Compositions and methods for increasing the metabolic lifetime of dextromethorphan and related pharmacodynamic effects

• US 9,421,176 B1
• Filed: 04/15/2016
• Issued: 08/23/2016
• Est. Priority Date: 11/05/2013
• Status: Active Grant

• Current Assignee: Antecip Bioventures II LLC
• Original Assignee: Antecip Bioventures II LLC
• Inventors: Tabuteau, Herriot
• Primary Examiner(s): Baek, Bong-Sook
• Application Number:
  US15/130,807
• Publication Number:
  US 20160228390A1
• Time in Patent Office: 130 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4748 forming part of bridged ring systems strychnine A61K31/475; morphinan derivatives A61K31/485
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine

Abstract

This disclosure relates to methods of increasing dextromethorphan plasma levels comprising co-administering hydroxybupropion, or a prodrug thereof, and dextromethorphan to a human being in need of treatment with dextromethorphan. Dosage forms, drug delivery systems, and methods related to dextromethorphan and hydroxybupropion or a prodrug of bupropion are also disclosed.

Claims

1. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, comprising:

administering, once or twice a day to the human being, a combination of active agents comprising;

1) bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion; and

2) dextromethorphan;

wherein the combination of active agents is administered for at least 8 consecutive days;

wherein about 40 mg to about 600 mg of dextromethorphan is administered per day;

wherein administering the combination of active agents results in an AUC_0-12 of dextromethorphan, on the eighth day, that is at least about 400 ng·

hr/mL; and

wherein administering the combination of active agents results in a C_max of dextromethorphan, on the eighth day, that is at least 15 times the C_max of dextromethorphan that would result from administering the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion for eight consecutive days.

2. The method of claim 1, wherein the AUC_0-12 of dextromethorphan on the eighth day is at least about 500 ng·

hr/mL.

3. The method of claim 1, wherein the C_max of dextromethorphan on the eighth day is at least about 45 ng/mL.

4. The method of claim 1 wherein, on the eighth day, the plasma concentration of dextromethorphan 12 hours after administering the combination of active agents is at least about 35 ng/mL.

5. The method of claim 1, wherein about 200 mg to about 250 mg of bupropion is administered per day.

6. The method of claim 1, wherein about 60 mg to about 100 mg of dextromethorphan is administered per day.

7. The method of claim 1, wherein dextromethorphan is in a form that comprises a deuterium-modified dextromethorphan.

8. The method of claim 1, wherein the combination of active agents is administered for at least 30 days.

9. The method of claim 1, wherein the combination of active agents is administered in a single dosage form.

10. The method of claim 1, wherein bupropion is in a hydrochloride salt form.

11. The method of claim 1, wherein dextromethorphan is in a salt form.

12. A method of increasing dextromethorphan plasma levels in a human being that is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, comprising:

administering, once or twice a day to the human being, a combination of active agents comprising;

1) bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion; and

2) dextromethorphan;

wherein the combination of active agents is administered for at least 8 consecutive days;

wherein about 40 mg to about 600 mg of dextromethorphan is administered per day;

wherein administering the combination of active agents results in a C_max of dextromethorphan, on the eighth day, that is at least about 40 ng/mL; and

wherein administering the combination of active agents results in an AUC_0-12 of dextromethorphan, on the eighth day, that is at least 15 times the AUC_0-12 of dextromethorphan that would result from administering the same amount of dextromethorphan without bupropion, hydroxybupropion, erythrohydroxybupropion, or threohydroxybupropion for eight consecutive days.

13. The method of claim 12, wherein the AUC_0-12 of dextromethorphan on the eighth day is at least about 450 ng·

hr/mL.

14. The method of claim 12, wherein the C_max of dextromethorphan on the eighth day is at least about 50 ng/mL.

15. The method of claim 12, wherein on the eighth day, the plasma concentration of dextromethorphan, 12 hours after the combination of active agents is administered, is at least about 30 ng/mL.

16. The method of claim 12, wherein about 100 mg to about 110 mg of bupropion is orally administered twice a day.

17. The method of claim 12, wherein about 105 mg of bupropion is orally administered twice a day.

18. The method of claim 12, wherein the combination of active agents is administered for at least 60 days.

19. The method of claim 12, wherein bupropion is in a hydrochloride salt form.