Claims for Patent: 11,850,225

Summary for Patent: 11,850,225

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 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, Wolfgang Mohr, Manuel Weinheimer
Assignee:	Amneal Pharmaceuticals LLC
Application Number:	US17/861,844
Patent Claims:	1. A stable oral multiparticulate pharmaceutical formulation comprising granules comprising an intimate mixture of 4-amino-3-(4-chlorophenyl) butanoic acid (baclofen) or a pharmaceutically acceptable salt thereof, and a stabilizer; wherein the stabilizer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate; wherein the formulation is administered at least three times per day; and wherein the formulation on administration in human subjects under fasting conditions provides a time to maximum plasma concentration (Tmax) of about 1.5 hours or less. 2. The formulation of claim 1, wherein the formulation on administration in human subjects under fasting conditions provides an elimination half-life (T½) of the baclofen or a pharmaceutically acceptable salt thereof of about 5.5 hours. 3. The formulation of claim 1, wherein the formulation comprises a dose of 5 mg, 10 mg, or 20 mg of baclofen. 4. The formulation of claim 3, wherein the formulation on administration in healthy adult subjects under fasting condition provides a baclofen exposure that is dose proportional across the dose range of 5 mg, 10 mg, and 20 mg. 5. The formulation of claim 3, wherein the formulation comprises 20 mg of baclofen. 6. The formulation of claim 5, wherein the formulation on administration in human subjects under fasting conditions provides a maximum plasma concentration (Geometric mean (% CV)) of the baclofen of from about 318 ng/ml (16%) to about 379 ng/ml (20%). 7. The formulation of claim 5, wherein the formulation is administered 4 times a day to provide a total daily dose of 80 mg. 8. The formulation of claim 1, wherein the granules can be taken with or without water. 9. The formulation of claim 1, wherein the granules are administered via enteral feeding tube. 10. The formulation of claim 1, wherein the granules are mixed with soft food for administration within 2 hours. 11. A stable oral multiparticulate pharmaceutical formulation comprising granules comprising an intimate mixture of 4-amino-3-(4-chlorophenyl) butanoic acid) (baclofen) or a pharmaceutically acceptable salt thereof, and a stabilizer; wherein the stabilizer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate; wherein the formulation is administered at least three times per day; and the formulation on administration under high fat meal conditions to a human subject in need thereof results in a 10% decrease in area under the time-concentration curve (AUC} compared to administration under fasted conditions. 12. A stable oral multiparticulate pharmaceutical formulation comprising granules comprising an intimate mixture of 4-amino-3-(4-chlorophenyl) butanoic acid (baclofen) or a pharmaceutically acceptable salt thereof, and a stabilizer; wherein the stabilizer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) m ethacrylate-co-methyl methacrylate; wherein the formulation is administered at least three times per day; and the formulation on administration under high fat meal conditions to a human subject in need thereof results in a 29% decrease in maximum plasma concentration (Cmax) compared to administration under fasted conditions. 13. A method of treating spasticity in a human subject in need thereof comprising: administering to the subject a stable oral multiparticulate pharmaceutical formulation comprising granules comprising an intimate mixture of 4-amino-3-(4-chlorophenyl) butanoic acid (baclofen) or a pharmaceutically acceptable salt thereof, and a stabilizer; wherein the stabilizer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate; wherein the formulation is administered at least three times per day; and the formulation on administration to the subject provides an elimination half-life (T½) of the baclofen or a pharmaceutically acceptable salt thereof of about 5.5 hours. 14. The method of claim 13, wherein the spasticity results from multiple sclerosis. 15. The method of claim 13, wherein the spasticity is associated with at least one of flexor spasms, pain, clonus, and muscular rigidity. 16. The method of claim 13, wherein the formulation comprises a dose of 5 mg 10 mg, or 20 mg of baclofen. 17. The method of claim 13, wherein the spasticity results from cerebral palsy, stroke, traumatic brain injury, spinal cord injury, spinal cord disease, or combinations thereof. 18. A method of controlling exposure to baclofen metabolite 3-(4-chlorophenyl)-4-hydroxybutyric acid in a human subject comprising: administering to the subject a stable oral multiparticulate pharmaceutical formulation comprising granules comprising an intimate mixture of 4-amino-3-(4-chlorophenyl) butanoic acid (baclofen) or a pharmaceutically acceptable salt thereof, and a stabilizer; wherein the stabilizer is poly(butylmethacrylate-co-(2-dimethylaminoethyl) m ethacrylate-co-methyl methacrylate; wherein the formulation is administered at least thrice-a-day; and on administration to the subject produces 3-(4-chlorophenyl)-4-hydroxybutyric acid (M1) as a metabolite in the patient; and provides an AUC(0-t)(baclofen):AUC(0-t)(M1) ratio of about 3.1 and 3.2 under fasted and fed conditions respectively. 19. The method of claim 18, wherein the AUC(0-t)(baclofen):AUC(0-t)(M1) ratios are substantially independent of presence or absence of food.