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

• US 9,968,568 B2
• Filed: 05/18/2017
• Issued: 05/15/2018
• 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): Barsky, Jared D
• Application Number:
  US15/599,163
• Publication Number:
  US 20170252309A1
• Time in Patent Office: 362 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031

Abstract

This disclosure relates to methods administering various compounds in conjunction with dextromethorphan to a human being. Dosage forms, drug delivery systems, and methods related to dextromethorphan or dextrorphan and bupropion, hydroxybupropion, erythrohydroxybupropion, threohydroxybupropion, or a metabolite or prodrug of any of these compounds are also disclosed.

Claims

1. A method of enhancing dextromethorphan plasma levels in a human being, comprising co-administering a bupropion with a dextromethorphan, to the human being, for at least nine consecutive days, wherein the human being is an extensive metabolizer of dextromethorphan in need of treatment with dextromethorphan, and the human being is not suffering from neuropathic pain, wherein the bupropion and the dextromethorphan, are the sole active agents administered to the human being, wherein the bupropion is administered in an amount that results in a C_max of dextromethorphan that is at least about 40 ng/mL, and wherein, on the ninth day that the bupropion and the dextromethorphan, are co-administered, the C_max of dextromethorphan is at least about 15 times the C_max of dextromethorphan that would result from administering the same amount of the dextromethorphan without the bupropion for nine consecutive days.

2. The method of claim 1, wherein the bupropion and the dextromethorphan are orally administered.

3. The method of claim 2, wherein the bupropion and the dextromethorphan are orally administered in a single, solid dosage form.

4. The method of claim 3, wherein the single, solid dosage form further comprises a binder, an excipient, a disintegrating agent, a lubricant, a sweetening agent, a flavoring agent, a coating, or a capsule.

5. The method of claim 1, wherein the bupropion is in a form that contains an enantiomeric excess of the S-enantiomer.

6. The method of claim 1, wherein the bupropion is in a form that contains an enantiomeric excess of the R-enantiomer.

7. The method of claim 1, wherein the bupropion is deuterium-modified.

8. The method of claim 1, wherein the dextromethorphan is deuterium-modified.

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

10. The method of claim 1, wherein the C_max of dextromethorphan on the ninth day is at least about 55 ng/mL.

11. The method of claim 1, wherein the C_max of dextromethorphan on the ninth day is at least about 75 ng/mL.

12. The method of claim 1, wherein the C_max of dextromethorphan on the ninth day is at least about 30 times the C_max of dextromethorphan that would result from administering the same amount of the dextromethorphan without the bupropion for nine consecutive days.

13. The method of claim 1, wherein the C_min of dextromethorphan on the ninth day is at least about 25 ng/mL.

14. The method of claim 1, wherein the bupropion is co-administered with the dextromethorphan for at least 14 consecutive days.

15. The method of claim 1, wherein about 40 mg to about 48 mg of the dextromethorphan is administered to the human being twice a day.

16. The method of claim 1, wherein about 44 mg to about 46 mg of the dextromethorphan is administered with each dose.

17. The method of claim 16, wherein about 100 mg to about 110 mg of the bupropion is administered to the human being twice a day.

18. The method of claim 17, wherein the bupropion is co-administered with the dextromethorphan for at least 30 consecutive days.

19. The method of claim 18, wherein the bupropion and the dextromethorphan are administered twice a day.

20. The method of claim 1, wherein the human being is at least 30 years of age.

21. The method of claim 1, wherein the human being is about 30 to about 50 years of age.

22. The method of claim 1, wherein the dextromethorphan is administered in a dosage form that provides immediate release of dextromethorphan.

23. The method of claim 1, wherein the bupropion is co-administered with the dextromethorphan, and the weight ratio of the dextromethorphan to the bupropion is about 0.4 to about 0.45.

24. The method of claim 1, wherein the fluctuation index value Fl(%) of the dextromethorphan on the ninth day is reduced by at least 2-fold as compared to dextromethorphan that is administered for nine days without co-administration with the bupropion.

25. The method of claim 1, wherein the Fl(%) of the dextromethorphan on the ninth day is less than 100%.

26. The method of claim 15, wherein the AUC_0-12 of hydroxybupropion on the ninth day is at least about 3000 ng·

hr/mL.

27. The method of claim 26, wherein the AUC_0-12 of erythrohydroxybupropion on the ninth day is at least about 400 ng·

hr/mL.

28. The method of claim 27, wherein the AUC_0-12 of threohydroxybupropion on the ninth day is at least about 2000 ng·

hr/mL.

29. The method of claim 28, wherein the human being does not smoke cigarettes.

30. The method of claim 3, wherein the dosage form further comprises gum tragacanth, acacia, corn starch, gelatin, dicalcium phosphate, corn starch, potato starch, alginic acid, methylparaben, or propylparaben.