Baclofen formulations and methods of minimizing patient exposure to metabolite variations

1. A pharmaceutical formulation comprising:

an effective amount of 4-amino-3-(4-chlorophenyl)butanoic acid) (baclofen), and one or more pharmaceutically acceptable excipients; wherein

the formulation is a granule formulation; and wherein

on administration to a patient produces 3(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in the patient; wherein

a ratio C max(baclofen) :C max(M1) is A, and AUC (0-t)(baclofen) :AUC (0-t)(M1) is B; and wherein

administering the pharmaceutical formulation to the patient produces A and B values that are within 10% of a ratio C max(baclofen) :C max(M1) and AUC (0-t)(baclofen) :AUC (0-t)(M1) for a baclofen tablet formulation according to Baclofen Tablets monograph as defined by US Pharmacopeia and containing an equal amount of baclofen.

2. A method of treating spasticity in a patient comprising:

administering to the patient a pharmaceutical formulation comprising:

an effective amount of 4-amino-3-(4-chlorophenyl)butanoic acid) (baclofen), and one or more pharmaceutically acceptable excipients; wherein

the formulation is a granule formulation; and wherein

on administration to a patient produces 3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in the patient; wherein

a ratio C max(baclofen) :C max(M1) is A, and AUC (0-t)(baclofen) :AUC (0-t)(M1) is B; and wherein

administering the pharmaceutical formulation to the patient produces A and B values that are within 10% of a ratio C max(baclofen) :C max(M1) and AUC (0-t)(baclofen) :AUC (0-t)(M1) for a baclofen tablet formulation according to Baclofen Tablets monograph as defined by US Pharmacopeia and containing an equal amount of baclofen.

3. The method of claim 2 , wherein administering the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces A and B values that are greater than the ratio C max(baclofen) :C max(M1) and AUC (0-t)(baclofen) :AUC (0-t)(M1) for a baclofen tablet formulation according to Baclofen Tablets as defined by US Pharmacopeia monograph.

4. The method of claim 2 , wherein administering the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces A and B values that are less than the ratio C max(baclofen) :C max(M1) and AUC (0-t)(baclofen) :AUC (0-t)(M1) for a baclofen tablet formulation according to Baclofen Tablets as defined by US Pharmacopeia monograph.

5. The method according to claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a C (max)(baclofen) value of from about 274 ng/mL to about 433 ng/mL.

6. The method according to claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a C (max)(M1) value of from about 37 ng/mL to about 75 ng/mL.

7. The method of claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a ratio C max(baclofen) :C max(M1) of from about 4 to about 11.

8. The method of claim 7 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a ratio C max(baclofen) :C max(M1) of from about 6.1 to about 7.5.

9. The method of claim 8 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a ratio C max(baclofen) :C max(M1) of from about 6.2 to about 6.4.

10. The method according to claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a AUC (0-t)(baclofen) value of from about 1707 h·ng/mL to about 2896 h·ng/mL.

11. The method according to claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation with or without water, or with soft foods or liquids, to the patient produces a AUC (0-t)(M1) value of from about 461 h·ng/mL to about 1017 h·ng/mL.

12. The method of claim 2 , wherein administering a 20-mg dose of the pharmaceutical formulation to the patient produces a ratio AUC (0-t)(baclofen) :AUC (0-t)(M1) of from about 2 to about 5.

13. The method of claim 11 , wherein administering a 20-mg dose of the pharmaceutical formulation to the patient produces a ratio AUC (0-t)(baclofen) :AUC (0-t)(M1) of from about 2.8 to about 3.4.

14. The method of claim 13 , wherein administering a 20-mg dose of the pharmaceutical formulation to the patient produces a ratio AUC (0-t)(baclofen) :AUC (0-t)(M1) of from about 3.0 to about 3.2.

15. The method of claim 2 , wherein the spasticity results from multiple sclerosis.

16. The method of claim 2 , wherein the spasticity is associated with at least one of flexor spasms, pain, clonus, and muscular rigidity.

17. The method of claim 2 , wherein the effective amount of baclofen is 20 mg.

18. The method of claim 2 , wherein the spasticity results from cerebral palsy, stroke, traumatic brain injury, spinal cord injury, spinal cord disease, or combinations thereof.

19. A method of controlling exposure to baclofen metabolite 3-(4-chlorophenyl)-4-hydroxybutyric acid in a patient comprising:

administering to the patient a pharmaceutical formulation comprising an effective amount of 4-amino-3-(4-chlorophenyl)butanoic acid) (baclofen), and one or more pharmaceutically acceptable excipients; wherein

the formulation is a granule formulation; and wherein

on administration to a patient produces 3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in the patient; and wherein

the coefficient of variation for AUC (0-t)(M1) is 0.34 or less.

20. The method of claim 19 , wherein the coefficient of variation for AUC (0-t)(M1) is 0.30 or less.