Controlled release carvedilol compositions
View Patent ↗A controlled release pharmaceutical composition for oral use comprising carvedilol. The composition releases carvedilol after oral administration to a mammal, including a human, in such a manner that a prolonged residence of carvedilol is obtained in the circulatory system compared with the known compositions of carvedilol. Furthermore, a composition according to the present invention makes available to the body a suitable plasma concentration of one or both of the enantiomeric species, namely R(+) and/or S(−) carvedilol for obtaining the desired therapeutic effect.
1. A controlled release pharmaceutical composition for oral use comprising:
a solid dispersion of
i) carvedilol at least partly in R(+) or S(−) form, wherein the carvedilol is at least partially present in amorphous form;
ii) a polymer selected from the group consisting of
(a) a polyethylene glycol and/or a polyethylene oxide each having a molecular weight of at least 20,000 daltons; and
(b) a block copolymer of ethylene oxide and propylene oxide having a molecular weight of from 5,000 to 30,000 daltons;
iii) a stabilizing agent comprising phosphoric acid or a pharmaceutically acceptable salt thereof; and
a coating on the solid dispersion which is insoluble in and impermeable to body fluids;
wherein said composition has improved stability shelf life.
2. A composition according to claim 1 , wherein said carvedilol is in the form of the R(+) carvedilol.
3. A composition according to claim 1 , wherein said carvedilol is in the form of the S(−) carvedilol.
4. The composition of claim 3 , wherein said release of carvedilol from said composition after administration to a human results in a t max of S(−) carvedilol of from about 1.5 hour to about 8 hours.
5. A composition according to claim 1 , wherein said composition is in the form of a matrix and said coating comprises a polymer and has at least one opening exposing at least one surface of said matrix.
6. A composition according to claim 1 , wherein said carvedilol is selected from the group consisting of the racemate: (RS)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, the two individual enantiomers: (S)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol and (R)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, metabolites of carvedilol including desmethylcarvedilol, pharmaceutically acceptable salts, complexes, solvates and anhydrate thereof, and mixtures thereof.
7. A composition according to claim 1 , wherein said carvedilol at least partially is present in solid form in the dispersion.
8. A composition according to claim 1 , wherein said carvedilol at least partially is present in amorphous form with a mean particle size of from about 0.01 μm to about 500 μm.
9. A controlled release composition according to claim 1 wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 10% and 90% of the total carvedilol absorbed is absorbed within 2 hours from administration.
10. A controlled release composition according to claim 1 wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 30% and 95% of the total carvedilol absorbed is absorbed within 3 hours from administration.
11. A controlled release composition according to claim 1 wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 40% and 98% of the total carvedilol absorbed is absorbed within 4 hours from administration.
12. The composition of claim 1 , wherein said release of carvedilol from said composition after administration to a human results in at t max of R(+) or S(−) carvedilol of from about 1.5 hour to about 8 hours.
13. A controlled release pharmaceutical composition for oral use comprising:
a solid dispersion of
i) carvedilol at least partly in R(+) or S(−) form, wherein the carvedilol is at least partially present in amorphous form;
ii) a polymer selected from the group consisting of
(a) a polyethylene glycol and/or a polyethylene oxide each having a molecular weight of at least 20,000 daltons and
(b) a block copolymer of ethylene oxide and propylene oxide having a molecular weight of from 5,000 to 30,000 daltons;
iii) a stabilizing agent comprising citric acid or a pharmaceutically acceptable salt thereof; and
a coating on the solid dispersion which is insoluble in and impermeable to body fluids.
14. A composition according to claim 13 , wherein said carvedilol is in the form of the R(+) carvedilol.
15. A composition according to claim 13 , wherein said carvedilol is in the form of the S(−) carvedilol.
16. The composition of claim 15 , wherein said release of carvedilol from said composition after administration to a human results in a t max of S(−) carvedilol of from about 1.5 hour to about 8 hours.
17. A composition according to claim 13 , wherein said carvedilol is selected from the group consisting of the racemate: (RS)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, the two individual enantiomers: (S)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol and (R)-1-(9H-carbazol-4-yloxy)-3-[2-(2.methoxyphenoxy)-ethylaminopropan-2-ol, metabolites of carvedilol including desmethylcarvedilol, pharmaceutically acceptable salts, complexes, solvates and anhydrate thereof, and mixtures thereof.
18. A composition according to claim 13 , wherein said carvedilol at least partially is present in solid form in the dispersion.
19. A composition according to claim 13 , wherein said carvedilol at least partially is present in amorphous form with a mean particle size of from about 0.01 μm to about 500 μm.
20. A controlled release composition according to claim 13 , wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 10% and 90% of the total carvedilol absorbed is absorbed within 2 hours from administration.
21. A controlled release composition according to claim 13 , wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 30% and 95% of the total carvedilol absorbed is absorbed within 3 hours from administration.
22. A controlled release composition according to claim 13 , wherein release of carvedilol from said composition after oral administration to a human results in an absorption of the carvedilol, wherein between 40% and 98% of the total carvedilol absorbed is absorbed within 4 hours from administration.
23. The composition of claim 13 , wherein said release of carvedilol from said composition after administration to a human results in at t max of R(+) or S(−) carvedilol of from about 1.5 hour to about 8 hours.
24. A controlled release pharmaceutical composition for oral use comprising:
a) a solid dispersion comprising:
i) carvedilol at least partly in R(+) or S(−) form and at least partially present in amorphous form, wherein the carvedilol is present in the solid dispersion in an amount of 14% w/w;
ii) polyethylene oxide having a molecular weight of 200,000 daltons, wherein the polyethylene oxide is present in the solid dispersion in an amount of 60.6% w/w;
iii) Poloxamer 188 present in the solid dispersion in an amount of 19.2% w/w;
iv) a stabilizing agent comprising phosphoric acid present in the solid dispersion in an amount of 4.5% w/w; and
b) a coating which is insoluble in and impermeable to body fluids.
25. The composition of claim 24 , wherein the solid dispersion comprises an anti-oxidative agent comprising potassium metabisulfite.
26. The composition of claim 25 , wherein the potassium metabisulfite is present in the solid dispersion in an amount of 0.2% w/w.
27. The composition of claim 24 , wherein the solid dispersion comprises butylhydroxytoluene.
28. The composition of claim 27 , wherein the butylhydroxytoluene is present in the solid dispersion in an amount of 0.5% w/w.
29. The composition of claim 24 , wherein the solid dispersion comprises potassium dihydrogen phosphate.
30. The composition of claim 29 , wherein the potassium dihydrogen phosphate is present in the solid dispersion in an amount of 1% w/w.
31. The composition of claim 24 , wherein the solid dispersion comprises:
an anti-oxidative agent comprising potassium metabisulfite in an amount of 0.2% w/w;
butylhydroxytoluene in an amount of 0.5% w/w; and
potassium dihydrogen phosphate in an amount of 1% w/w.
32. A controlled release pharmaceutical composition for oral use comprising:
a) a solid dispersion comprising:
i) carvedilol at least partly in R(+) or S(−) form and at least partially present in amorphous form, wherein the carvedilol is present in the solid dispersion in an amount of 14% w/w;
ii) polyethylene oxide having a molecular weight of 200,000 daltons, wherein the polyethylene oxide is present in the solid dispersion in an amount of 60.6% w/w;
iii) a stabilizing agent comprising phosphoric acid present in the solid dispersion in an amount of 4.5% w/w;
iv) an anti-oxidative agent comprising potassium metabisulfite present in the solid dispersion in an amount of 0.2% w/w;
v) butylhydroxytoluene present in the solid dispersion in an amount of 0.5% w/w;
vi) potassium dihydrogen phosphate present in the solid dispersion in an amount of 1% w/w; and
vii) a polaxamer; and
b) a coating which is insoluble in and impermeable to body fluids.