL), Alzheimer's disease quality of life scale (QoL-AD), Zarit burden of care scale, resource utilization in dementia (RUD), cognitive function subscales for assessing cognitive impairment in Alzheimer's disease (ADA(S)-Cog), Mini-Mental State Examination (MMSE), caregiver burden index (CSI), individual items of the Neuropsychiatric Symptom Assessment (NPI), total score of the Neuropsychiatric Symptom Assessment (NPI), Neuropsychiatric Symptom Assessment (NPI agitation / aggression item), Neuropsychiatric Symptom Assessment (NPI caregiver burden item), etc.

[0163] Drug addictions that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, drug addiction, cocaine addiction, psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol, opioids, anxiolytics and hypnotics, cannabis (marijuana), amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as tobacco smoking, cigar and / or pipe, e-cigarette, and chewing tobacco addiction.

[0164] Brain dysfunctions that can be treated by increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan include, but are not limited to, senile dementia, Alzheimer's disease, amnesia, amnesia / amnesic syndrome, epilepsy, impaired consciousness, coma, decreased attention, speech disorders, voice spasms, Parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and intellectual disabilities such as schizophrenia. Brain dysfunctions also include, but are not limited to, disorders caused by stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head trauma, and cerebrovascular disorders including symptoms such as impaired consciousness, senile dementia, coma, decreased attention, and speech disorders.

[0165] Movement disorders that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, akathisia, akinesia, associated movements, athetosis, ataxia, ballism, hemiballism, bradykinesia, cerebral palsy, chorea, Huntington's disease, rheumatic chorea, Sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spasmodic torticollis, dopamine-responsive dystonia, Parkinson's disease, restless leg syndrome (RLS), tremor, essential tremor, Tourette's syndrome, and Wilson's disease.

[0166] Dementia that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, Alzheimer's disease, Parkinson's disease, vascular dementia, Lewy body dementia, mixed dementia, frontotemporal dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, Huntington's disease, Wernicke-Korsakoff syndrome, and Pick's disease.

[0167] Motor neuron diseases that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy (SMA), spinal motor atrophy, Tay-Sachs disease, Sandhoff disease, and hereditary spastic paraplegia.

[0168] Neurodegenerative diseases that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, Alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), bulbar spinal muscular atrophy, Friedrich's ataxia, Huntington's disease, Lewy body dementia, Parkinson's disease, and muscular atrophy. This includes 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, autosomal dominant cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paraplegia, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatonigral degeneration, Guillain-Barré syndrome, and spastic paraplegia.

[0169] Seizure disorders that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, non-epileptic seizures, epilepsy, and febrile convulsions; partial seizures including, but not limited to, simple partial seizures, Jacksonian seizures, complex partial seizures, and persistent partial epilepsy; generalized convulsions including, but not limited to, generalized tonic-clonic seizures, absence seizures, atonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

[0170] The types of headaches that can be treated by increasing the bioavailability or plasma concentration of (S)-bupropion, increasing the bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increasing the bioavailability or plasma concentration of dextromethorphan include, but are not limited to, migraines, tension headaches, and cluster headaches.

[0171] Other neurological disorders that can be treated by increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan include Rett syndrome, autism, tinnitus, impaired consciousness, sexual dysfunction, intractable cough, narcolepsy, cataplexy; dysphonia due to uncontrolled laryngeal muscle spasms, including but not limited to abductor spasmodic dysphonia, adductor spasmodic dysphonia, myotonic dysphonia, and phonotremor; diabetic neuropathy, chemotherapy-induced neurotoxicity such as methotrexate neurotoxicity; incontinence, including but not limited to stress urinary incontinence, urge urinary incontinence, and fecal incontinence; and erectile dysfunction.

[0172] In some embodiments, increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan may be used for the treatment of pain, arthralgia, pain associated with sickle cell disease, emotional dysregulation, depression (including treatment-resistant depression), memory and cognitive impairment, schizophrenia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Rett syndrome, seizures, cough (including chronic cough), etc.

[0173] In some embodiments, increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan may be used for the treatment of refractory depression.

[0174] Increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan may be used for the treatment or relief of all types of pain, including but not limited to musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, inflammatory pain, arthritis pain, and complex regional pain syndrome.

[0175] In some embodiments, increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan may be useful for alleviating neuropathic pain.

[0176] Examples of neuropathic pain include diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain, and central pain. Other causes of neuropathic pain include cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation or chemotherapy-related neuropathy.

[0177] In some embodiments, increased bioavailability or plasma concentration of (S)-bupropion, increased bioavailability or plasma concentration of (R,R)-hydroxybupropion, and / or increased bioavailability or plasma concentration of dextromethorphan are administered to alleviate fibromyalgia.

[0178] Adverse events related to bupropion or dextromethorphan that can be avoided or reduced by the methods described herein include central nervous system adverse events, gastrointestinal events, or other types of adverse events related to either of these compounds. Central nervous system (CNS) adverse events include, but are not limited to, tension, dizziness, insomnia, confusion, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, increased irritability or agitation, tinnitus, drowsiness, dizziness, sedation, somnolence, confusion, disorientation, malaise, dyscoordination, fatigue, euphoria, nervousness, insomnia, sleep disturbances, seizures, agitation, tension, hysteria, hallucinations, delusions, paranoia, headache and / or migraine, as well as extrapyramidal symptoms such as gaze attacks, torticollis, hyperexcitability, hypertonia, ataxia and / or tongue thrust.

[0179] Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, indigestion, diarrhea, abdominal distension, flatulence, peptic ulcers with bleeding, loose stools, constipation, stomach pain, heartburn, gas, loss of appetite, fullness, indigestion, abdominal distension, excessive stomach acid, dry mouth, gastrointestinal disorders, and stomach pain.

[0180] Other adverse events that can be reduced or avoided by the methods described herein include: paresthesia of rotation or movement, agitation, weakness in the arms, bloating, blurred vision, burning in the eyes, tinnitus, changes in vital signs (including, but not limited to, heart rate, respiratory rate, body temperature, and blood pressure), coldness, constipation, difficulty maintaining concentration, difficulty falling asleep, difficulty falling asleep, difficulty urinating, difficulty defecating, ear discomfort, eye discomfort, stomach discomfort, dizziness, dry lips, dry mouth, dry throat, dysmenorrhea, fatigue, feverishness, heavy head, increased agitation, increased fatigue, hand tremors, hand These side effects include weakness, headache, heartburn, hot flashes, increased blood pressure, sensitive skin, sensitive skin on the head and face, involuntary muscle contractions, generalized involuntary muscle contractions, knee pain, leg weakness, drowsiness, loose stools, loss of appetite, back pain, menstrual irregularities, metallic taste, increased saliva production, dry mucous membranes, nasal congestion, nausea, runny nose, mild eye pressure, tremors during stretching or yawning, skin irritation, skin irritation of the arms, face, and / or head, sleep disturbances, loose stools, stomach pain, stomach discomfort, sweating of the hands and / or feet, throat irritation, sore throat, tinnitus, tremors, and / or weakness. Any of these side effects may be referenced or grouped according to the corresponding term, equivalent term, or other relevant term listed in the Drug Regulatory Terminology (MedRA).

[0181] The terms “to treat” or “to cure” include any activity that diagnoses, treats, alleviates, cures or prevents disease in a person or another animal, or that affects the structure or any function of the body in a person or another animal.

[0182] Patients who may benefit from the treatments described herein include pediatric patients such as those under approximately 18 years of age, approximately 0–5 years, approximately 5–10 years, approximately 10–12 years, or approximately 12 to 18 years of age; adult patients such as those approximately 18–65 years, approximately 18–30 years, approximately 30–50 years, or approximately 50–65 years of age; and elderly patients such as those 65 years of age or older, approximately 65–75 years, approximately 75–90 years, or 90 years of age or older.

[0183] U.S. Patent No. 9,867,819, filed on 10 July 2017 under application number 15 / 645,939 and registered on 16 January 2018, by Herriot Tabuteau, entitled “Compositions and Methods for Increasing the Metabolic Lifespan of Dextromethorphan, and Related Pharmacodynamic Effects,” is incorporated herein by reference in its entirety. In particular, the amounts and dosage regimens for bupropion described in U.S. Patent No. 9,867,819 may be applied to (S)-bupropion or (R)-bupropion as described herein. Furthermore, the amounts and dosage regimens for dextromethorphan described in U.S. Patent No. 9,867,819 may be applied herein. Furthermore, conditions that can be treated by the dosage forms described in U.S. Patent No. 9,867,819 may also be treated in a similar manner using the dosage forms and methods described herein.

[0184] The following embodiments are possible. Embodiment 1. A method for delivering bupropion or its metabolites to plasma, comprising orally administering to a human at least once daily a dosage form containing about 50 mg to about 100 mg of (S)-bupropion that is at least 95% enantiomerically pure.

[0185] Embodiment 2. Select human patients who require the pharmacokinetic profile obtained by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dose frequency, To achieve the same pharmacokinetic profile achieved by administering the reference dosage form at the first dose frequency by orally administering a second amount of (S)-bupropion containing at least 95% enantiomerically pure (S)-bupropion in a dosage form at the first dose frequency, Includes, The first administration frequency is once or twice a day. The second amount is approximately 40% to 60% of the first amount. A method for delivering bupropion to human plasma.

[0186] Embodiment 3. Select human patients who have a condition that can be treated by orally administering a reference dosage form containing a first amount of racemic bupropion at a first dose frequency, To achieve the same therapeutic effect as achieved by administering the reference dosage form at the first dose frequency by orally administering a second amount of (S)-bupropion that is at least 95% enantiomerically pure, Includes, The first administration frequency is once or twice a day. The second amount is approximately 40% to 60% of the first amount. A method for treating conditions treatable with racemic bupropion.

[0187] Embodiment 4. The method according to Embodiment 1, wherein the human being requires treatment with (S)-bupropion.

[0188] Embodiment 5. (S)-bupropion C max The method according to Embodiments 1, 2, 3, or 4, wherein the concentration is at least about 60 ng / mL.

[0189] Embodiment 6. When the same amount of (R)-bupropion is administered to humans, the C content of (R)-bupropion is... max In comparison, (S)-bupropion's C max The method according to Embodiments 1, 2, 3, 4, or 5, which has the effect of increasing by at least 5 times.

[0190] Embodiment 7. C of (R,R)-hydroxybupropion in the human max The method according to Embodiments 1, 2, 3, 4, 5, or 6, wherein the concentration is at least about 500 ng / mL.

[0191] Embodiment 8. When the same amount of (R)-bupropion is administered to the same person, the C of (R,R)-hydroxybupropion min In comparison, (R,R)-hydroxybupropion C min The method according to Embodiments 1, 2, 3, 4, 5, 6, or 7, which has the effect of increasing by at least three times.

[0192] Embodiment 9. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, or 8, wherein the dosage form is administered once daily.

[0193] Embodiment 10. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, or 8, wherein the dosage form is administered twice a day.

[0194] Embodiment 11. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human plasma.

[0195] Embodiment 12. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11, which is effective in providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion.

[0196] Embodiment 13. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, which is effective in providing a therapeutically effective plasma concentration of (S)-bupropion.

[0197] Embodiment 14. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the human being requires treatment with (R,R)-hydroxybupropion.

[0198] Embodiment 15. C of (R,R)-hydroxybupropion in the human max The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14, wherein the concentration is at least about 500 ng / mL.

[0199] Embodiment 16. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein the dosage form is administered for at least 8 consecutive days.

[0200] Embodiment 17. The method according to Embodiment 16, wherein the dosage form is administered for at least 14 consecutive days.

[0201] Embodiment 18. The method according to Embodiment 16, wherein the dosage form is administered for at least 21 consecutive days.

[0202] Embodiment 19. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein the dosage form contains about 60 mg to about 90 mg of (S)-bupropion.

[0203] Embodiment 20. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 4 to 7 consecutive days.

[0204] Embodiment 21. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the dosage form is administered once daily for 1 to 7 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days.

[0205] Embodiment 22. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21, wherein the dosage form contains approximately 70 mg to approximately 80 mg of (S)-bupropion.

[0206] Embodiment 23. C of (S)-bupropion in the human max The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, wherein the concentration is at least about 70 ng / mL.

[0207] Embodiment 24. AUC of (S)-bupropion in the human population 0-12 The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23, wherein the concentration is at least about 400 ng·hr / mL.

[0208] Embodiment 25. AUC of (S)-bupropion in the human population 0-12 The method according to Embodiment 24, wherein the concentration is at least about 500 ng·hr / mL to about 900 ng·hr / mL.

[0209] Embodiment 26. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25, wherein the dosage form releases the (S)-bupropion in a sustained manner.

[0210] Embodiment 27. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26, wherein the dosage form further contains dextromethorphan.

[0211] Embodiment 28. The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, wherein the dosage form contains about 70 mg to about 80 mg of (S)-bupropion.

[0212] Embodiment 29. C of (R,R)-hydroxybupropion in the human max The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28, wherein the concentration is at least about 600 ng / mL.

[0213] Embodiment 30. AUC of (R,R)-hydroxybupropion in the human population 0-12 The method according to Embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29, wherein the amount is at least about 7000 ng·hr / mL.

[0214] Embodiment 31. AUC of (R,R)-hydroxybupropion in the human population 0-12 The method according to Embodiment 30, wherein the concentration is at least about 8000 ng·hr / mL.

[0215] Embodiment 32. The treatment comprises co-administering, at least once daily, dextromethorphan and at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion to a person requiring treatment with both (S)-bupropion and dextromethorphan, wherein the C of (S)-bupropion in the person max The C of (R)-bupropion was at least approximately 90 ng / mL, and the C of (R)-bupropion when the same amount was administered to the same person was at least approximately 90 ng / mL. max In comparison, (S)-bupropion's C max A method for increasing plasma concentrations of (S)-bupropion and dextromethorphan, which has the effect of increasing them by at least three times.

[0216] Embodiment 33. The method according to Embodiment 32, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 8 consecutive days.

[0217] Embodiment 34. The method according to Embodiment 32, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 14 consecutive days.

[0218] Embodiment 35. The method according to Embodiment 32, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0219] Embodiment 36. The method according to Embodiments 33, 34, or 35, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 4 to 7 consecutive days.

[0220] Embodiment 37. The method according to Embodiments 33, 34, or 35, wherein the dosage form is administered once daily for 1 to 7 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 7 consecutive days.

[0221] Embodiment 38. The method according to Embodiments 32, 33, 34, 35, 36, or 37, wherein (S)-bupropion is administered in a dosage form containing approximately 100 mg to approximately 110 mg of (S)-bupropion.

[0222] Embodiment 39. C of (S)-bupropion in the human max The method according to embodiment 32, 33, 34, 35, 36, 37 or 38, wherein the concentration is at least about 110 ng / mL.

[0223] Embodiment 40. AUC of (S)-bupropion in the human population 0-12 The method according to embodiment 32, 33, 34, 35, 36, 37, 38 or 39, wherein the concentration is at least about 800 ng·hr / mL.

[0224] Embodiment 41. The method according to Embodiments 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein (S)-bupropion is administered in a sustained-release dosage form.

[0225] Embodiment 42. The treatment comprises co-administering, at least once daily, dextromethorphan and at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion to a person requiring treatment with both (R,R)-hydroxybupropion and dextromethorphan, wherein the C of (R,R)-hydroxybupropion in the person max The C of (R,R)-hydroxybupropion was at least approximately 700 ng / mL, and the C of (R,R)-bupropion when the same amount of (R)-bupropion was administered to the same person was at least approximately 700 ng / mL. maxIn comparison, (R,R)-hydroxybupropion C max A method for increasing the plasma concentrations of (R,R)-hydroxybupropion and dextromethorphan, which has the effect of increasing the concentration by at least three times.

[0226] Embodiment 43. The method according to Embodiment 42, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 8 consecutive days.

[0227] Embodiment 44. The method according to Embodiment 42, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 21 consecutive days.

[0228] Embodiment 45. The method according to embodiment 42, 43, or 44, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0229] Embodiment 46. The method according to Embodiments 42, 43, 44, or 45, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 4 to 7 consecutive days.

[0230] Embodiment 47. The method according to Embodiments 42, 43, 44, 45, or 46, wherein the dosage form is administered once daily for 1 to 7 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 7 consecutive days.

[0231] Embodiment 48. The method according to Embodiments 42, 43, 44, 45, 46, or 47, wherein (S)-bupropion is administered in a dosage form containing approximately 100 mg to approximately 110 mg of (S)-bupropion.

[0232] Embodiment 49. C of (R,R)-hydroxybupropion in the human max The method according to Embodiments 42, 43, 44, 45, 46, 47, or 48, wherein the concentration is at least about 900 ng / mL.

[0233] Embodiment 50. AUC of (R,R)-hydroxybupropion in the human population 0-12 The method according to Embodiments 42, 43, 44, 45, 46, 47, 48, or 49, wherein the concentration is at least about 10,000 ng·hr / mL.

[0234] Embodiment 51. The method according to Embodiments 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein (S)-bupropion is administered in a sustained-release dosage form.

[0235] Embodiment 52. The treatment comprises administering at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion orally at least once daily to a person in need of treatment with (S)-bupropion, wherein the C of (S)-bupropion in the person min The C of (R)-bupropion was at least about 20 ng / mL, and the C of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion was administered to the person was at least about 20 ng / mL. min In comparison, (S)-bupropion's C min A method to increase the plasma concentration of (S)-bupropion, which has the effect of increasing it by at least three times.

[0236] Embodiment 53. The method according to Embodiment 52, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 8 consecutive days.

[0237] Embodiment 54. The method according to Embodiment 52, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 14 consecutive days.

[0238] Embodiment 55. The method according to Embodiments 52, 53, or 54, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0239] Embodiment 56. The method according to Embodiments 52, 53, 54, or 55, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0240] Embodiment 57. The method according to Embodiments 52, 53, 54, 55, or 56, wherein the dosage form is administered once daily for 1 to 7 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 7 consecutive days.

[0241] Embodiment 58. The method according to Embodiments 52, 53, 54, 55, 56, or 57, wherein (S)-bupropion is administered in a dosage form containing approximately 100 mg to approximately 110 mg of (S)-bupropion.

[0242] Embodiment 59. C of (S)-bupropion in the human max The method according to embodiment 52, 53, 54, 55, 56, 57, or 58, wherein the concentration is at least about 110 ng / mL.

[0243] Embodiment 60. AUC of (S)-bupropion in the human population 0-12 The method according to embodiment 52, 53, 54, 55, 56, 57, 58, or 59, wherein the concentration is at least about 800 ng·hr / mL.

[0244] Embodiment 61. The method according to Embodiments 52, 53, 54, 55, 56, 57, 58, 59, or 60, wherein (S)-bupropion is administered in a sustained-release dosage form.

[0245] Embodiment 62. The treatment comprises administering at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion orally at least once daily to a person requiring treatment with (R,R)-hydroxybupropion, wherein the C of (R,R)-hydroxybupropion in the person min The C of (R,R)-hydroxybupropion was at least approximately 700 ng / mL, and the C of (R,R)-bupropion when the same amount of (R)-bupropion was administered to the same person was at least approximately 700 ng / mL. min In comparison, (R,R)-hydroxybupropion C min A method for increasing the plasma concentration of (R,R)-hydroxybupropion, which has the effect of increasing it by at least three times.

[0246] Embodiment 63. The method according to Embodiment 62, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 8 consecutive days.

[0247] Embodiment 64. The method according to Embodiment 62, wherein the dextromethorphan and the (S)-bupropion are administered together for at least 21 consecutive days.

[0248] Embodiment 65. The method according to embodiment 62, 63, or 64, wherein the dextromethorphan and the (S)-bupropion are co-administered in a single dosage form.

[0249] Embodiment 66. The method according to Embodiments 62, 63, 64, or 65, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0250] Embodiment 67. The method according to Embodiments 62, 63, 64, 65, or 66, wherein the dosage form is administered once daily for 1 to 7 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or twice daily for at least the next 7 consecutive days.

[0251] Embodiment 68. The method according to Embodiments 62, 63, 64, 65, 66, or 67, wherein (S)-bupropion is administered in a dosage form containing approximately 100 mg to approximately 110 mg of (S)-bupropion.

[0252] Embodiment 69. C of (R,R)-hydroxybupropion in the human max The method according to embodiment 62, 63, 64, 65, 66, 67, or 68, wherein the concentration is at least about 900 ng / mL.

[0253] Embodiment 70. AUC of (R,R)-hydroxybupropion in the human population 0-12 The method according to embodiment 62, 63, 64, 65, 66, 67, 68, or 69, wherein the concentration is at least about 10,000 ng·hr / mL.

[0254] Embodiment 71. The method according to Embodiments 62, 63, 64, 65, 66, 67, 68, 69, or 70, wherein (S)-bupropion is administered in a sustained-release dosage form.

[0255] Embodiment 72. A method for treating a central nervous system (CNS) disorder in a human, comprising administering to a human a dosage form containing at least about 95% enantiomerically pure (S)-bupropion and dextromethorphan in a therapeutically effective amount to treat the CNS disorder.

[0256] Embodiment 73. The method according to embodiment 72, wherein the CNS disorder includes depression.

[0257] Embodiment 74. The method according to embodiment 72, wherein the CNS disorder includes treatment-resistant depression.

[0258] Embodiment 75. The method according to embodiment 72, wherein the CNS disorder includes toxic disorders.

[0259] Embodiment 76. The method according to embodiment 72, wherein the CNS disorder includes nicotine intoxication.

[0260] Embodiment 77. The method according to embodiment 72, wherein the CNS disorder includes alcohol poisoning.

[0261] Embodiment 78. The method according to embodiment 72, wherein the CNS disorder includes Alzheimer's disease.

[0262] Embodiment 79. The method according to Embodiments 72, 73, 74, 75, 76, 77, or 78, wherein the dosage form is a tablet, capsule, or syrup.

[0263] Embodiment 80. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, or 79, wherein the dosage form is administered orally to a human.

[0264] Embodiment 81. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, or 80, wherein the dosage form is administered orally to a human on a daily basis.

[0265] Embodiment 82. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, or 81, wherein the dosage form is administered orally to the human once daily.

[0266] Embodiment 83. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, or 82, wherein the dosage form is administered orally to the human twice a day.

[0267] Embodiment 84. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, or 83, wherein the dosage form is administered orally to a person under fasting conditions.

[0268] Embodiment 85. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, or 84, wherein the dosage form is administered orally to the person daily for at least 8 consecutive days.

[0269] Embodiment 86. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, or 85, wherein the dosage form contains approximately 100 mg to approximately 200 mg of (S)-bupropion.

[0270] Embodiment 87. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, or 86, wherein the dosage form contains approximately 104 mg to approximately 106 mg of (S)-bupropion.

[0271] Embodiment 88. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, or 87, wherein the dosage form contains approximately 148 mg to approximately 152 mg of (S)-bupropion.

[0272] Embodiment 89. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, or 88, wherein both (S)-bupropion and dextromethorphan are included in the dosage form.

[0273] Embodiment 90. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, or 89, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.

[0274] Embodiment 91. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90, wherein the dosage form contains approximately 44 mg to approximately 46 mg of dextromethorphan.

[0275] Embodiment 92. The method according to Embodiments 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, or 91, wherein the dosage form is well tolerated.

[0276] Embodiment 93. A method for increasing the plasma concentration of (S)-bupropion while increasing the plasma concentration of dextromethorphan, comprising administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion and dextromethorphan to a person requiring treatment with bupropion.

[0277] Embodiment 94. Compared to administering the same amount of racemic bupropion, (S)-bupropion has a higher C content. max The method according to embodiment 93, which has the effect of increasing

[0278] Embodiment 95. (S)-bupropion C max The C of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to the person. max The method according to embodiment 93 or 94, which has the effect of increasing the value by at least three times.

[0279] Embodiment 96. Compared to administration of the same amount of racemic bupropion, the AUC of (S)-bupropion 0-12 The method according to embodiment 93, 94, or 95, which has the effect of increasing

[0280] Embodiment 97. (S)-bupropion AUC 0-12 The AUC of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to the human. 0-12 The method according to embodiment 96, which has the effect of increasing the value by at least three times.

[0281] Embodiment 98. The method according to Embodiments 95, 96, or 97, wherein the dosage form is administered at least once a day for at least eight consecutive days.

[0282] Embodiment 99. The method according to Embodiments 95, 96, 97, or 98, wherein the dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0283] Embodiment 100. The method according to Embodiments 95, 96, 97, 98, or 99, wherein the dosage form is well tolerated.

[0284] Embodiment 101. A dosage form containing at least approximately 95% enantiomerically pure (R)-bupropion and dextromethorphan, wherein oral administration of the dosage form to a human can increase the plasma concentration of dextromethorphan in the human compared to oral administration of a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0285] Embodiment 102. The dosage form according to Embodiment 101, containing approximately 100 mg to approximately 200 mg of (R)-bupropion.

[0286] Embodiment 103. The dosage form according to Embodiment 102, containing approximately 104 mg to approximately 106 mg of (R)-bupropion.

[0287] Embodiment 104. The dosage form according to Embodiment 102, containing approximately 148 mg to approximately 152 mg of (R)-bupropion.

[0288] Embodiment 105. A dosage form according to Embodiments 101, 102, 103, or 104, containing approximately 10 mg to approximately 50 mg of dextromethorphan.

[0289] Embodiment 106. The dosage form according to Embodiment 105, containing approximately 44 mg to approximately 46 mg of dextromethorphan.

[0290] Embodiment 107. The dosage form according to Embodiment 101, containing approximately 100 mg to approximately 110 mg of (R)-bupropion and approximately 40 mg to approximately 50 mg of dextromethorphan.

[0291] Embodiment 108. A dosage form according to Embodiment 101, 102, 103, 104, 105, 106, or 107, which is administered orally to the human being on a daily basis.

[0292] Embodiment 109. A dosage form according to Embodiments 101, 102, 103, 104, 105, 106, 107, or 108, which is administered orally to the human once daily.

[0293] Embodiment 110. A dosage form according to Embodiments 101, 102, 103, 104, 105, 106, 107, or 108, which is administered orally to the human being twice a day.

[0294] Embodiment 111. The dosage form according to Embodiment 109 or 110, which is administered orally to the human being daily for at least eight consecutive days.

[0295] Embodiment 112. A dosage form according to Embodiments 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, or 111, which is administered orally to a person under fasting conditions.

[0296] Embodiment 113. On the eighth day of daily oral administration of the dosage form for eight consecutive days, the C of dextromethorphan in humans max The dosage form according to Embodiment 111, wherein the concentration is at least about 80 ng / mL.

[0297] Embodiment 114. The dosage form according to Embodiment 113, which is in the form of a syrup, tablet, capsule, spray, or lozenge.

[0298] Embodiment 115. A dosage form according to embodiment 113 or 114, used for treating a neuropsychiatric disorder in a person requiring treatment.

[0299] Embodiment 116. A dosage form according to embodiment 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, used to treat a cold or cough in a person requiring treatment.

[0300] Embodiment 117. Dosage forms according to Embodiments 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, used to relieve pain in a human being in need of relief.

[0301] Embodiment 118. Dosage forms according to Embodiments 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, or 115, used to treat addiction in a person requiring treatment.

[0302] Embodiment 119. The dosage form according to Embodiments 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, or 118, which is well tolerated when administered to a human.

[0303] Embodiment 120. A method for increasing the plasma concentration of dextromethorphan in a human, comprising administering to a human a dosage form containing at least approximately 95% enantiomerically pure (R)-bupropion and dextromethorphan, wherein the dosage form can increase the plasma concentration of dextromethorphan in the human compared to a reference dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0304] Embodiment 121. The method according to Embodiment 120, wherein the dosage form contains approximately 100 mg to approximately 200 mg of (R)-bupropion.

[0305] Embodiment 122. The method according to Embodiment 120, wherein the dosage form contains approximately 100 mg to approximately 110 mg of (R)-bupropion.

[0306] Embodiment 123. The method according to Embodiment 120, wherein the dosage form contains approximately 148 mg to approximately 152 mg of (R)-bupropion.

[0307] Embodiment 124. The method according to Embodiments 120, 121, 122, or 123, wherein the dosage form contains about 10 mg to about 50 mg of dextromethorphan.

[0308] Embodiment 125. The method according to Embodiment 124, wherein the dosage form contains approximately 40 mg to approximately 50 mg of dextromethorphan.

[0309] Embodiment 126. The method according to Embodiment 125, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.

[0310] Embodiment 127. The method according to Embodiments 120, 121, 122, 123, 124, 125, or 126, wherein the dosage form is orally administered to a person under fasting conditions.

[0311] Embodiment 128. The method according to Embodiments 120, 121, 122, 123, 124, 125, 126, or 127, wherein the dosage form is well tolerated.

[0312] Embodiment 129. A method for treating a central nervous system (CNS) disorder in a human, comprising administering to a human a dosage form containing at least about 95% enantiomerically pure (S)-bupropion in a therapeutically effective amount, wherein the human is not administered dextromethorphan.

[0313] Embodiment 130. The method according to embodiment 129, wherein the CNS disorder includes depression.

[0314] Embodiment 131. The method according to embodiment 129 or 130, wherein the CNS disorder includes treatment-resistant depression.

[0315] Embodiment 132. The method according to embodiment 129, 130, or 131, wherein the CNS disorder is a toxic disorder.

[0316] Embodiment 133. The method according to embodiment 132, wherein the CNS disorder is nicotine addiction.

[0317] Embodiment 134. The method according to embodiment 132, wherein the CNS disorder is alcohol poisoning.

[0318] Embodiment 135.

[0319] The method according to embodiment 132, wherein the CNS disorder is Alzheimer's disease. Embodiment 136. The method according to Embodiments 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form contains no active agent other than (S)-bupropion.

[0320] Embodiment 137. The method according to Embodiments 129, 130, 131, 132, 133, 134, or 135, wherein the dosage form contains less than 0.1% of the active agent in addition to (S)-bupropion.

[0321] Embodiment 138. The method according to Embodiments 129, 130, 131, 132, 133, 134, 135, 136, or 137, wherein the dosage form is in the form of a tablet, capsule, or syrup.

[0322] Embodiment 139. The method according to Embodiments 129, 130, 131, 132, 133, 134, 135, 136, 137, or 138, wherein the dosage form is administered orally to a human on a daily basis.

[0323] Embodiment 140. The method according to Embodiment 139, wherein the dosage form is administered orally to a human once daily.

[0324] Embodiment 141. The method according to Embodiment 139, wherein the dosage form is administered orally to a human being twice a day.

[0325] Embodiment 142. The method according to Embodiments 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, or 141, wherein the dosage form is administered orally to a person under fasting conditions.

[0326] Embodiment 143. The method according to Embodiments 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, or 142, wherein the dosage form is administered orally to the person daily for at least eight consecutive days.

[0327] Embodiment 144. The method according to Embodiments 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, or 143, wherein the dosage form contains about 100 mg to about 200 mg of (S)-bupropion.

[0328] Embodiment 145. The method according to Embodiment 144, wherein the dosage form contains approximately 104 mg to approximately 106 mg of (S)-bupropion.

[0329] Embodiment 146. The method according to Embodiment 144, wherein the dosage form contains approximately 148 mg to approximately 152 mg of (S)-bupropion.

[0330] Embodiment 147. A method for increasing the plasma concentration of (S)-bupropion, comprising administering a dosage form containing at least about 95% enantiomerically pure (S)-bupropion in a therapeutically effective amount to a person in need of treatment with bupropion, wherein the dosage form does not contain dextromethorphan.

[0331] Embodiment 148. (S)-bupropion C max The method according to embodiment 147, which has the effect of increasing [something].

[0332] Embodiment 149. When a dosage form containing the same amount of (R)-bupropion is administered to a human, the C content of (R)-bupropion is max In comparison, (S)-bupropion's C max The method according to embodiments 147 and 148, which has the effect of increasing by at least three times.

[0333] Embodiment 150. (S)-bupropion AUC 0-12 The method according to embodiment 147, 148, or 149, which has the effect of increasing.

[0334] Embodiment 151. AUC of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to a human. 0-12 In comparison, the AUC of (S)-bupropion 0-12 The method according to Embodiments 147, 148, 149, or 150, which has the effect of increasing by at least three times.

[0335] Embodiment 152. The method according to Embodiments 147, 148, 149, 150, or 151, wherein the dosage form is administered at least once a day for at least eight consecutive days.

[0336] Embodiment 153. The method according to Embodiment 152, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0337] Embodiment 154. The method according to Embodiments 147, 148, 149, 150, 151, 152, or 153, wherein the dosage form is well tolerated.

[0338] Embodiment 155. A method for increasing the plasma concentration of (S)-bupropion, comprising orally administering an oral dosage form containing at least about 90 mg of at least 95% enantiomerically pure (S)-bupropion to a person requiring treatment with (S)-bupropion and dextromethorphan, wherein the C of (S)-bupropion in the person max The concentration becomes at least 90 ng / mL, and the C of (S)-bupropion max However, when a dosage form containing the same amount of (R)-bupropion is administered to the human, the C of (R)-bupropion max Compared to the method described above, the effect is increased by at least three times, and the person is not administered dextromethorphan.

[0339] Embodiment 156. The method according to Embodiment 155, wherein the oral dosage form is administered for at least 8 consecutive days.

[0340] Embodiment 157. The method according to Embodiment 156, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0341] Embodiment 158. The method according to Embodiments 155, 156, or 157, wherein the dosage form contains about 100 mg to about 110 mg of (S)-bupropion.

[0342] Embodiment 159. C of (S)-bupropion in the human max The method according to embodiment 155, 156, 157, or 158, wherein the concentration is at least about 110 ng / mL.

[0343] Embodiment 160. The oral dosage form containing at least approximately 90 mg of at least 95% enantiomerically pure (S)-bupropion is administered orally to a person requiring treatment with (R,R)-hydroxybupropion and dextromethorphan, wherein the C of (R,R)-hydroxybupropion max This is at least about 90 ng / mL, and the C of (R,R)-hydroxybupropion max However, when a dosage form containing the same amount of (R)-bupropion is administered to the human, the C of (R,R)-hydroxybupropion max A method for increasing the plasma concentration of (R,R)-hydroxybupropion in a person who is not administered dextromethorphan, with an effect of at least three times greater compared to the other method.

[0344] Embodiment 161. The method according to Embodiment 160, wherein the oral dosage form is administered for at least 8 consecutive days.

[0345] Embodiment 162. The method according to Embodiment 161, wherein the oral dosage form is administered once daily for 1 to 3 consecutive days, and thereafter the dosage form is administered once or twice daily for a total of at least 8 consecutive days, or the dosage form is administered twice daily for at least the next 4 to 7 consecutive days.

[0346] Embodiment 163. The method according to Embodiments 160, 161, or 162, wherein the dosage form contains about 100 mg to about 110 mg of (S)-bupropion.

[0347] Embodiment 164. An oral dosage form containing (R)-bupropion and dextromethorphan with at least a 95% enantiomer excess, which can increase the plasma concentration of dextromethorphan in humans compared to a reference oral dosage form containing the same amount of (S)-bupropion and the same amount of dextromethorphan.

[0348] Embodiment 165. An oral dosage form containing (R)-bupropion and dextromethorphan, which, when administered orally to a human on a daily basis for at least eight consecutive days, can increase the plasma concentration of dextromethorphan in the human on day 1 or day 8 to a much greater extent than that of a reference oral dosage form, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0349] Embodiment 166. An oral dosage form containing (R)-bupropion and dextromethorphan, when administered orally to humans daily for at least 8 consecutive days, shows the mean C1 level of dextromethorphan in humans on day 1. max An oral dosage form that increases by at least 150%, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as (S)-bupropion.

[0350] Embodiment 167. An oral dosage form containing (R)-bupropion and dextromethorphan, when administered orally to humans daily for at least 8 consecutive days, shows the mean C1 of dextromethorphan on day 8 in those humans. max An oral dosage form that increases by at least 25%, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as (S)-bupropion.

[0351] Embodiment 168. An oral dosage form containing (R)-bupropion and dextromethorphan, when administered orally to humans daily for at least 8 consecutive days, shows the mean C1 of dextromethorphan on day 8 in those humans. max An oral dosage form in which the amount is increased by at least 20 times compared to day 1 of the reference dosage form, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0352] Embodiment 169. An oral dosage form containing (R)-bupropion and dextromethorphan, when administered orally to humans daily for at least 8 consecutive days, shows the mean C1 level of dextromethorphan in humans on day 1. max An oral dosage form that increases the amount by at least 60%, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0353] Embodiment 170. An oral dosage form containing (R)-bupropion and dextromethorphan, when administered orally to humans daily for at least 8 consecutive days, shows the mean C1 of dextromethorphan on day 8 in those humans. max An oral dosage form having increased by at least 20%, wherein the reference oral dosage form contains the same amount of bupropion and the same amount of dextromethorphan as racemic bupropion.

[0354] Embodiment 171. A method for increasing the plasma concentration of dextromethorphan on day 1 or day 8 to a much greater extent than when an oral reference dosage form is administered, by orally administering a dosage form containing (R)-bupropion and dextromethorphan to a human being orally every day for at least 8 consecutive days, wherein the reference dosage form contains the same amount of bupropion and the same amount of dextromethorphan as (S)-bupropion.

[0355] Embodiment 172. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, or 171, wherein the (R)-bupropion in the dosage form is at least 95% enantiomerically pure.

[0356] Embodiment 173. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, or 171, wherein the (S)-bupropion in the reference dosage form is at least 95% enantiomerically pure.

[0357] Embodiment 174. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, or 171, wherein the dosage form contains approximately 100 mg to approximately 150 mg of (R)-bupropion.

[0358] Embodiment 175. The dosage form or method according to Embodiment 174, wherein the dosage form contains approximately 100 mg to approximately 110 mg of (R)-bupropion.

[0359] Embodiment 176. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, or 171, wherein the dosage form contains approximately 10 mg to approximately 50 mg of dextromethorphan.

[0360] Embodiment 177. The dosage form or method according to Embodiment 176, wherein the dosage form contains approximately 40 mg to approximately 50 mg of dextromethorphan.

[0361] Embodiment 178. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is administered orally once daily.

[0362] Embodiment 179. The dosage form or method according to Embodiments 164, 165, 166, 167, 168, 168, 170, 171, 172, 173, 174, 175, 176, or 177, wherein the dosage form is administered orally twice a day.

[0363] Embodiment 180. The dosage form or method according to Embodiment 178 or 179, wherein the dosage form is administered orally for at least 8 consecutive days.

[0364] Embodiment 181. The dosage form or method according to Embodiment 180, wherein the dosage form contains about 100 mg to about 110 mg of (R)-bupropion and about 40 mg to about 50 mg of dextromethorphan.

[0365] Embodiment 182. In the human being who received oral administration of the oral dosage form daily for eight consecutive days, the mean C of dextromethorphan on the eighth day was max The dosage form or method according to Embodiment 180 or 181, wherein the concentration is at least 80 ng / mL.

[0366] Embodiment 183. The dosage form or method according to Embodiments 180, 181, or 182, wherein the dosage form is in the form of a syrup, tablet, capsule, spray, or lozenge.

[0367] Embodiment 184. A method for treating a neuropsychiatric disorder, comprising administering a dosage form described in any of the above embodiments to a person in need of treatment.

[0368] Embodiment 185. A method for treating a cold or cough, comprising administering the dosage form described in any of the above embodiments to a person in need of treatment.

[0369] Embodiment 186. A method for relieving pain, comprising administering the dosage form described in any of the above embodiments to a person in need of relief.

[0370] Embodiment 187. A method for treating addiction, comprising administering a dosage form described in any of the above embodiments to a person in need of treatment.

[0371] Embodiment 188. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in a condition to be treated with (S)-bupropion, wherein the amount of (S)-bupropion administered is selected from about 20% to about 70% of the amount of racemic bupropion administered to treat the same condition in the same human being.

[0372] Embodiment 189. A method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion, at least 95% enantiomerically pure, once or twice daily to a person requiring treatment with (R,R)-hydroxybupropion, wherein the (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person, and the method provides the C of (R,R)-hydroxybupropion in the person. max A method that results in a concentration of at least 500 ng / mL.

[0373] Embodiment 190. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion to a human being in need of treatment with (S)-bupropion, wherein (S)-bupropion is the sole active agent used to treat the human being.

[0374] Embodiment 191. A method for treating a human being, comprising orally administering a dosage form containing approximately 50 mg to approximately 100 mg of (S)-bupropion that is at least 95% enantiomerically pure, once or twice daily to a human being in need of treatment with (S)-bupropion.

[0375] Embodiment 192. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the C max A method to achieve a concentration of at least approximately 60 ng / mL.

[0376] Embodiment 193. A method for treating a human being, comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the human's plasma.

[0377] Embodiment 194. A method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion, at least 95% enantiomerically pure, once or twice daily to a person requiring treatment with (R,R)-hydroxybupropion, wherein the (R,R)-hydroxybupropion constitutes at least 97% of the total amount of (R,R)-hydroxybupropion and (S,S)-hydroxybupropion present in the plasma of the person.

[0378] Embodiment 195. A method for providing a therapeutically effective plasma concentration of (R,R)-hydroxybupropion, comprising orally administering (S)-bupropion, at least 95% enantiomerically pure, once or twice daily to a person requiring treatment with (R,R)-hydroxybupropion, wherein the C of (R,R)-hydroxybupropion in the person max A method to achieve a concentration of at least approximately 500 ng / mL.

[0379] Embodiment 196. The method according to any of the above embodiments, such as Embodiments 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 193, 194, or 195, wherein dextromethorphan is not administered to the human.

[0380] Embodiment 197. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the C max A method to achieve a concentration of at least approximately 70 ng / mL.

[0381] Embodiment 198. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the AUC of (S)-bupropion 0-12 A method to ensure the concentration is at least approximately 600 ng·h / mL.

[0382] Embodiment 199. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the C of (R,R)-hydroxybupropion max A method to achieve a concentration of at least approximately 800 ng / mL.

[0383] Embodiment 200. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the AUC of (R,R)-hydroxybupropion 0-12 A method to ensure the concentration is at least approximately 8,000 ng·h / mL.

[0384] Embodiment 201. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the C of erythrohydroxybupropion max A method to achieve a concentration of at least approximately 90 ng / mL.

[0385] Embodiment 202. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the AUC of erythrohydroxybupropion 0-12 A method to ensure the concentration is at least approximately 1,000 ng·h / mL.

[0386] Embodiment 203. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the C of threohydroxybupropion max A method to achieve a concentration of at least approximately 450 ng / mL.

[0387] Embodiment 204. A method for treating a human being comprising orally administering a dosage form containing at least 95% enantiomerically pure (S)-bupropion once or twice daily to a human being in need of treatment with (S)-bupropion, wherein the AUC of threohydroxybupropion 0-12 A method to ensure the concentration is at least approximately 5,000 ng·h / mL.

[0388] Embodiment 205. A dosage form containing at least 95% enantiomerically pure (S)-bupropion.

[0389] Embodiment 206. The dosage form according to Embodiment 205, containing approximately 100 mg to approximately 200 mg of (S)-bupropion.

[0390] Embodiment 207. A dosage form according to any of the above embodiments, containing less than 0.1% of other active agents.

[0391] Embodiment 208. The dosage form according to any of the above embodiments, further containing dextromethorphan.

[0392] Embodiment 209. The dosage form according to Embodiment 208, containing approximately 10 mg to approximately 50 mg of dextromethorphan.

[0393] Embodiment 210. A method for increasing the plasma concentration of (S)-bupropion or its metabolites, comprising administering the dosage form described in Embodiment 205, 206, 207, 208, or 209 to a person in need of treatment with bupropion or its metabolites.

[0394] Embodiment 211. (S)-bupropion C max The method according to any of the above embodiments, which has the effect of increasing [something].

[0395] Embodiment 212. When a dosage form containing the same amount of (R)-bupropion is administered to a human, the C content of (R)-bupropion is max In comparison, (S)-bupropion's C max The method according to any of the above embodiments, which has the effect of increasing by at least three times.

[0396] Embodiment 213. (S)-bupropion AUC 0-12 The method according to any of the above embodiments, which has the effect of increasing

[0397] Embodiment 214. AUC of (R)-bupropion when a dosage form containing the same amount of (R)-bupropion is administered to a human. 0-12In comparison, the AUC of (S)-bupropion 0-12 The method according to any of the above embodiments, which has the effect of increasing by at least three times.

[0398] Embodiment 215. (R,R)-hydroxybupropion C max The method according to any of the above embodiments, which has the effect of increasing

[0399] Embodiment 216. When a dosage form containing the same amount of (R)-bupropion is administered to a human, the C content of (R,R)-hydroxybupropion is max In comparison, (R,R)-hydroxybupropion C max The method according to any of the above embodiments, which has the effect of increasing by at least three times.

[0400] Embodiment 217. AUC of (R,R)-hydroxybupropion 0-12 The method according to any of the above embodiments, which has the effect of increasing

[0401] Embodiment 218. AUC of (R,R)-hydroxybupropion when a dosage form containing the same amount of (R)-bupropion is administered to a human. 0-12 In comparison, the AUC of (R,R)-hydroxybupropion 0-12 The method according to embodiment 13, which has the effect of increasing by at least three times.

[0402] Embodiment 219. The method according to any of the above embodiments, wherein the dosage form is administered at least once a day for at least eight consecutive days.

[0403] Embodiment 220. A method for treating a neurological condition, comprising administering the dosage form described in any of the above embodiments to a person in need of treatment.

[0404] Embodiment 221. The method according to embodiment 16, wherein the neurological condition is depression.

[0405] Embodiment 222. A method for increasing the plasma concentration of dextromethorphan, comprising administering a combination of (R)-bupropion and dextromethorphan to a person in need of treatment with dextromethorphan, wherein the (R)-bupropion is at least 95% enantiomerically pure.

[0406] Embodiment 223. Compared to administering the same amount of (S)-bupropion and the same amount of dextromethorphan, the C of dextromethorphan was max The method according to embodiment 18, which increases by 20%.

[0407] Embodiment 224. A method for delivering (S)-bupropion to human plasma, comprising orally administering to a human a dosage form containing at least 95% enantiomerically pure (S)-bupropion.

[0408] Embodiment 225. A method for delivering both (R)-bupropion and (S)-bupropion to human plasma, comprising orally administering to a human a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the C of (R)-bupropion max This refers to the C of (R)-bupropion when the same amount of racemic bupropion is administered to the same person. max A method that is within 20% of the total.

[0409] Embodiment 226. A method for delivering bupropion to human plasma, comprising orally administering to a human a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein the AUC of (R)-bupropion 0-12 This is the AUC of (R)-bupropion when the same amount of racemic bupropion is administered to the same person. 0-12 A method that is within 20% of the total.

[0410] Embodiment 227. A method for delivering bupropion to human plasma, comprising orally administering to a human a dosage form containing at least 95% enantiomerically pure (S)-bupropion, wherein (R,R)-hydroxybupropion C max This refers to the C of (R,R)-hydroxybupropion when the same amount of racemic bupropion is administered to the same person. max A method that is within 20% of the total.

[0411] Embodiment 228. The method according to embodiment 224, 225, 226, or 227, wherein (S)-bupropion is administered for at least 8 consecutive days.

[0412] Embodiment 229. The method according to Embodiment 228, wherein (S)-bupropion is administered for at least 14 consecutive days.

[0413] Embodiment 230. The method according to Embodiments 224, 225, 226, 227, 228, or 229, wherein the dosage form contains approximately 50 mg to approximately 150 mg of (S)-bupropion.

[0414] Embodiment 231. The method according to Embodiments 224, 225, 226, 227, 228, or 229, wherein the dosage form contains approximately 40 mg to approximately 90 mg of (S)-bupropion.

[0415] Embodiment 232. As a result of administering this dosage form, the combined C of (S)-bupropion and (R)-bupropion on day 8 max The method according to any of the above embodiments, wherein the concentration is at least about 100 ng / mL.

[0416] Embodiment 233. As a result of administering this dosage form, the combined AUC of (S)-bupropion and (R)-bupropion on day 8 was 0-12 The method according to any of the above embodiments, wherein the concentration is at least about 800 ng·h / mL.

[0417] Embodiment 234. As a result of administering this dosage form, the combined C of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion on day 8 max The method according to any of the above embodiments, wherein the concentration is at least about 1,000 ng / mL.

[0418] Embodiment 235. As a result of administering this dosage form, the combined AUC of (S,S)-hydroxybupropion and (R,R)-hydroxybupropion on day 8 was 0-12 The method according to any of the above embodiments, wherein the concentration is at least about 10,000 ng·h / mL.

[0419] Embodiment 236. As a result of administering this dosage form, the C of erythrohydroxybupropion on day 8 max The method according to any of the above embodiments, wherein the concentration is at least about 100 ng / mL.

[0420] Embodiment 237. As a result of administration of this dosage form, the AUC of erythrohydroxybupropion on day 8 was 0-12 The method according to any of the above embodiments, wherein the concentration is at least about 1,500 ng·h / mL.

[0421] Embodiment 238. As a result of administering this dosage form, the C of threohydroxypropion on day 8 was max The method according to any of the above embodiments, wherein the concentration is at least about 600 ng / mL.

[0422] Embodiment 239. As a result of administration of this dosage form, the AUC of threohydroxybupropion on day 8 was 0-12 The method according to any of the above embodiments, wherein the concentration is at least about 5,000 ng·h / mL.

[0423] Unless otherwise stated, the numerical values ​​representing properties such as quantities, amounts, and AUC values ​​of the components used herein and in the claims should be understood in all cases to represent both the exact values ​​shown and the values ​​modified by the term “approximately.” Therefore, unless otherwise indicated, the numerical parameters described herein and in the appended claims are approximations that may vary depending on the desired properties to be obtained. At the very least, without attempting to limit the application as equivalents to the claims, each numerical parameter should be interpreted by applying ordinary rounding means in light of the number of significant figures reported.

[0424] In the context describing the present invention (particularly in the context of the following claims), the terms “a,” “an,” “the,” and similar references should be construed to cover both singular and plural forms unless otherwise stated or unless the context clearly contradicts this. All embodiments or use of exemplary language (e.g., “like”) provided herein are intended to better illustrate the present invention and do not limit the scope of the claims. Nothing described herein should be construed as indicating non-claimed elements essential to the practice of the present invention.

[0425] The grouping of alternative elements or embodiments disclosed herein should not be construed as limitation. Each group's components may be referenced and claimed individually or in any combination with other components of the group or other elements found herein. For convenience or patentability reasons, it is anticipated that one or more components of a group may be included in or removed from the group. If such inclusion or removal occurs, this specification shall be deemed to include the modified group and shall satisfy all descriptions of the Markush group used in the appended claims.

[0426] This specification describes several embodiments of the invention, including the best mode for carrying out the invention as known to the inventor. Of course, variations of these described embodiments will be apparent to those skilled in the art by reading the preceding description. The inventor expects those skilled in the art to use such variations appropriately, and the inventor intends to carry out the invention in ways other than those specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter described in the claims, as permitted by applicable law. Furthermore, unless otherwise stated herein, or unless it is clearly inconsistent with the context, any possible combination of the above elements is conceivable.

[0427] Finally, it should be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be adopted are within the scope of the claims. Therefore, alternative configurations of the present invention can be utilized in accordance with the teachings herein, not as limitations but as embodiments. Accordingly, the claims are not limited to the embodiments shown and described.

Claims

[Claim 1] A composition containing at least 95% enantiomerically pure (S)-bupropion, and containing less than 0.1% of any remaining active agents other than (R)-bupropion, relative to the weight of (S)-bupropion and (R)-bupropion.

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