Dosage forms with improved bioavailability
View Patent ↗A solid dispersion product comprising an effective amount of one or more active ingredients and an effective amount of one or more hydroxypropyl methylcellulose(s), which satisfies the Formula 0.35>ΔH tr (1) (wherein AH tr represents the endotherm (J/g) accompanying a transition at about 240° C.). The solid dispersion product is used for the manufacture of a dosage form having improved bioavailability of said one or more active ingredients by oral administration to a patient in need thereof.
1. A solid dispersion product comprising
(i) an effective amount of one active ingredient or a mixture of two or more active ingredients and
(ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses, wherein said solid dispersion product satisfies the formula
0.35>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C., and wherein said transition is the melting of mesomorphic domains of the hydroxypropyl methylcellulose(s).
2. The solid dispersion product of claim 1 , which satisfies the formula
0.20>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C.
3. The solid dispersion product of claim 1 , which satisfies the formula
0.15>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C.
4. The solid dispersion product of claim 1 , wherein the endothermic peak temperature is in the range of from about 240° C. to about 250° C.
5. The solid dispersion product of claim 1 , having a weight-average particle size of less than 600 μm.
6. The solid dispersion product of claim 1 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight.
7. The solid dispersion product of claim 6 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight.
8. The solid dispersion product of claim 7 , wherein the hydroxypropyl methylcellulose has an apparent viscosity of from about 3 to about 15 mPa·s, as determined as a 2 wt. % aqueous solution at 20° C.
9. The solid dispersion product of claim 1 , wherein the weight ratio of active ingredient to hydroxypropyl methylcellulose is in the range of 1:1 to 1:17.
10. A pharmaceutical dosage form comprising particles of the solid dispersion product of claim 1 and at least one additive selected from the group consisting of a diluent and a disintegrant.
11. A method for preparing a solid dispersion product, which comprises:
a) blending (i) an effective amount of one active ingredient or a mixture of two or more active ingredients and (ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses;
b) heating the blend, under preset conditions of temperature, shear and throughput rate, to obtain a homogeneous melt;
c) forcing the thus obtained melt through one or more nozzles;
d) allowing the melt to solidify to obtain a solid dispersion product;
e) subjecting a representative sample of the obtained solid dispersion product to differential scanning calorimetry measurement; and, if necessary, e) adjusting the conditions of temperature, shear and throughput rate used in step b) such that the solid dispersion product satisfies the formula
0.35>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C., and wherein said transition is the melting of mesomorphic domains of the hydroxypropyl methylcellulose(s).
12. The method of claim 11 , wherein step b) is carried out in an extruder and the blend is subjected to a kneading action in a kneading section of the extruder.
13. The method of claim 11 , wherein step b) is carried out in an extruder, the extruder operating temperature and the nozzle temperature being in the range of from about 195° C. to about 300° C.
14. The method of claim 11 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight.
15. The method of claim 14 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight.
16. The method of claim 15 , wherein the hydroxypropyl methylcellulose has an apparent viscosity of from about 3 to about 15 mPa·s, as determined as an 2 wt. % aqueous solution at 20° C.
17. The method of claim 11 , wherein the weight ratio of active ingredient:hydroxypropyl methylcellulose is in the range of 1:1 to 1:17.
18. The method of claim 11 , additionally comprising grinding the solid dispersion product.
19. The method of claim 18 , additionally comprising sieving the ground solid dispersion product.
20. The method of claim 18 , additionally comprising compressing the ground solid dispersion product into a tablet.
21. A process for the manufacture of a dosage form having improved bioavailability of one or more active ingredients by oral administration to a patient in need thereof, said process comprising preparing a solid dispersion product by blending
(i) an effective amount of one active ingredient or a mixture of two or more active ingredients and
(ii) an effective amount of a hydroxypropyl methylcellulose or a mixture of two or more hydroxypropyl methylcelluloses, wherein said solid dispersion product satisfies the formula
0.35>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C., and wherein said transition is the melting of mesomorphic domains of the hydroxypropyl methylcellulose(s).
22. The process of claim 21 , wherein said solid dispersion product satisfies the formula
0.20>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C.
23. The process of claim 21 , wherein said solid dispersion product satisfies the formula
0.15>ΔH tr
wherein ΔH tr represents the endotherm (J/g) accompanying a transition at an endothermic peak temperature in the range of from about 230° C. to about 260° C.
24. The process of claim 21 , wherein the endothermic peak temperature is in the range of from about 240° C. to about 250° C.
25. The process of claim 21 , wherein the solid dispersion product is comprised of particles having a weight-average particle size of less than 600 μm.
26. The process of claim 21 , wherein the total content of methoxy and hydroxypropyl groups in the hydroxypropyl methylcellulose is in the range of 23 to 42% by weight.
27. The process of claim 26 , wherein the methoxy group content is in the range of 19 to 30 wt % and the hydroxypropyl group content is in the range of 4 to 12% by weight.
28. The process of claim 27 , wherein the hydroxypropyl methylcellulose has apparent viscosity of from about 3 to about 15 mPa·s, as determined as an 2 wt. % aqueous solution at 20° C.
29. The process of claim 21 , wherein the weight ratio of active ingredient: hydroxypropyl methylcellulose is in the range of 1:1 to 1:17.
30. The method of claim 11 , wherein the solid dispersion product satisfies the formula
0.20>ΔH tr .
31. The method of claim 11 , wherein the solid dispersion product satisfies the formula
0.15>ΔH tr .