阅读说明：本技术 包含安非他酮或相关化合物和右美沙芬的组合物和方法 (Compositions and methods comprising bupropion or related compounds and dextromethorphan ) 是由 赫里奥特·塔布提奥 于 2014-11-05 设计创作，主要内容包括：本公开涉及包含安非他酮或相关化合物和右美沙芬的组合物和方法。本公开涉及通过将抗抑郁剂化合物和右美沙芬向有此需要的人施用来治疗神经病症的方法。该方法可用于右美沙芬快代谢者的人。还描述了包含抗抑郁剂化合物和右美沙芬的组合物、药物和剂型。(The present disclosure relates to compositions and methods comprising bupropion or related compounds and dextromethorphan. The present disclosure relates to methods of treating neurological disorders by administering an antidepressant compound and dextromethorphan to a human in need thereof. The method can be used for people who are fast metabolizing dextromethorphan. Also described are compositions, medicaments, and dosage forms comprising an antidepressant compound and dextromethorphan.)

1. A method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, the method comprising co-administering bupropion with dextromethorphan to the human.

2. A method of inhibiting dextromethorphan metabolism comprising administering bupropion to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as bupropion.

3. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering bupropion to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as the bupropion.

4. A method of increasing a plasma level of dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of co-administration of bupropion and dextromethorphan for at least two days, wherein the increase in the plasma level of dextromethorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to administration of the same amount of dextromethorphan without bupropion.

5. A method of increasing a dextromethorphan plasma level comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 5 consecutive days without bupropion, preferably for at least 6 consecutive days, for at least 7 consecutive days, or for at least 8 consecutive days.

6. A method of reducing plasma levels of dextrorphan comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of dextromethorphan treatment, wherein the reduction in plasma levels of dextrorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to the same amount of dextromethorphan administration without bupropion.

7. A method of reducing adverse events associated with dextromethorphan treatment, comprising co-administering bupropion and dextromethorphan to a patient in need of dextromethorphan treatment, wherein the patient is at risk for an adverse event as a result of dextromethorphan treatment.

8. A method of correcting the fast metabolism of dextromethorphan, comprising administering bupropion to a human in need thereof, wherein preferably bupropion is administered to said human for at least 8 days, at least 1 time per day, and further preferably dextromethorphan is administered to said human for at least 8 days, at least 1 time per day.

9. A method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human in need thereof, wherein preferably said bupropion and dextromethorphan are administered at least 8 days, at least 1 time per day, further preferably bupropion is administered at about 150 mg/day to about 300 mg/day and dextromethorphan is administered at about 15 mg/day to about 60 mg/day.

10. A method of reducing the number of doses of dextromethorphan capable of being administered without loss of efficacy, comprising orally administering an effective amount of bupropion or a prodrug thereof to a human in need of treatment with dextromethorphan.

Technical Field

The present disclosure relates to compositions and methods comprising bupropion or related compounds and dextromethorphan.

Background

Dextromethorphan (dextromethorphan) is widely used as an antitussive. Bupropion (bupropion) is an antidepressant approved for the treatment of depression and smoking cessation.

Disclosure of Invention

Antidepressant compounds such as bupropion, hydroxybupropion (hydroxybupropion), erythrohydroxybupropion (erythrohydroxybupropion), threo hydroxybupropion (threo hydroxybupropion), or metabolites or prodrugs of any of these compounds may be used to improve the therapeutic efficacy of dextromethorphan, for example in the treatment of neurological disorders. Regardless of the stereochemistry, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds can be effective in inhibiting or reducing the metabolism of dextromethorphan in some humans. This can be achieved by co-administering bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, with dextromethorphan.

Some embodiments include a method of treating a neurological disorder comprising administering to a human in need thereof an antidepressant compound and dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan.

Some embodiments include a method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, comprising co-administering bupropion and dextromethorphan to the human, wherein the human is a fast metabolizer of dextromethorphan.

Some embodiments include a method of inhibiting dextromethorphan metabolism comprising administering bupropion to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human concurrently with bupropion.

Some embodiments include a method of increasing the metabolic lifespan of dextromethorphan, comprising administering bupropion to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with bupropion.

Some embodiments include methods of correcting fast metabolism of dextromethorphan, comprising administering bupropion to a human in need thereof.

Some embodiments include methods of improving the antitussive performance of dextromethorphan, comprising administering bupropion to a human in need of treatment for cough in combination with administration of dextromethorphan.

Some embodiments include methods of treating cough comprising administering a combination of bupropion and dextromethorphan to a human in need thereof.

Some embodiments include methods of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

Some embodiments include methods of treating a neurological disorder comprising administering bupropion at about 150 mg/day to about 300 mg/day and dextromethorphan at about 15 mg/day to about 60 mg/day to a human in need thereof.

Some embodiments include a method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, comprising co-administering to the human hydroxyamphetadone or a prodrug thereof and dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan.

Some embodiments include a method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, comprising co-administering erythrohydroxybupropion or a prodrug thereof with dextromethorphan to the human, wherein the human is a fast metabolizer of dextromethorphan.

Some embodiments include a method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to the human, wherein the human is a fast metabolizer of dextromethorphan.

Some embodiments include a method of inhibiting dextromethorphan metabolism comprising administering bupropion to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human concurrently with bupropion.

Some embodiments include a method of inhibiting dextromethorphan metabolism comprising administering hydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and hydroxybupropion are present in the human at the same time.

Some embodiments include a method of inhibiting dextromethorphan metabolism comprising administering erythrohydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with erythrohydroxybupropion.

Some embodiments include a method of inhibiting dextromethorphan metabolism comprising administering threo-hydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with threo-hydroxybupropion.

Some embodiments include a method of increasing the metabolic lifespan of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as hydroxybupropion.

Some embodiments include a method of increasing the metabolic lifespan of dextromethorphan, comprising administering erythrohydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with erythrohydroxybupropion.

Some embodiments include methods of increasing the metabolic lifespan of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with threo-hydroxybupropion.

Some embodiments include a method of increasing a plasma level of dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of co-administration of bupropion and dextromethorphan, wherein an increase in the plasma level of dextromethorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to the same amount of dextromethorphan administered without bupropion.

Some embodiments include a method of increasing dextromethorphan plasma levels comprising co-administering to a human in need of treatment with dextromethorphan, a hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the hydroxybupropion or a prodrug thereof is administered on the first day of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein an increase in dextromethorphan plasma levels occurs on the first day of co-administration of the hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan administered without the hydroxybupropion or a prodrug thereof.

Some embodiments include a method of increasing plasma levels of dextromethorphan, comprising co-administering erythro-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein erythro-hydroxybupropion or a prodrug thereof is administered on the first day of co-administration of erythro-hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein an increase in plasma levels of dextromethorphan occurs on the first day of co-administration of erythro-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan administered without erythro-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein threo-hydroxybupropion or a prodrug thereof is administered on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein an increase in dextromethorphan plasma levels occurs on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan used in the absence of threo-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of increasing a dextromethorphan plasma level comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if administered without bupropion for the same amount of dextromethorphan for 5 consecutive days.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma levels are higher than those obtained if administered without hydroxybupropion or a prodrug thereof with the same amount of dextromethorphan for 5 consecutive days.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma levels are higher than dextromethorphan plasma levels obtained if administered without erythrohydroxybupropion or a prodrug thereof for 5 consecutive days in the same amount of dextromethorphan.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5, the dextromethorphan plasma levels are higher than dextromethorphan plasma levels obtained if administered with the same amount of dextromethorphan for 5 consecutive days without threo-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of increasing a dextromethorphan plasma level comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if administered without bupropion for the same amount of dextromethorphan for 6 consecutive days.

Some embodiments include methods of increasing a plasma level of dextromethorphan, comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 6 consecutive days, wherein on day 6, the plasma level of dextromethorphan is higher than that obtained if administered without hydroxybupropion or a prodrug thereof with the same amount of dextromethorphan for 6 consecutive days.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma levels are higher than dextromethorphan plasma levels obtained if administered without erythrohydroxybupropion or a prodrug thereof with the same amount of dextromethorphan for 6 consecutive days.

Some embodiments include methods of increasing dextromethorphan plasma levels comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6, the dextromethorphan plasma levels are higher than dextromethorphan plasma levels obtained if administered with the same amount of dextromethorphan for 6 consecutive days without threo-hydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing plasma levels of dextrorphan (dextromethorphan), comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein bupropion is administered on the first day of dextromethorphan treatment for at least two days, wherein a reduction in plasma levels of dextrorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to administration of the same amount of dextromethorphan without bupropion.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering to a human in need of treatment with dextromethorphan, hydroxybupropion or a prodrug thereof, and dextromethorphan, wherein the hydroxybupropion or the prodrug thereof is administered on the first day of dextromethorphan treatment for at least two days, wherein the reduction in plasma levels of dextrorphan occurs on the first day when the hydroxybupropion or the prodrug thereof is co-administered with dextromethorphan as compared to the same amount of dextromethorphan administered without hydroxybupropion or the prodrug thereof.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering erythro-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein erythro-hydroxybupropion or a prodrug thereof is administered on the first day of the dextromethorphan treatment for at least two days, wherein a reduction in plasma levels of dextrorphan occurs on the first day of co-administration of erythro-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to administration of the same amount of dextromethorphan without erythro-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein threo-hydroxybupropion or a prodrug thereof is administered on the first day of dextromethorphan treatment for at least two days, wherein a reduction in plasma levels of dextrorphan occurs on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to administration of the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8, the dextrorphan plasma levels are lower than those obtained if administered with the same amount of dextromethorphan in the absence of bupropion for 8 consecutive days.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 8 consecutive days, wherein on day 8 the plasma levels of dextrorphan are lower than those obtained if administered with the same amount of dextromethorphan in the absence of hydroxybupropion or a prodrug thereof for 8 consecutive days.

Some embodiments include methods of reducing plasma levels of dextrorphan comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8 the plasma levels of dextrorphan are lower than the plasma levels of dextrorphan obtained if administered with the same amount of dextromethorphan for 8 consecutive days without erythrohydroxybupropion or a prodrug thereof.

Some embodiments include methods of reducing dextrorphan plasma levels comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8, the dextrorphan plasma levels are lower than dextrorphan plasma levels obtained if the same amount of dextromethorphan were administered for 8 consecutive days without threo-hydroxybupropion or a prodrug thereof.

Some embodiments include a method of attenuating the dextromethorphan valley effect (trough effect) comprising co-administering bupropion and dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administration of bupropion and dextromethorphan that is at least twice the plasma level obtained if administered with the same amount of dextromethorphan without bupropion.

Some embodiments include methods of attenuating the effects of dextromethorphan glutamate comprising co-administering to a patient in need of treatment with dextromethorphan, hydroxybupropion or a prodrug thereof, wherein dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered with the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

Some embodiments include a method of attenuating the effects of dextromethorphan trough, comprising co-administering erythro-hydroxybupropion or a prodrug thereof with dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has at least twice the plasma level 12 hours after co-administration of erythro-hydroxybupropion or a prodrug thereof with dextromethorphan than would be obtained if administered with the same amount of dextromethorphan without erythro-hydroxybupropion or a prodrug thereof.

Some embodiments include methods of attenuating the effects of dextromethorphan trough, comprising co-administering threo-hydroxybupropion or a prodrug thereof with dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has at least twice the plasma level 12 hours after co-administration of threo-hydroxybupropion or a prodrug thereof with dextromethorphan than would be obtained if administered with the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

Some embodiments include a method of reducing adverse events associated with dextromethorphan therapy, comprising co-administering bupropion and dextromethorphan to a patient in need of dextromethorphan therapy, wherein the patient is at risk for an adverse event due to dextromethorphan therapy.

Some embodiments include methods of reducing adverse events associated with dextromethorphan therapy, comprising co-administering to a patient in need of dextromethorphan therapy hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the patient is at risk for an adverse event from dextromethorphan therapy.

Some embodiments include methods of reducing adverse events associated with dextromethorphan therapy, comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a patient in need of dextromethorphan therapy, wherein the patient is at risk for an adverse event from dextromethorphan therapy.

Some embodiments include methods of reducing adverse events associated with dextromethorphan therapy, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a patient in need of dextromethorphan therapy, wherein the patient is at risk for an adverse event from dextromethorphan therapy.

Some embodiments include methods of reducing adverse events associated with bupropion treatment comprising co-administering dextromethorphan and bupropion to a patient in need of bupropion treatment, wherein the patient is at risk for an adverse event due to the bupropion treatment.

Some embodiments include methods of correcting fast metabolism of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof to a human in need thereof.

Some embodiments include methods of correcting fast metabolism of dextromethorphan, comprising administering erythrohydroxybupropion or a prodrug thereof to a human in need thereof.

Some embodiments include methods of correcting fast metabolism of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof to a human in need thereof.

Some embodiments include methods of improving the antitussive performance of dextromethorphan, comprising administering bupropion to a human in need of treatment for cough in combination with administration of dextromethorphan.

Some embodiments include methods of improving the antitussive performance of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

Some embodiments include methods of improving the antitussive performance of dextromethorphan, comprising administering erythrohydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

Some embodiments include methods of improving the antitussive performance of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

Some embodiments include methods of treating cough comprising administering a combination of hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

Some embodiments include methods of treating cough comprising administering a combination of erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

Some embodiments include methods of treating cough comprising administering a combination of threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

Some embodiments include methods of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

Some embodiments include methods of treating a neurological disorder comprising administering to a human in need thereof hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

Some embodiments include methods of treating a neurological disorder comprising administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

Some embodiments include methods of treating a neurological disorder comprising administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

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

Some embodiments include methods of reducing the number of doses of dextromethorphan that can be administered without loss of potency comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a prodrug of any of these compounds to a human in need of treatment with dextromethorphan.

Some embodiments include a pharmaceutical composition, dosage form, or medicament comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, and a pharmaceutically acceptable excipient.

Drawings

Fig. 1 is a graph of mean plasma concentration of dextromethorphan over time after dosing on day 8 to a subject administered dextromethorphan alone or dextromethorphan and bupropion.

FIG. 2 depicts the mean dextromethorphan AUC for subjects administered dextromethorphan alone or with dextromethorphan and bupropion on day 8_0-12。

FIG. 3 depicts the mean dextromethorphan AUC for subjects administered dextromethorphan alone or with dextromethorphan and bupropion on day 8_0-24。

FIG. 4 depicts the mean dextromethorphan AUC for subjects administered dextromethorphan alone or with dextromethorphan and bupropion on day 8_0-inf。

Fig. 5 depicts the fold change in dextromethorphan AUC for subjects administered dextromethorphan alone on day 8 compared to dextromethorphan and bupropion administration.

FIG. 6 depicts the mean dextromethorphan AUC for subjects on days 1 and 8 administered dextromethorphan alone or with dextromethorphan and bupropion_0-12。

Figure 7 depicts the mean dextromethorphan trough plasma concentrations of subjects administered dextromethorphan alone or with dextromethorphan and bupropion.

Figure 8 depicts mean dextromethorphan maximum plasma concentrations for subjects on days 1 and 8 administered dextromethorphan alone or with dextromethorphan and bupropion.

Figure 9 is a graph of mean plasma concentrations of dextrorphan over time after dosing on day 8 to subjects administered dextromethorphan alone or dextromethorphan and bupropion.

Figure 10 depicts mean maximum plasma dextrorphan concentrations in subjects on days 1 and 8 with dextromethorphan alone or with dextromethorphan and bupropion.

FIG. 11 depicts the mean dextrorphan AUC for subjects administered dextromethorphan alone or with dextromethorphan and bupropion on days 1 and 8_0-12。

Detailed Description

Detailed description of the invention

Some embodiments include methods of treating a neurological disorder comprising administering to a human in need thereof a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

Some embodiments include methods of enhancing the therapeutic properties of dextromethorphan in the treatment of neurological disorders comprising co-administering dextromethorphan and an antidepressant, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

Some embodiments include methods of increasing plasma levels of dextromethorphan in a human that is a fast metabolite of dextromethorphan, comprising co-administering to the human an antidepressant compound such as bupropion and dextromethorphan.

Some embodiments include methods of inhibiting dextromethorphan metabolism comprising administering an antidepressant compound, such as bupropion, to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with the antidepressant.

Some embodiments include methods of increasing the metabolic lifespan of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as the antidepressant compound.

Some embodiments include methods of correcting the fast metabolism of dextromethorphan, comprising administering an antidepressant compound, such as bupropion, to a human in need thereof, e.g., a human in need of treatment for pain.

Some embodiments include methods of improving the therapeutic properties of dextromethorphan in the treatment of neurological disorders comprising administering an antidepressant compound, such as bupropion, to a human in need of treatment of the neurological disorder in combination with the administration of dextromethorphan.

Some embodiments include methods of treating a neurological condition comprising administering to a human in need thereof a combination of an antidepressant compound such as bupropion and dextromethorphan.

Dextromethorphan has the structure shown below.

Dextromethorphan is used as an antitussive. Dextromethorphan should be administered 6 times per day (once every 4 hours), 4 times per day (once every 6 hours), or 3 times per day (once every 8 hours), as required by the FDA dextromethorphan product labeling under the OTC monograph [21CFR341.74 ].

Dextromethorphan is rapidly metabolized in the human liver. This rapid hepatic metabolism may limit systemic drug exposure in individuals who are fast metabolizers. The person may be: 1) fast metabolizers of dextromethorphan-they metabolize dextromethorphan rapidly; 2) poor metabolizers of dextromethorphan-they are only weakly metabolized for dextromethorphan; or 3) moderate metabolites of dextromethorphan-they metabolize dextromethorphan somewhere between fast and weak metabolizers. Fast metabolizers may also be ultrafast metabolizers. Fast metabolizers of dextromethorphan are a substantial part of the human population. Dextromethorphan can be metabolized, for example, to dextrorphan.

When given the same oral dose of dextromethorphan, the plasma levels of dextromethorphan are significantly higher in weak or moderate metabolizers as compared to dextromethorphan fast metabolizers. The low plasma concentration of dextromethorphan can limit its clinical utility as a single agent for use in dextromethorphan fast and possibly moderate metabolizers. Some antidepressants, such as bupropion, inhibit the metabolism of dextromethorphan and may thus improve its therapeutic efficacy. Similarly, antidepressants may enable less frequent administration of dextromethorphan without loss of therapeutic efficacy, e.g., once per day rather than twice per day, once per day rather than three times per day, once per day rather than four times per day, twice per day rather than three times per day, or twice per day rather than four times per day.

Pain or other neurological conditions can be treated by a method comprising administering to a human in need thereof a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

Examples of neurological disorders that may be treated with a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, or that may be treated with increased efficacy, include, but are not limited to: affective disorders, psychotic disorders, brain disorders, movement disorders, dementia, motor neuron diseases, neurodegenerative diseases, episodic disorders and headache.

Affective disorders that can be treated by combination therapy with dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, depression, major depression, refractory depression and refractory bipolar depression, bipolar disorders including cyclothymic disorder, seasonal affective disorder, mania, anxiety, Attention Deficit Disorder (ADD), attention deficit disorder with hyperactivity (ADDH), attention deficit/hyperactivity disorder (AD/HD), bipolar and manic disorders, obsessive compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or abuse, nicotine addiction, psychological dysfunction, pseudobulbar mood, and mood swings.

Depression may be manifested as mood changes, feelings of intense sadness, hopelessness, thought retardation, lack of concentration, pessimistic anxiety, agitation, and self-depreciation. Physical symptoms of depression may include insomnia, anorexia, weight loss, decreased vitality and libido, and abnormal hormonal circadian rhythms.

Psychiatric disorders that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, anxiety disorders including, but not limited to, phobias, generalized anxiety disorder, social anxiety disorder, panic disorder, agoraphobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD); mania, manic depression, mild mania, unipolar depression, stress disorder, somatoform disorder, personality disorder, psychosis, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform (schizotypy), aggression, alzheimer's aggression, agitation, and alzheimer's agitation.

Substance addiction abuse that can be treated by combination of dextromethorphan with antidepressants such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or metabolites or prodrugs of any of these compounds includes, but is not limited to, drug dependence, addiction to cocaine, psychostimulants (e.g., tacaine, cocaine, bolus, methamphetamine), nicotine, alcohol, opioids, sedatives and hypnotics, cannabis, amphetamines, hallucinogens, phencyclidine, volatile solvents, and volatile nitrites. Nicotine addiction includes all known forms of nicotine addiction, such as smoking cigarettes, cigars and/or pipes, and also addiction to chewing tobacco.

Brain disorders that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, conditions involving intellectual deficits such as senile dementia, dementia of the alzheimer's type, memory loss, amnesia/amnesia syndrome, epilepsy, disturbances of consciousness, coma, attention deficit, language disorders, voice spasms, parkinson's disease, Lennox-Gastaut syndrome, autism, hyperactivity syndrome, and schizophrenia. Brain disorders also include conditions caused by cerebrovascular disorders, including, but not limited to, stroke, cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, cerebral venous thrombosis, head injury, and the like, wherein the symptoms include disturbance of consciousness, senile dementia, coma, reduced attention, and language disorders.

Movement disorders that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, akathisia, akinesia, joint movement, athetosis, ataxia, ballism, unilateral twitching, bradykinesia, cerebral palsy, chorea, huntington's disease, rheumatic chorea, sydenham's chorea, dyskinesia, tardive dyskinesia, dystonia, blepharospasm, spastic torticollis, dopamine-responsive dystonia, parkinson's disease, Restless Leg Syndrome (RLS), tremor, essential tremor, and Tourette's syndrome, and wilson's disease.

Dementias that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, alzheimer's disease, parkinson's disease, vascular dementia, dementia with lewy bodies, dementia of mixed type, frontotemporal dementia, creutzfeldt-jakob disease, hydrocephalus under normal pressure, huntington's disease, wernick-Korsakoff syndrome, and pick's disease.

Motor neuron diseases that can be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, Amyotrophic Lateral Sclerosis (ALS), progressive bulbar palsy, Primary Lateral Sclerosis (PLS), progressive amyotrophic lateral sclerosis, Polio Postpolio Syndrome (PPS), Spinal Muscular Atrophy (SMA), spinal motor atrophy, tajsar's disease, Sandoff's disease, and hereditary spastic paraplegia.

Neurodegenerative diseases that can be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo-hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, alzheimer's disease, prion-related diseases, cerebellar ataxia, spinocerebellar ataxia (SCA), Spinal Muscular Atrophy (SMA), bulbar muscular atrophy, friedrich's ataxia, huntington's disease, lewy body disease, parkinson's disease, amyotrophic lateral sclerosis (ALS or gray's disease), Multiple Sclerosis (MS), multiple system atrophy, Shy-Drager syndrome, corticobasal degeneration, progressive supranuclear palsy, wilson's disease, menkes disease, adrenoleukodystrophy, autosomal hereditary cerebral disease with subcortical infarction and leukoderma (cail) dasil, Muscular dystrophy, Charcot-Marie-Tooth disease (CMT), familial spastic paresis, neurofibromatosis, olivopontocerebellar atrophy or degeneration, striatal substantia nigra degeneration, Guillain-Barr é syndrome, and spastic paraplegia.

Seizure disorders that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, epileptic seizures, non-epileptic seizures, epilepsy, febrile seizures; partial seizures, including but not limited to simple partial seizures, jackson's seizures, complex partial seizures, and persistent partial epilepsy; systemic seizures include, but are not limited to, systemic tonic clonic seizures, absence seizures, dystonic seizures, myoclonic seizures, juvenile myoclonic seizures, and infantile spasms; and status epilepticus.

Types of headache that can be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include, but are not limited to, migraine, tension headache, and cluster headache.

Other neurological disorders that may be treated by combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds include Rett syndrome, autism, tinnitus, a disturbance of consciousness disorder, sexual dysfunction, refractory cough, narcolepsy, cataplexy; voice disorders due to uncontrolled laryngeal muscle spasm including, but not limited to, abductor spasmodic vocalization disorder, adductor spasmodic vocalization disorder, muscle tone vocalization disorder, and vocal tremor; 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.

In some embodiments, a combination of dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo-hydroxybupropion, or a metabolite or prodrug of any of these compounds, is useful in treating pain, pseudobulbar mood, depression (including treatment-refractory depression), memory and consciousness-related disorders, schizophrenia, parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Rhett syndrome, episodic disorders, cough (including chronic cough), and the like.

In some embodiments, a combination of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds can be used to treat dermatitis.

The analgesic properties of dextromethorphan can be enhanced by a method comprising co-administering dextromethorphan with an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo-hydroxybupropion, or a metabolite or prodrug of any of these compounds, together with dextromethorphan.

The analgesic properties of bupropion can be enhanced by a method comprising co-administering dextromethorphan with bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

These methods may be used to treat or alleviate any type of pain, including, but not limited to, musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, nociceptive pain, and the like.

Examples of musculoskeletal pain include low back pain (i.e., lumbosacral pain), primary dysmenorrhea, and arthritic pain, such as pain associated with rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, axial spine arthritis including ankylosing spondylitis, and the like.

In some embodiments, the combination of dextromethorphan with an antidepressant such as bupropion is used to treat chronic musculoskeletal pain.

Examples of neuropathic pain include diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, mononeuropathies, phantom limb pain, central pain, and the like. Neuropathic pain of other causes includes cancer-related pain, lumbar nerve root compression, spinal cord injury, post-stroke pain, central multiple sclerosis pain, HIV-related neuropathy, and radiation therapy and chemotherapy-related neuropathy, among others.

The term "treating" includes any activity in a human or other animal that diagnoses, cures, alleviates, treats, or prevents disease, or otherwise affects the structure or any function of the human or other animal's body.

Any antidepressant may be used in combination with dextromethorphan to improve the therapeutic properties of dextromethorphan. The dextromethorphan and antidepressant compounds may be administered in separate compositions or dosage forms, or may be administered in a single composition or dosage form comprising both.

Antidepressant compounds that may be co-administered with dextromethorphan include, but are not limited to, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloropropimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimetropizine, nortriptyline, maprotiline, phenelzine, isoxazole, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benatidine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, sibutramine, milnacipran, tebufenpyran, busoprofen, moclosamide, rasidone, rex, iprodione, valprozin, and nicotinon, Butilin, duloxetine, dibenzepine, iprindole, lofepramine, opipramol, norfluoxetine, dapoxetine, or the like, or a metabolite or prodrug of any of these compounds, or a pharmaceutically acceptable salt of any of these compounds.

Bupropion has the structure shown below (bupropion hydrochloride is shown).

Bupropion in combination with dextromethorphan can provide higher efficacy, e.g., better pain relief, than either component administered alone. In fast metabolizers, dextromethorphan can be metabolized quickly and well, resulting in low systemic exposure even at high doses. In addition to their antidepressant and analgesic properties, bupropion is also an inhibitor of dextromethorphan metabolism. Metabolites of bupropion are also inhibitors of dextromethorphan metabolism, and include hydroxybupropion, threo-hydroxybupropion (also known as threo-hydridobupropion or threo-dihydro-bupropion), and erythrohydroxybupropion (also known as erythrohydridobupropion or erythrodihydro-bupropion). Thus, bupropion is a prodrug of hydroxybupropion, threo-hydroxybupropion, and erythrohydroxybupropion.

As noted above, this inhibition may increase dextromethorphan plasma levels, resulting in additive or synergistic effects, such as neurological disorders including pain, relief from depression, smoking cessation, and the like. Thus, although inhibiting dextromethorphan metabolism is only one of many potential benefits of this combination, co-administration of dextromethorphan with bupropion can also thereby enhance the efficacy of bupropion in many individuals. For many individuals, co-administration of dextromethorphan with bupropion can enhance the analgesic properties of bupropion. For many individuals, co-administration of dextromethorphan with bupropion can also enhance the antidepressant properties of bupropion, including a faster onset of action.

Another potential benefit of co-administration of dextromethorphan and bupropion is that it can be used to reduce the likelihood of adverse events associated with dextromethorphan treatment, such as lethargy. This may be useful, for example, in patients at risk of an adverse event due to dextromethorphan treatment.

Another potential benefit of co-administration of dextromethorphan and bupropion is that it can be used to reduce the likelihood of adverse events, such as ictal disorders, associated with bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or metabolites or prodrugs of any of these compounds. This may be useful, for example, in patients at risk of an adverse event arising from treatment with bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

For dextromethorphan, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds can reduce central nervous system adverse events, gastrointestinal events, or another type of adverse event associated with any of these compounds. Central Nervous System (CNS) adverse events include, but are not limited to, nervousness, vertigo, insomnia, mild headache, tremor, hallucinations, convulsions, CNS depression, fear, anxiety, headache, irritability or excitability, tinnitus, drowsiness, vertigo, sedation, somnolence, confusion, disorientation, lassitude, incoordination, fatigue, euphoria, nervousness, insomnia, sleep disorders, convulsive seizures, excitation, catatonic states, hysteria, hallucinations, delusions, paranoia, headache and/or migraine, and extrapyramidal syndromes such as oculomotor crisis, torticollis, hyperexcitability, increased muscle tone, ataxia, and tongue vomiting.

Gastrointestinal adverse events include, but are not limited to, nausea, vomiting, abdominal pain, dysphagia, dyspepsia, diarrhea, abdominal distension, bloating, gastric ulcers with bleeding, loose stools, constipation, abdominal pain, heartburn, belching, loss of appetite, satiety, dyspepsia, bloating, hyperacidity, dry mouth, gastrointestinal disturbances, and stomachache.

Co-administration of dextromethorphan and an antidepressant such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds does not necessarily require that the two compounds be administered in the same dosage form. For example, the two compounds may be administered in a single dosage form, or they may be administered in two separate dosage forms. In addition, the two compounds may be administered simultaneously, but need not be. These compounds may be administered at different times, so long as both are present in the human for at least a portion of the time of treatment by co-administration.

In some embodiments, co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan results in bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or both a metabolite or prodrug of any of these compounds and dextromethorphan contributing to the pain relief performance of the combination. For example, the combination may have improved pain relief properties, including potentially faster onset of action, compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, or compared to dextromethorphan alone.

In some embodiments, the combination has an improved pain relieving property of at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, or a metabolite or prodrug of any of these compounds, as compared to bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, the combination, About 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief defined by or within a range between any of these values.

In some embodiments, the combination has improved pain relief properties compared to dextromethorphan alone, the improvement is at least about 0.5%, at least about 1%, at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least 100%, up to about 500% or up to about 1000%, about 0.5% to about 1000%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, about 90% to about 100%, about 100% to about 110%, about 110% to about 120%, about 120% to about 130%, about 130% to about 140%, about 140% to about 150%, about 150% to about 160%, about 160% to about 170%, about 170% to about 180%, about 180% to about 190%, about 190% to about 200%, or any amount of pain relief defined by or between any of these values.

Unless otherwise indicated, any reference to a compound herein, such as dextromethorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, by structure, name, or in any other way, includes pharmaceutically acceptable salts; alternative solid forms such as polymorphs, solvates, hydrates, and the like; tautomers; deuterium-modified compounds, such as deuterium-modified dextromethorphan; or any chemical species that can be rapidly converted to a compound described herein under the conditions used as described herein.

Examples of deuterium modified dextromethorphan include, but are not limited to, those shown below.

The dosage form or composition may be a blend or mixture of dextromethorphan and a compound that inhibits dextromethorphan metabolism, such as bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, either alone or in a carrier. For example, dextromethorphan and bupropion can be dispersed within each other or together in a carrier. Dispersions may comprise a mixture of solids in which small individual particles are essentially one compound, but small particles are dispersed in each other, as would occur, for example, if two powders of two different drugs were blended with a solid carrier and the blending was done in solid form. In some embodiments, dextromethorphan and bupropion can be substantially uniformly dispersed within the composition or dosage form. Alternatively, dextromethorphan and bupropion can be in separate domains or phases within a composition or dosage form. For example, one drug may be in the coating and the other drug may be in the core within the coating. For example, one drug may be configured for sustained release, while another drug may be configured for immediate release.

Some embodiments include administration of a tablet containing bupropion providing a sustained release form and dextromethorphan providing an immediate release form. Although there are many ways to achieve sustained release of bupropion, in some embodiments bupropion is combined with hydroxypropylmethyl cellulose. For example, bupropion hydrochloride particles can be combined with microcrystalline cellulose and hydroxypropyl methylcellulose (e.g., sodium hydroxide, and sodium hydroxide) Blended to form a blend of blended powders. This can then be combined with immediate release dextromethorphan in a single tablet.

Dextromethorphan and/or antidepressants, such as bupropion, hydroxybupropion, threo-hydroxybupropion, and erythrohydroxybupropion, or non-bupropion antidepressants (which are collectively referred to herein as "therapeutic compounds" for convenience) can be combined with a Pharmaceutical carrier selected based on the chosen route of administration and standard Pharmaceutical procedures, such as described in Remington's Pharmaceutical Sciences, 2005. The relative proportions of active ingredient and carrier can be determined, for example, by the solubility and chemical nature of the compound, the chosen route of administration, and standard pharmaceutical practice.

The therapeutic compound may be administered by any means that results in the active agent being in contact with one or more desired sites within the patient's body. These compounds may be administered by any conventional means useful in medicine, either as a sole therapeutic agent or in a combination of therapeutic agents. For example, they may be administered as the sole active ingredient in a pharmaceutical composition, or they may be used in combination with other therapeutically active ingredients.

The therapeutic compound may be administered to the patient in a variety of forms adapted to the chosen route of administration (e.g., oral or parenteral administration). In this regard, parenteral administration includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transdermal (including transdermal), ocular, sublingual and buccal; topical applications include ocular, dermal, ocular, rectal and by insufflation, nasal inhalation of aerosols, and rectal systems.

The ratio of dextromethorphan to bupropion can vary. In some embodiments, the weight ratio of dextromethorphan to bupropion can be about 0.1 to about 10, about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.5, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio defined by or within a range between any of these values. The ratio of 0.1 represents 1/10 where dextromethorphan weighs bupropion. Ratio 10 indicates that dextromethorphan weighs 10 times more than bupropion.

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

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

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

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

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

In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or any of these compoundsMay be administered at a time that results in an area under the curve (AUC) at day 8 of 12 hours from the time of dextromethorphan administration_0-12) Or the average plasma concentration (C) in humans 12 hours after dextromethorphan administration_avg) Is administered to a human in an amount of at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, at least about 40 times, at least about 50 times, at least about 60 times, at least about 70 times, at least about 80 times the plasma concentration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds can be administered at a dose that results in a maximum plasma concentration (Cmax) of dextromethorphan in humans at day 8 (Cmax)_max) Is administered to a human in an amount that is at least about 2 times, at least about 5 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 30 times, or at least about 40 times the plasma concentration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

For co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, an increase in dextromethorphan plasma concentration can occur on the first day of administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, as compared to administration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, on the first day of administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan plasma level can be at least about 1.5 times, at least about 2 times, at least about 2.5 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, or at least about 10 times the level that would be obtained if the same amount of dextromethorphan were administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

In some embodiments, on the first day of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds administration, the dextromethorphan AUC can be at least 2-fold the AUC obtained if the same amount of dextromethorphan is administered without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

In some embodiments, dextromethorphan C is administered on the first day of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds_maxCan be C if administered in the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds_maxAt least 2 times higher.

In some embodiments, on the first day of administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, the dextromethorphan trough level (e.g., plasma level at 12 hours after administration) can be at least 2-fold the trough level that would be obtained if administered with the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds.

In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds is administered on the first day of treatment with dextromethorphan for at least two days, wherein a decrease in the plasma levels of dextrorphan occurs on the first day of co-administration of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds, as compared to administration of the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds. For example, the first day dextrorphan plasma levels may be reduced by at least 5% compared to the dextrorphan plasma levels obtained if the same amount of dextromethorphan was administered without bupropion.

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

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

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

In some embodiments, bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a metabolite or prodrug of any of these compounds and dextromethorphan are co-administered for at least 8 consecutive days, wherein on day 8, e.g., 0 hour, 1 hour, 3 hours, 6 hours, or 12 hours after co-administration of bupropion and dextromethorphan, the plasma level of dextromethorphan is at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 60 times, at least 70 times, at least 80 times, at least 90 times, at least 100 times, or up to about 1000 times the plasma level obtained if dextromethorphan is administered in the same amount for 8 consecutive days without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or any metabolite or prodrug of these compounds.

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

In some embodiments, the bupropion can be administered at a dose that results in an AUC of bupropion in humans at day 8_0-12Is administered to a human in an amount of at least about 100 ng-hr/mL, at least about 200 ng-hr/mL, at least about 500 ng-hr/mL, at least about 600 ng-hr/mL, at least about 700 ng-hr/mL, at least about 800 ng-hr/mL, at least about 900 ng-hr/mL, at least about 1,000 ng-hr/mL, at least about 1,200 ng-hr/mL, at least 1,600 ng-hr/mL, or up to about 15,000 ng-hr/mL.

In some embodiments, the bupropion can be administered at a C that results in bupropion being in the human body at day 8_avgIs administered to the human in an amount of at least about 10ng/mL, at least about 20ng/mL, at least about 40ng/mL, at least about 50ng/mL, at least about 60ng/mL, at least about 70ng/mL, at least about 80ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least 120ng/mL, or up to 1,500 ng/mL.

In some embodiments of the present invention, the substrate is,bupropion can be administered at a C that results in bupropion being in humans at day 8_maxIs administered to the human in an amount of at least about 10ng/mL, at least about 20ng/mL, at least about 50ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least about 110ng/mL, at least about 120ng/mL, at least about 130ng/mL, at least about 140ng/mL, at least 200ng/mL, or up to 1,500 ng/mL.

Some liquid compositions may comprise from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% to about 10% (w/v), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v), from about 30% (w/v) to about 40% (w/v); and, Or about 40% (w/v) to about 50% (w/v) bupropion, or any amount of bupropion defined by or within the range between these values.

Some liquid dosage forms may contain from about 10mg to about 1000mg, from about 50mg to about 1000mg, from about 10mg to about 50mg, from about 50mg to about 100mg, from about 40mg to about 90mg, from about 200mg to about 300mg, from about 70mg to about 95mg, from about 100mg to about 200mg, from about 105mg to about 200mg, from about 110mg to about 140mg, from about 180mg to about 220mg, from about 280mg to about 320mg, from about 200mg, about 150mg, or about 300mg of bupropion, or any amount of bupropion defined by or within the ranges therebetween.

Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), About 70% (w/w) to about 80% (w/w), or about 80% (w/w) to about 90% (w/w) bupropion, or any amount of bupropion defined by or within a range between any of these values.

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

In some embodiments, bupropion is administered at a dose that results in a plasma level of bupropion of from about 0.1 μ Μ to about 10 μ Μ, from about 0.1 μ Μ to about 5 μ Μ, from about 0.2 μ Μ to about 3 μ Μ, from 0.1 μ Μ to about 1 μ Μ, from about 0.2 μ Μ to about 2 μ Μ, from 1 μ Μ to about 10 μ Μ, from about 1 μ Μ to about 5 μ Μ, from about 2 μ Μ to about 3 μ Μ, or from about 2.8 μ Μ to about 3 μ Μ, from about 1.5 μ Μ to about 2 μ Μ, from about 4.5 μ Μ to about 5 μ Μ, from about 2.5 μ Μ to about 3 μ Μ, about 1.8 μ Μ, about 4.8 μ Μ, about 2.9 μ Μ, about 2.8 μ Μ, or any plasma level defined by or between any of these values.

In some embodiments, the bupropion, hydroxybupropion, or prodrug of hydroxybupropion is administered at a dose that results in a plasma level of hydroxybupropion of from about 0.1 μ M to about 10 μ M, from about 0.1 μ M to about 5 μ M, from about 0.2 μ M to about 3 μ M, from 0.1 μ M to about 1 μ M, from about 0.2 μ M to about 2 μ M, from 1 μ M to about 10 μ M, from about 1 μ M to about 5 μ M, from about 2 μ M to about 3 μ M, or from about 2.8 μ M to about 3 μ M, from about 1.5 μ M to about 2 μ M, from about 4.5 μ M to about 5 μ M, from about 2.5 μ M to about 3 μ M, about 1.8 μ M, about 4.8 μ M, about 2.9 μ M, about 2.8 μ M, or any range defined by or between any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion can be administered at a time that results in an AUC of hydroxybupropion in humans at day 8_0-12Is at least about 3,000 ng-hr/mL, at least about 7,000 ng-hr/mL, at least about 10,000 ng-hr/mL, at least about 15,000 ng-hr/mL, at least about 20,000 ng-hr/mL, at least about 30,000 ng-hr/mL, up to about 50,000 ng-hr/mL, up to about 150,000 ng-hr/mL, or any AUC defined by or within a range between any of these values.

In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion can be administered at a time that results in a C of hydroxybupropion in humans at day 8_maxIs at least about 300ng/mL, at least about 700ng/mL, at least about 1,000ng/mL, at least about 1,500ng/mL, at least about 2,000ng/mL, at least about 4,000ng/mL, up to about 10,000ng/mL, up to about 50,000ng/mL, or any C defined by or within a range between any of these values_maxIs administered to a human.

In some embodiments, bupropion, hydroxybupropion, or a prodrug of hydroxybupropion can be administered at a time that results in a C of hydroxybupropion in humans at day 8_avgIs at least about 200ng/mL, at least about 300ng/mL, at least about 700ng/mL, at least about 1,000ng/mL, at least about 1,500ng/mL, at least about 2,000ng/mL, at least about 4,000ng/mL, up to about 10,000ng/mL, up to about 50,000ng/mL, or any C defined by or within a range between any of these values_avgIs administered to a human.

In some embodiments, bupropion, threo-hydroxy bupropion, or a prodrug of threo-hydroxy bupropion is administered at a dose that results in a threo-hydroxy bupropion plasma level of about 0.1 μ M to about 10 μ M, about 0.1 μ M to about 5 μ M, about 0.2 μ M to about 3 μ M, 0.1 μ M to about 1 μ M, about 0.2 μ M to about 2 μ M, 1 μ M to about 10 μ M, about 1 μ M to about 5 μ M, about 2 μ M to about 3 μ M, or about 2.8 μ M to about 3 μ M, about 1.5 μ M to about 2 μ M, about 4.5 μ M to about 5 μ M, about 2.5 μ M to about 3 μ M, about 1.8 μ M, about 4.8 μ M, about 2.9 μ M, about 2.8 μ M, or any range defined by or between any of these values.

In some embodiments, bupropion, threo-hydroxy bupropion, or a prodrug of threo-hydroxy bupropion can be administered in a dosage form that results in a AUC of threo-hydroxy bupropion in humans at day 8_0-12Is at least about 1,000 ng-hr/mL, at least about 2,000 ng-hr/mL, at least about 4,000 ng-hr/mL, at least about 5,000 ng-hr/mL, at least about 8,000 ng-hr/mL, up to about 10,000 ng-hr/mL, up to about 40,000 ng-hr/mL, or any range defined by or between any of these valuesThe amount of AUC is administered to humans.

In some embodiments, bupropion, threo-hydroxy bupropion, or a prodrug of threo-hydroxy bupropion can result in a C of threo-hydroxy bupropion in humans at day 8_maxIs at least about 100ng/mL, at least about 200ng/mL, at least about 400ng/mL, at least about 500ng/mL, at least about 600ng/mL, at least about 800ng/mL, up to about 2,000ng/mL, up to about 10,000ng/mL, or any C defined by or within a range between any of these values_maxIs administered to a human.

In some embodiments, bupropion, threo-hydroxy bupropion, or a prodrug of threo-hydroxy bupropion can be administered at a time that results in a C of the hydroxy bupropion in humans at day 8_avgIs at least about 100ng/mL, at least about 300ng/mL, at least about 400ng/mL, at least about 600ng/mL, at least about 800ng/mL, up to about 2,000ng/mL, up to about 10,000ng/mL, or any C defined by or within a range between any of these values_avgIs administered to a human.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion is administered at a dose that results in an erythrohydroxybupropion plasma level of about 0.1 μ M to about 10 μ M, about 0.1 μ M to about 5 μ M, about 0.2 μ M to about 3 μ M, 0.1 μ M to about 1 μ M, about 0.2 μ M to about 2 μ M, 1 μ M to about 10 μ M, about 1 μ M to about 5 μ M, about 2 μ M to about 3 μ M, or about 2.8 μ M to about 3 μ M, about 1.5 μ M to about 2 μ M, about 4.5 μ M to about 5 μ M, about 2.5 μ M to about 3 μ M, about 1.8 μ M, about 4.8 μ M, about 2.9 μ M, about 2.8 μ M, or any range defined by or between any of these values.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion can be administered in an amount that results in an AUC of erythrohydroxybupropion in humans at day 8_0-12Is at least about 200 ng-hr/mL, at least about 400 ng-hr/mL, at least about 700 ng-hr/mL, at least about 1,000 ng-hr/mL, at least about 1,500 ng-hr/mL, at least about 3,000 ng-hr/mL, up to about 5,000 ng-hr/mL, up to about 30,000 ng-hr/mL, or defined by or between any of these valuesAny amount of plasma level within the range is administered to the human.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion can result in a C of erythrohydroxybupropion in humans at day 8_maxIs at least about 30ng/mL, at least about 60ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least about 150ng/mL, at least about 200ng/mL, at least about 300ng/mL, up to about 1,000ng/mL, or any C defined by or within a range between any of these values_maxIs administered to a human.

In some embodiments, bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion can result in a C of erythrohydroxybupropion in humans at day 8_avgIs at least about 20ng/mL, at least about 30ng/mL, at least about 50ng/mL, at least about 80ng/mL, at least about 90ng/mL, at least about 100ng/mL, at least about 150ng/mL, at least about 200ng/mL, at least about 300ng/mL, up to about 1,000ng/mL, up to about 5,000ng/mL, or any C defined by or within a range between any of these values_avgIs administered to a human.

For compositions comprising dextromethorphan and bupropion, some liquids may comprise from about 0.0001% (w/v) to about 50% (w/v), from about 0.01% (w/v) to about 20% (w/v), from about 0.01% to about 10% (w/v), from about 1% (w/v) to about 3% (w/v), from about 3% (w/v) to about 5% (w/v), from about 5% (w/v) to about 7% (w/v), from about 5% (w/v) to about 15% (w/v), from about 7% (w/v) to about 10% (w/v), from about 10% (w/v) to about 15% (w/v), from about 15% (w/v) to about 20% (w/v), from about 20% (w/v) to about 30% (w/v) About 30% (w/v) to about 40% (w/v), or about 40% (w/v) to about 50% (w/v) dextromethorphan and bupropion combination, or any amount defined by or within a range between these values. Some solid compositions may comprise at least about 5% (w/w), at least about 10% (w/w), at least about 20% (w/w), at least about 50% (w/w), at least about 70% (w/w), at least about 80%, about 10% (w/w) to about 30% (w/w), about 10% (w/w) to about 20% (w/w), about 20% (w/w) to about 30% (w/w), about 30% (w/w) to about 50% (w/w), about 30% (w/w) to about 40% (w/w), about 40% (w/w) to about 50% (w/w), about 50% (w/w) to about 80% (w/w), about 50% (w/w) to about 60% (w/w), About 70% (w/w) to about 80% (w/w), about 80% (w/w) to about 90% (w/w) dextromethorphan and bupropion combination, or any amount defined by or within a range between any of these values. In some embodiments, the weight ratio of dextromethorphan to bupropion in a single composition or dosage form can be about 0.1 to about 2, about 0.2 to about 1, about 0.1 to about 0.3, about 0.2 to about 0.4, about 0.3 to about 0.5, about 0.5 to about 0.7, about 0.8 to about 1, about 0.2, about 0.3, about 0.4, about 0.45, about 0.6, about 0.9, or any ratio defined by or within a range between any of these values.

The therapeutically effective amount of the therapeutic compound may vary from case to case. For example, in some cases the daily dose of dextromethorphan may be from about 0.1mg to about 1000mg, from about 40mg to about 1000mg, from about 20mg to about 600mg, from about 60mg to about 700mg, from about 100mg to about 400mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, from about 45mg to about 50mg, from about 50mg to about 55mg, from about 55mg to about 60mg, from about 20mg to about 60mg, from about 60mg to about 100mg, about 100mg to about 200mg, about 100mg to about 140mg, about 160mg to about 200mg, about 200mg to about 300mg, about 220mg to about 260mg, about 300mg to about 400mg, about 340mg to about 380mg, about 400mg to about 500mg, about 500mg to about 600mg, about 15mg, about 30mg, about 60mg, about 120mg, about 180mg, about 240mg, about 360mg, or any daily dose defined by or within a range between any of these values. Dextromethorphan may be administered once daily; or twice daily or once every 12 hours, 3 times daily, 4 times daily or 6 times daily, in amounts of about one-half, one-third, one-fourth or one-sixth of the daily dose, respectively.

In some cases the daily dose of bupropion can be in the range of about 10mg to about 1000mg, about 50mg to about 600mg, about 100mg to about 2000mg, about 50mg to about 100mg, about 70mg to about 95mg, about 100mg to about 200mg, about 105mg to about 200mg, about 100mg to about 150mg, about 150mg to about 300mg, about 150mg to about 200mg, about 200mg to about 250mg, about 250mg to about 300mg, about 200mg to about 300mg, about 300mg to about 400mg, about 400mg to about 500mg, about 400mg to about 600mg, about 360mg to about 440mg, about 560mg to about 640mg, or about 500mg to about 600mg, about 100mg, about 150mg, about 200mg, about 300mg, about 400mg, about 600mg, or any daily dose defined by or between any of these values. Bupropion can be administered once daily; or twice daily or once every 12 hours, or 3 times daily, in amounts of about half or one third of the daily dose, respectively.

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

In some embodiments, about 150 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 60 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 90 mg/day of dextromethorphan, about 150 mg/day of bupropion and about 120 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 60 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 90 mg/day of dextromethorphan, about 200 mg/day of bupropion and about 120 mg/day of dextromethorphan, about 300 mg/day of bupropion and about 30 mg/day of dextromethorphan, about 300 mg/day of bupropion and about 60 mg/day of dextromethorphan, Administering to a human about 300 mg/day of bupropion and about 90 mg/day of dextromethorphan, or about 300 mg/day of bupropion and about 120 mg/day of dextromethorphan.

In some embodiments, about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan are administered to a human for 1,2, or 3 days, followed by 200 mg/day of bupropion and about 30 mg/day of dextromethorphan. In some embodiments, about 100 mg/day of bupropion and about 30 mg/day of dextromethorphan are administered to a human for 1,2, or 3 days, followed by 200 mg/day of bupropion and about 60 mg/day of dextromethorphan.

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

Antidepressant compounds such as bupropion can be administered for as long as necessary to treat neurological conditions such as pain, depression, or cough. In some embodiments, an antidepressant compound such as bupropion and dextromethorphan are administered at least once daily, e.g., once or twice daily, for at least 1 day, at least 3 days, at least 5 days, at least 7 days, at least 8 days, at least 14 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

The therapeutic compound may be configured for oral administration, e.g., with an inert diluent or with an edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the diet's food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

The tablets, troches, pills, capsules and the like may also contain one or more of the following ingredients: a binder such as gum tragacanth, gum acacia, corn starch, or gelatin; excipients, such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, and the like; lubricants, such as magnesium stearate; a sweetening agent, such as sucrose, lactose, or saccharin; or flavoring agents, such as mint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings, for example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor. It may be desirable that the materials in the dosage form or pharmaceutical composition be pharmaceutically pure and substantially non-toxic in the amounts employed.

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

The therapeutic compound may be configured for parenteral or intraperitoneal administration. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. The dispersion may also have an oil dispersed therein or in glycerol, liquid polyethylene glycol, or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

Embodiments of particular interest

The following are examples of embodiments specifically contemplated by the inventors:

embodiment 1. a method of treating pain or a neurological condition comprising administering to a human in need thereof a therapeutically effective amount of dextromethorphan and a therapeutically effective amount of an antidepressant compound.

Embodiment 2. a method of treating pain comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.

Embodiment 3. a method of enhancing the pain relieving properties of dextromethorphan, comprising co-administering dextromethorphan and an antidepressant compound.

Embodiment 4. a method of increasing plasma levels of dextromethorphan in a human that is a fast metabolite of dextromethorphan, comprising co-administering an antidepressant compound to a human receiving treatment comprising dextromethorphan administration.

Embodiment 5. a method of inhibiting dextromethorphan metabolism comprising administering an antidepressant compound to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human with the antidepressant compound.

Embodiment 6. a method of increasing the metabolic lifespan of dextromethorphan, comprising administering an antidepressant compound to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as the antidepressant compound.

Embodiment 7. a method of correcting the fast metabolism of dextromethorphan comprising administering an antidepressant compound to a human in need thereof.

Embodiment 8. a method of improving the pain relieving properties of dextromethorphan, comprising administering an antidepressant compound to a human in need of treatment for pain in conjunction with the administration of dextromethorphan.

Embodiment 9. a method of improving the antitussive performance of dextromethorphan, comprising administering an antidepressant compound to a human in need of treatment for cough in combination with the administration of dextromethorphan.

Embodiment 10. a method of treating cough comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.

Embodiment 11. a method of improving the therapeutic profile of dextromethorphan, comprising administering an antidepressant compound to a human in need of treatment of a neurological condition in combination with the administration of dextromethorphan.

Embodiment 12. a method of treating a neurological disorder comprising administering to a human in need thereof a combination of an antidepressant compound and dextromethorphan.

Embodiment 13. a method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human in need thereof, wherein the human is a fast metabolizer of dextromethorphan.

Embodiment 14 the method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, wherein the dextromethorphan and the antidepressant compound are administered in separate dosage forms.

Embodiment 15. a pharmaceutical composition comprising a therapeutically effective amount of dextromethorphan, a therapeutically effective amount of an antidepressant compound, and a pharmaceutically acceptable excipient.

Embodiment 16. an oral dosage form comprising at least 20mg of dextromethorphan and an effective amount of an antidepressant compound that inhibits the metabolism of dextromethorphan in a human that is a fast metabolizer of dextromethorphan.

Embodiment 17 the oral dosage form of embodiment 16, wherein about 30mg to about 350mg of dextromethorphan is present in the dosage form.

Embodiment 18 the oral dosage form of embodiment 16 or 17, wherein from about 100mg to about 400mg of bupropion is present in the dosage form.

Embodiment 19 the oral dosage form of any one of embodiments 16, 17 or 18, comprising an amount of bupropion that results in a plasma level of bupropion from about 0.1 μ M to about 10 μ M when the oral dosage form is administered to a human.

Embodiment 20 the oral dosage form of embodiment 19, comprising an amount of bupropion that results in a plasma level of bupropion from about 0.1 μ Μ to about 2 μ Μ when the oral dosage form is administered to a human.

Embodiment 21 the method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 wherein the bupropion is administered at a dose that results in a plasma level of bupropion from about 0.1 μ Μ to about 10 μ Μ.

Embodiment 22 the method of embodiment 21, wherein the bupropion is administered at a dose that results in a plasma level of bupropion from about 0.3 μ M to about 1 μ M.

Embodiment 23 the method, composition or dosage form of any one of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is bupropion or a metabolite thereof.

Embodiment 24 the method, composition or dosage form of any one of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 wherein the antidepressant compound is bupropion.

Embodiment 25 the method, composition or dosage form of any one of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17, wherein the antidepressant compound is clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloropropimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isoxazole, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindane, benatidine, escitalopram, fluvoxamine, venlafaxine, desvenlafaxine, duloxetine, mirtazapine, nefazodone, selegiline, or a pharmaceutically acceptable salt thereof.

Embodiment 26 the method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 21, 22, 23, 24, or 25, wherein dextromethorphan is administered to a human for the treatment of cough.

Embodiment 27. a method of treating a neurological disorder comprising administering bupropion at about 150 mg/day to about 300 mg/day and dextromethorphan at about 30 mg/day to about 120 mg/day to a human in need thereof.

Embodiment 28. a method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered at least once daily for at least 8 days.

Embodiment 29 the method of embodiment 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, or 27 wherein the bupropion is administered to the human for at least 8 days, at least once daily.

Embodiment 30 the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, or 28, wherein dextromethorphan is administered to a human for at least 8 days at least once daily.

Embodiment 31 the method of embodiment 28, 29 or 30, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human on day 8 that is at least 10 times the same amount of dextromethorphan administered without the plasma concentration of bupropion.

Embodiment 32, embodiments 28 and 29,30. The method of (1) or (31), wherein the bupropion is administered at a dose that results in a AUC of hydroxybupropion at day 8_0-12Is administered in an amount of at least about 3000 ng-hr/mL.

Embodiment 33 the method of embodiment 28, 29, 30, 31, or 32, wherein the bupropion is administered in a manner that results in an AUC of erythrohydroxybupropion at day 8_0-12Is administered in an amount of at least about 400 ng-hr/mL.

Embodiment 34 the method of embodiment 28, 29, 30, 31, 32, or 33, wherein the bupropion is administered at an AUC that results in threo hydroxy bupropion at day 8_0-12Is administered in an amount of at least about 2000 ng-hr/mL.

Embodiment 35 the method, composition or dosage form of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33 or 34, wherein the weight ratio of dextromethorphan to bupropion is from about 0.1 to about 0.5.

Embodiment 36 the method of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35, wherein the human is a fast metabolizer of dextromethorphan.

Embodiment 37, the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 150 mg/day and dextromethorphan is administered at about 30 mg/day to a human.

Embodiment 38 the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 150 mg/day and dextromethorphan is administered at about 60 mg/day to a human.

Embodiment 39 the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 200 mg/day and dextromethorphan is administered at about 30 mg/day to a human.

Embodiment 40 the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 100 mg/day and dextromethorphan at about 15 mg/day for about 1 to about 3 days and then bupropion is administered at about 200 mg/day and dextromethorphan at about 30 mg/day.

Embodiment 41 the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 200 mg/day and dextromethorphan is administered at about 60 mg/day to a human.

Embodiment 42. the method of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, wherein bupropion is administered at about 100 mg/day and dextromethorphan at about 30 mg/day for about 1 to about 3 days and then bupropion is administered at about 200 mg/day and dextromethorphan at about 60 mg/day.

Embodiment 43, embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or 42, wherein dextromethorphan is administered to a human for the treatment of pain.

Embodiment 44 the method of embodiment 43, wherein the pain comprises post-operative pain, cancer pain, arthritis pain, lumbosacral pain, musculoskeletal pain, central multiple sclerosis pain, nociceptive pain, or neuropathic pain.

Embodiment 45 the method of embodiment 43, wherein the pain comprises musculoskeletal pain, neuropathic pain, cancer-related pain, acute pain, or nociceptive pain.

Embodiment 46 the method of embodiment 43, wherein the pain comprises post-operative pain.

Embodiment 47 the method of embodiment 43, wherein the pain comprises cancer pain.

Embodiment 48 the method of embodiment 43, wherein the pain comprises arthritis pain.

Embodiment 49 the method of embodiment 43, wherein the pain comprises lumbosacral pain.

Embodiment 50 the method of embodiment 43, wherein the pain comprises musculoskeletal pain.

Embodiment 51 the method of embodiment 43, wherein the pain comprises neuropathic pain.

Embodiment 52 the method of embodiment 43, wherein the pain comprises nociceptive pain.

Embodiment 53 the method of embodiment 43, wherein the pain comprises chronic musculoskeletal pain.

Embodiment 54 the method of embodiment 43, wherein the pain is associated with rheumatoid arthritis.

Embodiment 55 the method of embodiment 43, wherein the pain is associated with juvenile rheumatoid arthritis.

Embodiment 56 the method of embodiment 43, wherein the pain is associated with osteoarthritis.

Embodiment 57 the method of embodiment 43, wherein the pain is associated with central spine arthritis.

Embodiment 58 the method of embodiment 43, wherein the pain is associated with ankylosing spondylitis.

Embodiment 59 the method of embodiment 43, wherein the pain is associated with diabetic peripheral neuropathy.

Embodiment 60 the method of embodiment 43, wherein the pain is associated with post-herpetic neuralgia.

Embodiment 61 the method of embodiment 43, wherein the pain is associated with trigeminal neuralgia.

Embodiment 62 the method of embodiment 43, wherein the pain is associated with radiculopathy.

Embodiment 63 the method of embodiment 43, wherein the pain is associated with phantom limb pain.

Embodiment 64 the method of embodiment 43, wherein the pain is associated with central pain.

Embodiment 65 the method of embodiment 43, wherein the pain comprises cancer-related pain.

Embodiment 66 the method of embodiment 43, wherein the pain is associated with lumbar nerve root compression.

Embodiment 67 the method of embodiment 43, wherein the pain is associated with spinal cord injury.

Embodiment 68 the method of embodiment 43, wherein the pain is associated with post-stroke pain.

Embodiment 69 the method of embodiment 43, wherein the pain is associated with central multiple sclerosis pain.

Embodiment 70 the method of embodiment 43, wherein the pain is associated with HIV-associated neuropathy.

Embodiment 71 the method of embodiment 43, wherein the pain is associated with radiation therapy-associated neuropathy.

Embodiment 72 the method of embodiment 43, wherein the pain is associated with chemotherapy-associated neuropathy.

Embodiment 73 the method of embodiment 43, wherein the pain comprises a dental pain.

Embodiment 74 the method of embodiment 43, wherein the pain is associated with primary dysmenorrhea.

Embodiment 75, embodiment 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, or 74, wherein dextromethorphan is administered to a human at 90 mg/day.

Embodiment 76 the method of embodiment 75, wherein 45mg of dextromethorphan is administered to the human twice daily.

Embodiment 77 the method of embodiment 75 or 76, wherein the bupropion is administered to the human at 150 mg/day.

Embodiment 78 the method of embodiment 75 or 76, wherein the bupropion is administered at 180 mg/day to the human.

Embodiment 79 the method of embodiment 75 or 76, wherein bupropion is administered to the human at 200 mg/day.

The method of claim 123 or 124, wherein the bupropion is administered to the human at 300 mg/day.

U.S. provisional application No.61/900,354 is incorporated herein by reference in its entirety.

Examples

Example 1

The 15 human subjects were randomized to one of two treatment groups, receiving Dextromethorphan (DM) alone, or DM in combination with bupropion, as shown in table 1 below.

TABLE 1 study design

All subjects were fast metabolizers of dextromethorphan, including ultrafast metabolizers, as determined by the CYP2D6 gene test. Dextromethorphan is administered at 12 hour intervals on days 1 to 8, with the last dose on day 8 in the morning. Bupropion is administered once daily on days 1 to 3, followed by 12 hour intervals, and the last dose on day 8 in the morning.

Plasma samples were collected on days 1 and 8 for concentration analysis of dextromethorphan, total dextrorphan, bupropion, hydroxybupropion, erythrohydroxybupropion, and threo hydroxybupropion. Plasma samples were obtained approximately 12 hours after dosing on days 1,5, 6 and 8 for determining the trough concentration of dextromethorphan.

The concentrations of dextromethorphan, total dextrorphan (unconjugated and glucuronide forms), bupropion, hydroxybupropion, erythrohydroxybupropion, and threo hydroxybupropion were determined using LC-MS/MS. Pharmacokinetic parameters were calculated.

Phenotypic determination of the status of dextromethorphan metabolites was performed by calculating the ratio of dextromethorphan/dextrorphan metabolism as described in Journal of Clinical Pharmacy and Therapeutics,2012,37, 486-490 of Jurica et al. Using the plasma concentrations of dextromethorphan and dextrorphan at 3 hours post-administration, a dextromethorphan/dextrorphan ratio of 0.3 or more indicates a weak metabolite phenotype.

As a result:

with bupropion administration, the plasma concentration of dextromethorphan was significantly increased, as shown in figure 1 and table 2.

TABLE 2 mean plasma concentration of dextromethorphan (ng/mL) on day 8

As shown in figures 2 to 4, AUC for dextromethorphan increased significantly with bupropion administration. As shown in figure 5, administration of bupropion in conjunction with dextromethorphan resulted in an average dextromethorphan AUC, respectively, at day 8 compared to dextromethorphan alone administration_0-12、AUC_0-24And AUC_0-infThe increases were approximately 60-fold, 80-fold, and 175-fold. As shown in fig. 6, an increase in dextromethorphan AUC (AUC) occurs as early as day one_0--12Approximately a 3-fold increase).

With bupropion administration, the trough plasma concentration of dextromethorphan was significantly increased, as shown in fig. 7 and table 3. Administration of bupropion in conjunction with dextromethorphan resulted in an approximately 105-fold increase in the mean plasma concentration of dextromethorphan at day 8 compared to dextromethorphan alone.

Mean plasma concentration (C) of mean dextromethorphan at day 8 with bupropion administration compared to dextromethorphan administration alone_avg) The increase is about 60 times. Maximum mean plasma concentration (C)_max) Also significantly increased as shown in figure 8.

TABLE 3 average dextromethorphan trough plasma concentration (ng/mL)

T of dextromethorphan on day 8 with bupropion administration_maxAnd elimination half-life (T)_1/2el) Is remarkably increased. Administration of bupropion in conjunction with dextromethorphan resulted in an average T compared to 2.3 hours for dextromethorphan alone_maxIt was 3.6 hours. Administration of bupropion in conjunction with dextromethorphan resulted in an average T for 6.6 hours compared to dextromethorphan alone_1/2elIt was 27.7 hours.

With bupropion administration, the plasma concentration of dextrorphan was significantly reduced, as shown in figure 9 and table 4.

TABLE 4 mean plasma concentration of dextrorphan (ng/mL) on day 8

As shown in FIGS. 10 to 11, when administered with bupropion, 8 th balance homodextrorphan C_maxThere was an approximate 78% reduction, mean dextrorphan AUC_0-12There is a reduction of about 55%.

Phenotypic determination of dextromethorphan metabolite status showed that none of the subjects in either treatment group were weak metabolites at day 1. However, on day 8, 100% of subjects treated with bupropion converted to a weak metabolizer state compared to 0% of subjects treated with dextromethorphan alone. With bupropion administration, the mean plasma dextromethorphan/dextrorphan metabolic ratio increased from 0.01 on day one to 0.71 on day 8. The average proportion in the DM-alone group was 0.00 on day 8 and remained unchanged.

On day 8, mean plasma concentrations of bupropion, hydroxybupropion, erythrohydroxybupropion, and threo hydroxybupropion were at least 10ng/mL, 200ng/mL, 20ng/mL, and 100ng/mL, respectively, after bupropion administration.

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

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

The use of quantitative terms in the context of describing the invention (especially in the context of the following claims) is to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Members of each group may be referred to or claimed individually, or in any combination with other members of that group or other elements found herein. It is envisioned that one or more members of a group may be included in or deleted from the group for convenience and/or patentability. When any such inclusion or deletion occurs, the specification is to be considered as including the modified group, thus completing the written description of all markush groups used in the appended claims.

Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, modifications to the described embodiments will be apparent to those skilled in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, as permitted by applicable law, the appended claims include all modifications and equivalents of the subject matter recited in the claims. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.

Finally, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications may be employed within the scope of the claims. Accordingly, by way of example, and not limitation, alternative embodiments may be used in accordance with the teachings herein. Accordingly, the claims are not limited to the embodiments shown and described at the very least.

The following corresponds to the original claims in the parent application, which are now incorporated as part of the specification:

1. a method of treating a neurological disorder comprising administering an antidepressant compound and dextromethorphan to a human in need thereof, wherein the human is a fast metabolizer of dextromethorphan.

2. The method of item 1, wherein the neurological disorder is depression.

3. The method of item 1, wherein the neurological disorder is cough.

4. The method of item 1,2 or 3, wherein the antidepressant comprises hydroxybupropion or a prodrug thereof.

5. The method of clauses 1,2, 3 or 4, wherein the antidepressant comprises erythrohydroxybupropion or a prodrug thereof.

6. The method of items 1,2, 3, 4, or 5, wherein the antidepressant comprises threo hydroxy bupropion or a prodrug thereof.

7. A method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, the method comprising co-administering bupropion with dextromethorphan to the human.

8. A method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, comprising co-administering to the human a hydroxybupropion or a prodrug thereof and dextromethorphan.

9. A method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, comprising co-administering to the human erythrohydroxybupropion or a prodrug thereof with dextromethorphan.

10. A method of increasing plasma levels of dextromethorphan in a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, comprising co-administering threo-hydroxybupropion or a prodrug thereof to the human.

11. A method of inhibiting dextromethorphan metabolism comprising administering bupropion to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as bupropion.

12. A method of inhibiting dextromethorphan metabolism comprising administering hydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and hydroxybupropion are present in the human at the same time.

13. A method of inhibiting dextromethorphan metabolism comprising administering erythrohydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and erythrohydroxybupropion are present in the human at the same time.

14. A method of inhibiting dextromethorphan metabolism comprising administering threo-hydroxybupropion or a prodrug thereof to a human, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan and threo-hydroxybupropion are present in the human at the same time.

15. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering bupropion to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as the bupropion.

16. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as hydroxybupropion.

17. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering erythrohydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as erythrohydroxybupropion.

18. A method of increasing the metabolic lifespan of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof to a human in need of treatment with dextromethorphan, wherein the human is a fast metabolizer of dextromethorphan, and wherein dextromethorphan is present in the human at the same time as threo-hydroxybupropion.

19. A method of increasing a plasma level of dextromethorphan, comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of co-administration of bupropion and dextromethorphan for at least two days, wherein the increase in the plasma level of dextromethorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to administration of the same amount of dextromethorphan without bupropion.

20. The method of item 19, wherein the dextromethorphan plasma level on the first day of co-administration of bupropion and dextromethorphan is at least 2-fold the level obtained if administered in the same amount of dextromethorphan without bupropion.

21. A method of increasing plasma levels of dextromethorphan, comprising co-administering to a human in need of treatment with dextromethorphan, a hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the hydroxybupropion or prodrug thereof is administered on the first day of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein the increase in plasma levels of dextromethorphan occurs on the first day of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan compared to the same amount of dextromethorphan administered without hydroxybupropion or a prodrug thereof.

22. The method of item 21, wherein the dextromethorphan plasma level on the first day of co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan is at least 2-fold the level that would be obtained if administered in the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

23. A method of increasing a plasma level of dextromethorphan, comprising co-administering erythro-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the erythro-hydroxybupropion or the prodrug thereof is administered on the first day of co-administration of erythro-hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein the increase in the plasma level of dextromethorphan occurs on the first day of co-administration of erythro-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan without erythro-hydroxybupropion or a prodrug thereof.

24. The method of item 23, wherein the dextromethorphan plasma level on the first day of co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan is at least 2-fold the level that would be obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

25. A method of increasing a plasma level of dextromethorphan, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the threo-hydroxybupropion or prodrug thereof is administered on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan for at least two days, wherein the increase in the plasma level of dextromethorphan occurs on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

26. The method of item 25, wherein the dextromethorphan plasma level on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof with dextromethorphan is at least 2-fold the level obtained if administered in the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

27. A method of increasing a dextromethorphan plasma level comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if administered with the same amount of dextromethorphan for 5 consecutive days without bupropion.

28. The method of item 27, wherein the dextromethorphan plasma level on day 5 of co-administration of bupropion and dextromethorphan is at least 20-fold greater than the level obtained if administered with the same amount of dextromethorphan for 5 consecutive days without bupropion.

29. A method of increasing a plasma level of dextromethorphan, comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 5 consecutive days, wherein on day 5 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 5 consecutive days without hydroxybupropion or a prodrug thereof.

30. The method of item 29, wherein the dextromethorphan plasma level on day 5 of co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan is at least 20-fold greater than the level obtained if the same amount of dextromethorphan were administered for 5 consecutive days without hydroxybupropion or a prodrug thereof.

31. A method of increasing a plasma level of dextromethorphan, comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 5 consecutive days without erythrohydroxybupropion or a prodrug thereof.

32. The method of item 31, wherein the dextromethorphan plasma level on day 5 of co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan is at least 20-fold greater than the level obtained if the same amount of dextromethorphan were administered for 5 consecutive days without erythrohydroxybupropion or a prodrug thereof.

33. A method of increasing a plasma level of dextromethorphan, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 5 consecutive days, wherein on day 5 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 5 consecutive days without threo-hydroxybupropion or a prodrug thereof.

34. The method according to item 33, wherein the dextromethorphan plasma level on day 5 of co-administration of threo-hydroxybupropion or a prodrug thereof with dextromethorphan is at least 20-fold greater than the level obtained if the same amount of dextromethorphan were administered for 5 consecutive days without threo-hydroxybupropion or a prodrug thereof.

35. A method of increasing a dextromethorphan plasma level comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if administered with the same amount of dextromethorphan for 6 consecutive days without bupropion.

36. The method of item 35, wherein the dextromethorphan plasma level on day 6 of co-administration of bupropion and dextromethorphan is at least 30-fold the level obtained if administered with the same amount of dextromethorphan for 6 consecutive days without bupropion.

37. A method of increasing a plasma level of dextromethorphan, comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 6 consecutive days, wherein on day 6 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 6 consecutive days without hydroxybupropion or a prodrug thereof.

38. The method of item 37, wherein the dextromethorphan plasma level on day 6 of co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan is at least 30-fold the level that would be obtained if the same amount of dextromethorphan were administered for 6 consecutive days without hydroxybupropion or a prodrug thereof.

39. A method of increasing a plasma level of dextromethorphan, comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 6 consecutive days without erythrohydroxybupropion or a prodrug thereof.

40. The method of item 39, wherein the dextromethorphan plasma level on day 6 of co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan is at least 30-fold the level obtained if the same amount of dextromethorphan is administered for 6 consecutive days without erythrohydroxybupropion or a prodrug thereof.

41. A method of increasing a plasma level of dextromethorphan, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 6 consecutive days, wherein on day 6 the dextromethorphan plasma level is higher than a dextromethorphan plasma level obtained if the same amount of dextromethorphan is administered for 6 consecutive days without threo-hydroxybupropion or a prodrug thereof.

42. The method of item 41, wherein the dextromethorphan plasma level on day 6 of co-administration of threo-hydroxybupropion or a prodrug thereof with dextromethorphan is at least 30-fold the level obtained if the same amount of dextromethorphan is administered for 6 consecutive days without threo-hydroxybupropion or a prodrug thereof.

43. A method of reducing plasma levels of dextrorphan comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the bupropion is administered on the first day of at least two days of dextromethorphan treatment, wherein the reduction in plasma levels of dextrorphan occurs on the first day of co-administration of bupropion and dextromethorphan as compared to the same amount of dextromethorphan administration without bupropion.

44. The method of item 43, wherein the dextrorphan plasma levels are reduced by at least 5% on the first day of co-administration of bupropion and dextromethorphan as compared to dextrorphan plasma levels obtained if administered at the same amount of dextromethorphan without bupropion.

45. A method of reducing plasma levels of dextrorphan comprising co-administering to a human in need of treatment with dextromethorphan, hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the hydroxybupropion or prodrug thereof is administered on the first day of dextromethorphan treatment for at least two days, wherein the reduction in plasma levels of dextrorphan occurs on the first day of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan administration without hydroxybupropion or a prodrug thereof.

46. The method of clause 45, wherein the dextrorphan plasma levels are reduced by at least 5% on the first day of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan as compared to dextrorphan plasma levels obtained if administered at the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

47. A method of reducing plasma levels of dextrorphan comprising co-administering erythro hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan, wherein the erythro hydroxybupropion or the prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, wherein the reduction in plasma levels of dextrorphan occurs on the first day of co-administration of erythro hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan administration without erythro hydroxybupropion or a prodrug thereof.

48. The method of clause 47, wherein the dextrorphan plasma levels are reduced by at least 5% on the first day of co-administration of erythrohydroxybupropion or a prodrug thereof and dextromethorphan as compared to dextrorphan plasma levels obtained if administered at the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

49. A method of reducing plasma levels of dextrorphan comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein the threo-hydroxybupropion or prodrug thereof is administered on the first day of at least two days of dextromethorphan treatment, wherein the reduction in plasma levels of dextrorphan occurs on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to the same amount of dextromethorphan administration without threo-hydroxybupropion or a prodrug thereof.

50. The method of clause 49, wherein the dextrorphan plasma levels are reduced by at least 5% on the first day of co-administration of threo-hydroxybupropion or a prodrug thereof and dextromethorphan as compared to dextrorphan plasma levels obtained if administered at the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

51. A method of reducing plasma levels of dextrorphan comprising co-administering bupropion and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8 the dextrorphan plasma levels are lower than those obtained if administered with the same amount of dextromethorphan for 8 consecutive days without bupropion.

52. The method of clause 51, wherein the plasma levels are reduced by at least 30% on day 8 of co-administration of bupropion and dextromethorphan as compared to dextrorphan plasma levels obtained if administered at the same amount of dextromethorphan for 8 consecutive days without bupropion.

53. A method of reducing plasma levels of dextrorphan comprising co-administering to a human in need of treatment with dextromethorphan with hydroxybupropion or a prodrug thereof for at least 8 consecutive days, wherein on day 8 the dextrorphan plasma levels are lower than those obtained if the same amount of dextromethorphan were administered for 8 consecutive days without hydroxybupropion or a prodrug thereof.

54. The method of clause 53, wherein the plasma levels are reduced by at least 30% on day 8 of co-administration of hydroxybupropion or a prodrug thereof and dextromethorphan compared to dextrorphan plasma levels obtained if administered with the same amount of dextromethorphan for 8 consecutive days without hydroxybupropion or a prodrug thereof.

55. A method of reducing plasma levels of dextrorphan comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8 the dextrorphan plasma levels are lower than those obtained if administered with the same amount of dextromethorphan for 8 consecutive days without erythrohydroxybupropion or a prodrug thereof.

56. The method of clause 55, wherein the plasma level is reduced by at least 30% on day 8 of co-administration of erythrohydroxybupropion or a prodrug thereof and dextromethorphan, as compared to dextrorphan plasma level obtained if administered with the same amount of dextromethorphan for 8 consecutive days without erythrohydroxybupropion or a prodrug thereof.

57. A method of reducing plasma levels of dextrorphan comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need of treatment with dextromethorphan for at least 8 consecutive days, wherein on day 8 the dextrorphan plasma levels are lower than those obtained if the same amount of dextromethorphan were administered for 8 consecutive days without threo-hydroxybupropion or a prodrug thereof.

58. The method of clause 57, wherein the plasma level is reduced by at least 30% on day 8 of co-administration of threo-hydroxybupropion or prodrug thereof and dextromethorphan, as compared to dextrorphan plasma level obtained if administered with the same amount of dextromethorphan for 8 consecutive days without threo-hydroxybupropion or prodrug thereof.

59. A method of attenuating the effects of dextromethorphan valley comprising co-administering bupropion and dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administration of bupropion and dextromethorphan that is at least twice the plasma level obtained if administered at the same amount of dextromethorphan without bupropion.

60. The method of item 59, wherein, after the first co-administration of bupropion and dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administration of bupropion and dextromethorphan that is at least twice the plasma level obtained if administered at the same amount of dextromethorphan without bupropion.

61. A method of attenuating the effects of dextromethorphan valley comprising co-administering to a patient in need of treatment with dextromethorphan a hydroxybupropion or a prodrug thereof, wherein dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered with the same amount of dextromethorphan without hydroxybupropion or a prodrug thereof.

62. The method of item 61, wherein, after the first co-administration of hydroxybupropion or prodrug thereof with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or prodrug thereof with dextromethorphan that is at least twice the plasma level that would be obtained if administered in the same amount of dextromethorphan without hydroxybupropion or prodrug thereof.

63. A method of attenuating the effects of dextromethorphan valley comprising co-administering erythro-hydroxybupropion or a prodrug thereof with dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administration of erythro-hydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered in the same amount of dextromethorphan without erythro-hydroxybupropion or a prodrug thereof.

64. The method of item 63, wherein, after the first co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan, dextromethorphan has a plasma level 12 hours after the co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

65. A method of attenuating the effects of dextromethorphan trough, comprising co-administering threo-hydroxybupropion or a prodrug thereof with dextromethorphan to a patient in need of treatment with dextromethorphan, wherein dextromethorphan has a plasma level 12 hours after co-administration of threo-hydroxybupropion or a prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered with the same amount of dextromethorphan without threo-hydroxybupropion or a prodrug thereof.

66. The method of item 65, wherein, after the first co-administration of threo-hydroxybupropion or prodrug thereof with dextromethorphan, dextromethorphan has a plasma level 12 hours after co-administration of threo-hydroxybupropion or prodrug thereof with dextromethorphan that is at least twice the plasma level obtained if administered in the same amount of dextromethorphan without threo-hydroxybupropion or prodrug thereof.

67. The method of clauses 1,2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, or 60, wherein bupropion is co-administered with dextromethorphan for at least 5 consecutive days, wherein, on day 5, dextromethorphan has a plasma level 12 hours after co-administration of bupropion and dextromethorphan that is at least 40-fold the plasma level obtained if administered in the same amount of dextromethorphan without bupropion.

68. The method of clauses 1,2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, or 62, wherein the hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 5 consecutive days, wherein, on day 5, dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or prodrug thereof with dextromethorphan that is at least 40-fold higher than the plasma level obtained if administered in the same amount of dextromethorphan without hydroxybupropion or prodrug thereof.

69. The method of any one of items 1,2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, or 64, wherein the co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan is for at least 5 consecutive days, wherein on day 5 dextromethorphan has a plasma level 12 hours after the co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan that is at least 40 times greater than the plasma level obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

70. The method of any of items 1,2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, wherein threo hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 5 consecutive days, wherein on day 5 dextromethorphan has a plasma level 12 hours after co-administration of threo hydroxybupropion or prodrug thereof with dextromethorphan that is at least 40-fold the plasma level obtained if administered in the same amount of dextromethorphan without threo hydroxybupropion or prodrug thereof.

71. The method of clauses 1,2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, or 67, wherein bupropion is co-administered with dextromethorphan for at least 6 consecutive days, wherein, on day 6, dextromethorphan has a plasma level 12 hours after co-administration of bupropion with dextromethorphan that is at least 50 times the plasma level obtained if administered in the same amount of dextromethorphan without bupropion.

72. The method of clauses 1,2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, or 68, wherein the hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 6 consecutive days, wherein on day 6, dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or prodrug thereof with dextromethorphan that is at least 50-fold the plasma level obtained if administered in the same amount of dextromethorphan without hydroxybupropion or prodrug thereof.

73. The method of any one of items 1,2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, or 69, wherein erythrohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least 6 consecutive days, wherein on day 6 dextromethorphan has a plasma level 12 hours after co-administration of erythrohydroxybupropion or a prodrug thereof and dextromethorphan that is at least 50 times greater than the plasma level obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

74. The method of clauses 1,2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, or 70, wherein threo hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 6 consecutive days, wherein on day 6 dextromethorphan has a plasma level 12 hours after co-administration of threo hydroxybupropion or prodrug thereof with dextromethorphan that is at least 50 times the plasma level obtained if administered in the same amount of dextromethorphan without threo hydroxybupropion or prodrug thereof.

75. The method of clauses 1,2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, 67, or 71, wherein bupropion is co-administered with dextromethorphan for at least 7 consecutive days, wherein, on day 7, dextromethorphan has a plasma level 12 hours after co-administration of bupropion with dextromethorphan that is at least 70 times the plasma level obtained if administered in the same amount of dextromethorphan without bupropion.

76. The method of clauses 1,2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, 68, or 72, wherein the hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 7 consecutive days, wherein on day 7 dextromethorphan has a plasma level 12 hours after co-administration of hydroxybupropion or prodrug thereof with dextromethorphan that is at least 70-fold higher than the plasma level obtained if administered in the same amount of dextromethorphan without hydroxybupropion or prodrug thereof.

77. The method of items 1,2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, or 73, wherein erythrohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least 7 consecutive days, wherein on day 7 dextromethorphan has a plasma level 12 hours after co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan that is at least 70 times the plasma level obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

78. The method of clauses 1,2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 70, or 74, wherein threo hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 7 consecutive days, wherein on day 7 dextromethorphan has a plasma level 12 hours after co-administration of threo hydroxybupropion or prodrug thereof and dextromethorphan that is at least 70 times the plasma level obtained if administered in the same amount of dextromethorphan without threo hydroxybupropion or prodrug thereof.

79. The method of clauses 1,2, 3, 7, 11, 15, 19, 20, 27, 28, 35, 36, 43, 44, 51, 52, 59, 60, 67, 71, or 75, wherein bupropion is co-administered with dextromethorphan for at least 8 consecutive days, wherein, on day 8, dextromethorphan has a plasma level 12 hours after co-administration of bupropion with dextromethorphan that is at least 80-fold the plasma level obtained if administered in the same amount of dextromethorphan without bupropion.

80. The method of clauses 1,2, 3, 4, 8, 12, 16, 21, 22, 29, 30, 37, 38, 45, 46, 53, 54, 61, 62, 68, 72, or 76, wherein the hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 8 consecutive days, wherein on day 8, dextromethorphan has a plasma level 12 hours after co-administration of the hydroxybupropion or prodrug thereof and dextromethorphan that is at least 80-fold the plasma level obtained if administered in the same amount of dextromethorphan without hydroxybupropion or prodrug thereof.

81. The method of any one of items 1,2, 3, 5, 9, 13, 17, 23, 24, 31, 32, 39, 40, 47, 48, 55, 56, 63, 64, 69, 73, or 77, wherein erythrohydroxybupropion or a prodrug thereof is co-administered with dextromethorphan for at least 8 consecutive days, wherein on day 8 dextromethorphan has a plasma level 12 hours after co-administration of erythrohydroxybupropion or a prodrug thereof with dextromethorphan that is at least 80-fold the plasma level obtained if administered in the same amount of dextromethorphan without erythrohydroxybupropion or a prodrug thereof.

82. The method of any of items 1,2, 3, 6, 10, 14, 18, 25, 26, 33, 34, 41, 42, 49, 50, 57, 58, 65, 66, 70, 74, or 78, wherein threo hydroxybupropion or prodrug thereof is co-administered with dextromethorphan for at least 8 consecutive days, wherein on day 8 dextromethorphan has a plasma level 12 hours after co-administration of threo hydroxybupropion or prodrug thereof with dextromethorphan that is at least 80-fold the plasma level obtained if administered in the same amount of dextromethorphan without threo hydroxybupropion or prodrug thereof.

83. A method of reducing adverse events associated with dextromethorphan treatment, comprising co-administering bupropion and dextromethorphan to a patient in need of dextromethorphan treatment, wherein the patient is at risk for an adverse event as a result of dextromethorphan treatment.

84. A method of reducing adverse events associated with dextromethorphan therapy, comprising co-administering to a patient in need of dextromethorphan therapy hydroxyamphetadone or a prodrug thereof and dextromethorphan, wherein the patient is at risk of an adverse event as a result of dextromethorphan therapy.

85. A method of reducing adverse events associated with dextromethorphan therapy, comprising co-administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a patient in need of dextromethorphan therapy, wherein the patient is at risk for an adverse event as a result of dextromethorphan therapy.

86. A method of reducing adverse events associated with dextromethorphan therapy, comprising co-administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a patient in need of dextromethorphan therapy, wherein the patient is at risk for an adverse event as a result of dextromethorphan therapy.

87. The method of item 86, wherein the adverse event is lethargy.

88. A method of reducing adverse events associated with bupropion treatment comprising co-administering dextromethorphan and bupropion to a patient in need of bupropion treatment, wherein the patient is at risk for an adverse event due to the bupropion treatment.

89. The method of item 88, wherein the adverse event is a seizure disorder.

90. A method of correcting the fast metabolism of dextromethorphan, comprising administering bupropion to a human in need thereof.

91. A method of correcting fast metabolism of dextromethorphan comprising administering hydroxybupropion or a prodrug thereof to a human in need thereof.

92. A method of correcting fast metabolism of dextromethorphan comprising administering erythrohydroxybupropion or a prodrug thereof to a human in need thereof.

93. A method of correcting fast metabolism of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof to a human in need thereof.

94. The method of any preceding claim, wherein bupropion is administered to the human for at least 8 days, at least 1 time per day.

95. The method of any preceding claim, wherein dextromethorphan is administered to the human for at least 8 days, at least 1 time per day.

96. The method of any preceding claim, wherein dextromethorphan is administered to the human for treating cough.

97. A method of improving the antitussive performance of dextromethorphan, comprising administering bupropion in combination with administration of dextromethorphan to a human in need of treatment for cough.

98. A method of improving the antitussive performance of dextromethorphan, comprising administering hydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

99. A method of improving the antitussive performance of dextromethorphan, comprising administering erythrohydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

100. A method of improving the antitussive performance of dextromethorphan, comprising administering threo-hydroxybupropion or a prodrug thereof in combination with administration of dextromethorphan to a human in need of treatment for cough.

101. A method of treating cough comprising administering a combination of bupropion and dextromethorphan to a human in need thereof.

102. A method of treating cough comprising administering a combination of hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

103. A method of treating cough comprising administering a combination of erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

104. A method of treating cough comprising administering a combination of threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof.

105. A method of treating a neurological disorder comprising administering bupropion and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered for at least 8 days at least 1 time per day.

106. A method of treating a neurological disorder comprising administering to a human in need thereof hydroxybupropion or a prodrug thereof and dextromethorphan, wherein the bupropion and dextromethorphan are administered for at least 8 days at least 1 time per day.

107. A method of treating a neurological disorder comprising administering erythrohydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered for at least 8 days at least 1 time per day.

108. A method of treating a neurological disorder comprising administering threo-hydroxybupropion or a prodrug thereof and dextromethorphan to a human in need thereof, wherein the bupropion and dextromethorphan are administered for at least 8 days at least 1 time per day.

109. The method of any preceding claim, wherein the human is a fast metabolizer of dextromethorphan.

110. The method of any preceding claim, wherein bupropion is administered in an amount that results in a plasma concentration of dextromethorphan in the human on day 8 that is at least 10 times the same amount of dextromethorphan administered without bupropion.

111. The method of any preceding claim, wherein bupropion, hydroxybupropion, or a prodrug of hydroxybupropion results in a AUC for hydroxybupropion at day 8_0-12Is administered in an amount of at least about 3000 ng-hr/mL.

112. The method of any preceding claim, wherein bupropion, erythrohydroxybupropion, or a prodrug of erythrohydroxybupropion results in an AUC of erythrohydroxybupropion at day 8_0-12Is administered in an amount of at least about 400 ng-hr/mL.

113. The method of any preceding claim, wherein bupropion, threo hydroxybupropion, or a prodrug of threo hydroxybupropion results in a AUC of threo hydroxybupropion at day 8_0-12Is administered in an amount of at least about 2000 ng-hr/mL.

114. The method of any preceding claim, wherein the weight ratio of dextromethorphan to bupropion is from about 0.1 to about 0.5.

115. A method of treating a neurological disorder comprising administering bupropion at about 150 mg/day to about 300 mg/day and dextromethorphan at about 15 mg/day to about 60 mg/day to a human in need thereof.

116. The method of item 115, wherein the human is a fast metabolizer of dextromethorphan.

117. The method of item 115, wherein bupropion is administered at about 150 mg/day and dextromethorphan is administered to the human at about 30 mg/day.

118. The method of item 115, wherein bupropion is administered at about 150 mg/day and dextromethorphan is administered at about 60 mg/day to the human.

119. The method of item 115, wherein bupropion is administered at about 200 mg/day and dextromethorphan is administered at about 30 mg/day to the human.

120. The method of item 119, which is administered to the human at about 100 mg/day of bupropion and about 15 mg/day of dextromethorphan for about 1 to about 3 days, followed by administration of bupropion at about 200 mg/day and dextromethorphan at about 30 mg/day.

121. The method of item 115, wherein bupropion is administered at about 200 mg/day and dextromethorphan is administered at about 60 mg/day to the human.

122. The method of item 121, which is administered bupropion at about 100 mg/day and dextromethorphan at about 30 mg/day to said human for about 1 to 3 days, followed by administration of bupropion at 200 mg/day and dextromethorphan at about 60 mg/day.

123. An oral sustained release delivery system for dextromethorphan comprising bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a prodrug of any of these compounds, dextromethorphan, and a water soluble carrier.

124. The oral sustained release delivery system of clause 123, comprising about 45mg of dextromethorphan.

125. The oral sustained release delivery system of clause 123, comprising about 60mg of dextromethorphan.

126. The oral sustained release delivery system of clauses 123, 124, or 125, comprising about 70mg to about 95mg of bupropion.

127. The oral sustained release delivery system of clauses 123, 124, or 125, comprising about 105mg to about 200mg of bupropion.

128. The oral sustained release delivery system of clauses 123, 124, or 125, comprising about 150mg of bupropion.

129. The oral sustained release delivery system of clauses 123, 124, 125, 126, 127 or 128, wherein the bupropion is in a form that enables sustained release upon swallowing the sustained release delivery system.

130. A method of reducing the number of doses of dextromethorphan capable of being administered without loss of efficacy comprising orally administering an effective amount of bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a prodrug of any of these compounds, to a human in need of treatment with dextromethorphan.

131. The method of clause 130, wherein bupropion is administered to the patient.

132. The method of clause 130, wherein the hydroxyamphetazone is administered to the patient.

133. The method of clause 130, wherein erythrohydroxybupropion is administered to the patient.

134. The method of clause 130, wherein threo-hydroxybupropion is administered to the patient.

135. The method of clauses 131, 132, 133, or 134, wherein the patient is taking dextromethorphan 2 times daily, and the treatment is as effective as administering the same amount of dextromethorphan 4 times daily without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a prodrug of any of these compounds.

136. The method of clauses 131, 132, 133, or 134, wherein the patient is taking dextromethorphan 2 times daily, and the treatment is as effective as administering the same amount of dextromethorphan 3 times daily without bupropion, hydroxybupropion, erythrohydroxybupropion, threo hydroxybupropion, or a prodrug of any of these compounds.