Stabilized formulations of 4-amino-3-substituted butanoic acid derivatives
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.
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.