Claims for Patent: 11,931,328

Summary for Patent: 11,931,328

Title:	Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives
Abstract:	Pharmaceutical compositions including an active ingredient and a stabilizer, as well as methods of manufacture of the compositions, and methods of their use. The composition may include the active ingredient dispersed throughout a matrix of the stabilizer. In some embodiments, the active ingredient and the stabilizer are intimately mixed in a matrix formulation. In some embodiments, the active ingredient is selected from 4 amino-3-(4-chlorophenyl)butanoic acid) (“baclofen”) and its pharmaceutically acceptable salts.
Inventor(s):	David Penake, Sharon Hamm, Leonard O'MAHONY, John Devane, Wolfgang Mohr, Manuel Weinheimer
Assignee:	Amneal Pharmaceuticals LLC
Application Number:	US18/122,515
Patent Claims:	1. An immediate release pharmaceutical composition comprising granules comprising an active ingredient selected from 4-amino-3-(4-chlorophenyl) butanoic acid) (“baclofen”) and a pharmaceutically acceptable salt thereof; a stabilizer; and 4-(4-chlorophenyl)-2-pyrrolidone (4-CPP) impurity in an amount of less than 0.2 wt % of the active ingredient, wherein the stabilizer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), wherein the impurity does not increase to more than 0.2 wt % after storage under accelerated storage conditions, and wherein the accelerated storage conditions comprise storage of the composition for 6 months at 40° C. and 75% relative humidity (RH). 2. The composition of claim 1, wherein the composition is a stabilized composition that results in the formation of 4-(4-chlorophenyl)-2-pyrrolidone (4-CPP) impurity in less than 0.2 wt %. 3. The composition of claim 1, wherein the composition is a stick pack composition. 4. The composition of claim 1, wherein the active ingredient is baclofen. 5. The composition of claim 4, comprising 5 mg, 10 mg, or 20 mg of baclofen. 6. The composition of claim 1, wherein the 4-(4-chlorophenyl)-2-pyrrolidone (4-CPP) impurity is present in an amount of less than 0.1 wt % and wherein the impurity does not increase to more than 0.2 wt % after 6 month storage under accelerated storage conditions. 7. The composition of claim 1, wherein the 4-(4-chlorophenyl)-2-pyrrolidone (4-CPP) impurity is present in an amount of less than 0.05 wt % and wherein the impurity does not increase to more than 0.2 wt % after 6 month storage under accelerated storage conditions. 8. The composition of claim 1, wherein the 4-CPP is a lactam auto degradation product of baclofen. 9. The composition of claim 1, wherein the stabilizer is not an amino acid. 10. The composition of claim 1, wherein the composition on infrared (IR) spectral analysis provides a shift in IR peak of a carboxylic carbonyl group of baclofen from 1530 cm−1 to 1525 cm−1 and provides a lowered signal at 1495 cm−1. 11. The composition of claim 1, wherein the active ingredient and the stabilizer are intimately mixed in a granular matrix composition. 12. The composition of claim 1, wherein a weight ratio of the stabilizer to the active ingredient is from about 1.5:1 to about 20:1. 13. The composition of claim 11, wherein the active ingredient and the stabilizer are intimately mixed via wet granulation. 14. The composition of claim 1, further comprising one or more excipients selected from the group consisting of xylitol, calcium stearate, colloidal silicon dioxide, crospovidone, hypromellose, mannitol, saccharin sodium, talc, flavoring agent, and mixtures thereof. 15. A method of making an immediate release pharmaceutical stick pack composition comprising an active ingredient comprising 4-amino-3-(4-chlorophenyl) butanoic acid) (“baclofen”) or a pharmaceutically acceptable salt thereof; poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) (stabilizer); and at least one excipient selected from the group consisting of xylitol, crospovidone, hypromellose, mannitol, saccharin sodium, and mixtures thereof; the method comprising: a) dry blending the active ingredient, the stabilizer, and the at least one excipient to obtain a dry blend; and wet granulating the dry blend to obtain active granules; b) dry blending the stabilizer, and the at least one excipient to obtain a dry blend; and wet granulating the dry blend to obtain placebo granules; c) mixing the active granules, the placebo granules, colloidal silicon dioxide, calcium stearate, a flavoring agent and talc in a mixer to obtain a final blend; and d) filling the final blend in one or more stick packs. 16. The method of claim 15, wherein the wet granulation comprises wetting the dry blend with ethanol, wet mixing, drying, and cooling to obtain placebo granules and active granules. 17. A method of increasing shelf life of an immediate release baclofen stick pack composition comprising baclofen or a pharmaceutically acceptable salt thereof, the method comprising reducing formation of 4-(4-chlorophenyl)-2-pyrrolidone (4-CPP) impurity to an amount of less than 0.2 wt %, wherein the formation of the 4-CPP impurity is reduced by intimately mixing the baclofen or a pharmaceutically acceptable salt thereof and a stabilizer in a stabilizer to baclofen weight ratio of from about 1.5:1 to about 20:1; wherein the stabilizer is poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate), wherein the impurity does not increase to more than 0.2 wt % after storage under accelerated storage conditions, and wherein the accelerated storage conditions comprise storage of the stick pack composition for 6 months at 40° C. and 75% relative humidity (RH). 18. The method of claim 17, wherein the intimately mixing comprises dry blending of the active ingredient and the stabilizer to obtain a dry blend, followed by wet granulation of the dry blend.