Pharmaceutical formulations
View Patent ↗The present invention is directed to novel pharmaceutically acceptable polymeric compositions suitable for melt extrusion and injection molding of single or multi-component pharmaceutical dosage forms comprising a plurality of drug substance containing sub-units, being capsule compartments and/or solid sub-units comprising a solid matrix of a polymer which contains a drug substance, the sub-units being connected together in the assembled dosage form.
1. A dosage form comprising a capsule having a shell with an outer surface and an opposed inner surface, the inner surface defining at least in part a confined space for holding a drug substance, and the outer surface being exposed to a gastro-intestinal environment, the shell being composed of an extruded and injection molded composition comprising
(i) Ammonio methacrylate Copolymer Type A or ammonium methacrylate Copolymer Type B present in an amount of about 10 to about 80% w/w;
(ii) at least one dissolution modifying excipient selected from a swellable solid present in an amount of about 20 to about 65% w/w, and wherein the swellable solid is a blend of hydroxypropylcelluloses having differing molecular weights and wherein such blend comprises a low molecular weight hydroxypropylcellulose having a molecular weight of about 80,000 and a high molecular weight hydroxypropyl cellulose selected from a hydroxyproplycellulose having a molecular weight of about 140,000 and a hydroxypropylcellulose having a molecular weight of about 370,000;
optionally in combination with a second dissolution modifying excipient selected from the group consisting of a
a) disintegrant present in an amount of about 10 to 40%,
b) a water soluble filler present in the range of about 5 to about 70% w/w,
c) a low molecular weight solute present in the range of about 2.5 to about 70% w/w, and
d) non-reducing sugar present in the range of about 2.5 to about 15% w/w;
(iii) a lubricant present in an amount of about 5% to about 25% w/w; and
(iv) optionally a surfactant present in an amount of 0 to about 10%, a plasticizer present in an amount of 0 to about 10% w/w and/or a processing agent present in an amount of 0 to about 10% w/w.
2. The dosage form according to claim 1 wherein the copolymer is Ammonio methacrylate Copolymer Type A.
3. The dosage form according to claim 2 wherein the copolymer is present in an amount of about 15 to about 50% w/w.
4. The dosage form according to claim 2 wherein the copolymer is present in an amount of about 20 to about 40% w/w.
5. The dosage form according to claim 2 wherein the lubricant is stearyl alcohol present from about 10 to about 15% w/w.
6. The dosage form according to claim 1 wherein the surfactant is present in an amount of less than 2% w/w.
7. The dosage form according to claim 6 wherein the surfactant is sodium dodecyl sulphate or is a block copolymer of ethylene oxide and propylene oxide.
8. The dosage form according to claim 1 wherein the lubricant is stearyl alcohol, glycerol monostearate (GMS), talc, magnesium stearate, silicon dioxide, amorphous silicic acid, or fumed silica; and combinations or mixtures thereof.
9. The dosage form according to claim 8 wherein the lubricant is stearyl alcohol.
10. The dosage form according to claim 9 wherein the stearyl alcohol is present from about 10 to about 15% w/w.
11. The dosage form according to claim 1 wherein the lubricant is stearyl alcohol present from about 10 to about 15% w/w.
12. The dosage form according to claim 1 wherein the swellable solid is composed of a blend of hydroxypropyl cellulose polymers, each having a differing molecular weight, present in a total amount of about 30% to about 80% w/w.
13. The dosage form according to claim 1 wherein the second dissolution modifying excipient is a non-reducing sugar, a low molecular weight solute, or a water soluble filler.
14. The dosage form according to claim 13 wherein the second dissolution modifying excipient is selected from the group consisting of xylitol, mannitol, lactose, starch, and sodium chloride, and combinations or mixtures thereof.
15. The dosage form according to claim 1 wherein the second dissolution modifying excipient is a disintegrant.
16. The dosage form according to claim 15 wherein the disintegrant is selected from the group consisting of sodium starch glycollate, croscarmellose sodium, crospovidone (cross-linked polyvinyl pyrrolidone), copovidone, polyvinyl pyrrolidone; and combinations or mixtures thereof.
17. The dosage form according to claim 1 wherein the plasticizer is triethyl cifrate (TEC), tributyl cifrate, acetyl triethyl citrate (ATEC), acetyl tributyl citrate (ATBC), dibutyl phthalate, dibutyl sebacate (DBS), diethyl phthalate, vinyl pyrrolidone glycol triacetate, polyethylene glycol, polyoxyethylene sorbitan monolaurate, propylene glycol, or castor oil; and combinations or mixtures thereof.
18. The dosage form according to claim 1 wherein the processing agent is talc.
19. The dosage form according to claim 18 wherein the processing agent is present in an amount of about 1 to about 5% w/w.
20. The dosage form according to claim 1 which further comprises an absorption enhancer.
21. The dosage form according to claim 20 wherein the absorption enhancer is chitosan, lecithin, lectin, a sucrose fatty acid ester, Vitamin E-TPGS; and combinations or mixtures thereof.
22. The dosage form according to claim 1 wherein the Ammonio methacrylate Copolymer Type A is present in an amount of about 15 to 50% w/w, the lubricant is stearyl alcohol, and the at least one dissolution modifying excipient is a blend of hydroxypropylcelluloses having differing molecular weights.
23. The dosage form according to claim 22 wherein the blend of hydroxypropyl cellulose polymers comprises a hydroxypropylcellulose having a molecular weight of about 80,000 and a hydroxypropylcellulose having a molecular weight of about 370,000.
24. The dosage form according to claim 12 wherein the blend of hydroxypropyl cellulose is a hydroxypropylcellulose having a molecular weight of about 80,000 and a hydroxypropylcellulose having a molecular weight of about 370,000.
25. The dosage form according to claim 22 wherein the blend of hydroxypropyl cellulose is of equal % w/w.
26. The dosage form according to claim 22 wherein the blend of hydroxypropyl cellulose is about 32% w/w.
27. The dosage form according to claim 22 wherein the hydroxypropyl cellulose is present in an amount of about 50% w/w.
28. The dosage form according to claim 22 which comprises a second dissolution modifying excipient which is a wicking agent.
29. The dosage form according to claim 28 wherein the wicking agent is lactose.
30. The dosage form according to claim 29 wherein the lactose is present in an amount of about 13% w/w.
31. A dosage form comprising at least one subcomponent having a wall portion made from an extruded material comprising a pharmaceutical composition selected from the group consisting of:
#
Formulations
% w/w
1.
Eudragit RL100
25.00
Klucel EF
31.50
Klucel JF
31.50
Stearyl alcohol
12.00
2.
Eudragit RL100
21.60
Eudragit RS100
2.40
Klucel EF
32.00
Klucel JF
32.00
Stearyl alcohol
12.00;
and
3.
Eudragit RL100
2.40
Eudragit RS100
21.60
Klucel EF
32.00
Klucel JF
32.00
Stearyl alcohol
12.00.
32. A dosage form according to claim 1 , in which the capsule shell has a wall with a thickness in the range of about 0.1-0.8 mm.