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.
1. A pharmaceutical composition, comprising:
an active ingredient selected from 4-amino-3-(4-chlorophenyl)butanoic acid) (“baclofen”) and its pharmaceutically acceptable salts; and
poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) (“stabilizer”);
wherein a weight ratio of the stabilizer to the active ingredient is from 1.5:1 to 10:1 and wherein the active ingredient and stabilizer are present in a matrix.
2. The composition of claim 1 , wherein the active ingredient is dispersed throughout a matrix of the stabilizer.
3. The composition of claim 2 , wherein the active ingredient and the stabilizer are intimately mixed in a matrix formulation.
4. The composition of claim 1 , wherein the weight ratio of the stabilizer to the active ingredient is from 1.8:1 to 7.2:1.
5. The pharmaceutical composition of claim 4 , further comprising one or more excipients selected from xylitol, calcium stearate, colloidal silicon dioxide, talc, and flavoring.
6. The composition according to claim 4 , further comprising a saliva-forming agent.
7. The composition of claim 1 , further comprising an excipient.
8. The pharmaceutical composition of claim 7 , wherein the excipient comprises one or more glidants, lubricants, fillers, sweeteners, taste-masking agents, disintegrants, saliva-forming agents, binding agents, or flavorings.
9. The composition of claim 8 , wherein the at least one excipient is xylitol, mannitol, saccharin sodium, hypromellose, crospovidone, calcium stearate, colloidal silicon dioxide, talc, or flavoring.
10. The pharmaceutical composition of claim 1 , wherein the composition is in a solid dosage form.
11. A method of making the composition of claim 1 , comprising intimately mixing together the active ingredient and stabilizer.
12. The method according to claim 11 , wherein the intimately mixing comprises at least one of wet granulation and dry granulation.
13. The method according to claim 12 , comprising wet granulation, wherein the wet granulation comprises dry blending the active ingredient and stabilizer, then adding a solvent, and granulating the mixture.
14. The method according to claim 11 , wherein the intimately mixing comprises dry blending.
15. The method according to claim 11 , further comprising dry compacting or slugging to form a solid dosage form.
16. The method according to claim 15 , further comprising coating the solid dosage form.
17. A method of treating spasticity, comprising administering to a patient in need thereof an effective amount of the composition of claim 1 .
18. A method of reducing lactam formation in a baclofen formulation, the method comprising intimately mixing together baclofen or a pharmaceutically acceptable salt thereof and poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) (“stabilizer”); wherein a weight ratio of the stabilizer to the baclofen or a pharmaceutically acceptable salt thereof is from 1.5:1 to 10:1.
19. The method according to claim 18 , wherein the baclofen is micronized.
20. The method according to claim 18 , further comprising milling the baclofen to reduce its particle size before intimately mixing with the stabilizer.
21. A method of increasing the shelf life of a solid baclofen formulation, the method comprising:
reducing formation of 4-(4-chlorophenyl)-2-pyrrolidine (4-CPP) in a baclofen formulation by intimately mixing together baclofen or a pharmaceutically acceptable salt thereof and a poly(butylmethacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) (“stabilizer”) to form a solid baclofen formulation; wherein a weight ratio of the stabilizer to the baclofen or a pharmaceutically acceptable salt thereof is from 1.5:1 to 10:1.
22. The method according to claim 21 , wherein an amount of 4-CPP in the solid baclofen formulation increases by no more than 0.2% after six months of stability testing at 40° C., 75% relative humidity.
23. The method according to claim 22 , wherein an amount of 4-CPP in the solid baclofen formulation increases by no more than 0.1% after six months of stability testing at 40° C., 75% relative humidity.