Claims for Patent: 11,491,125

Summary for Patent: 11,491,125

Title:	Baclofen formulations and methods of minimizing patient exposure to metabolite variations
Abstract:	Baclofen formulations, including formulations that minimize variability between doses, that minimize variation in patient exposure to baclofen metabolites, and are bioequivalent in regards to baclofen versus M1 metabolite ratios of baclofen tablets.
Inventor(s):	Leonard O'MAHONY, Sharon Hamm, John Devane, David Penake
Assignee:	Amneal Pharmaceuticals LLC
Application Number:	US17/489,343
Patent Claims:	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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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 Cmax(baclofen):Cmax(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.