Diltiazem controlled release formulation and method of manufacture
First Claim
Patent Images
1. A process for manufacturing a controlled release diltiazem dosage formulation comprising the steps of:
- a) adding a first allotment of active pellets containing diltiazem to a coating equipment;
b) coating the first allotment of active pellets with a first amount of extended release coating;
c) adding a second allotment of active pellets containing diltiazem to the equipment;
d) coating the first and second allotment of active pellets with a second amount of extended release coating;
e) optionally adding a third allotment of active pellets containing diltiazem to the equipment; and
f) optionally coating the first, second and third allotments of active pellets with an optional third amount of extended release coating.
5 Assignments
0 Petitions
Accused Products
Abstract
A controlled release diltiazem dosage formulation comprising a plurality of active pellets coated with an extended release coating wherein the active pellets contain diltiazem or a pharmaceutically acceptable salt, a pharmaceutically acceptable inert seed and a binder and the extended release coating contains a water insoluble water permeable polymer, a channeling agent, a lubricant and optionally a surfactant. A single batch intermittent method of manufacturing a heterogeneous population of extended release pellets for use as a dosage formulation is also disclosed.
135 Citations
26 Claims
-
1. A process for manufacturing a controlled release diltiazem dosage formulation comprising the steps of:
-
a) adding a first allotment of active pellets containing diltiazem to a coating equipment;
b) coating the first allotment of active pellets with a first amount of extended release coating;
c) adding a second allotment of active pellets containing diltiazem to the equipment;
d) coating the first and second allotment of active pellets with a second amount of extended release coating;
e) optionally adding a third allotment of active pellets containing diltiazem to the equipment; and
f) optionally coating the first, second and third allotments of active pellets with an optional third amount of extended release coating. - View Dependent Claims (2, 3, 4, 5)
-
-
6. A process for manufacturing a controlled release diltiazem dosage formulation comprising the steps of:
-
a) adding a first allotment of active pellets which consist essentially of;
(i) from 10-30% of a pharmaceutically acceptable inert core based on the total weight of the active pellets;
(ii) from 50-85% of diltiazem or a pharmaceutically acceptable salt thereof based on the total weight of the active pellets;
(iii) from 0.25-5% of a water soluble binder based on the total weight of the active pellets; and
(iv) from 0.75-10% of a water insoluble binder based on the total weight of the active pellets;
to a fluidized bed coating equipment wherein the active pellets are prepared by applying a suspension of the diltiazem, water soluble binder and the water insoluble binder to the inert core; b) coating the first allotment of active pellets with a first amount of extended release coating suspension which consists essentially of;
(i) from 60-85% of a water insoluble water permeable polymer based on the total weight of the extended release coating;
(ii) from 0.5-5% of a channeling agent based on the total weight of the extended release coating;
(iii) from 5-20% of talc based on the total weight of the coating;
(iv) 5-20% of magnesium stearate based on the total weight of the coating; and
(v) 0 to less than 1% of a surfactant based on the total weight of the coating;
c) adding a second allotment of active pellets as defined in step (a) to the equipment;
d) coating the first and second allotment of active pellets with a second amount of extended release coating suspension as defined in step (b);
e) adding a third allotment of active pellets as defined in step (a) to the equipment; and
f) coating the first, second and third allotments of active pellets with a third amount of extended release coating suspension as defined in step (b) wherein the first allotment of active pellets comprise 34-90% of the total weight of active pellets to be coated, the second allotment of active pellets comprise 5-33% of the total weight of the active pellets to be coated and the third allotment of active pellets comprises 5-43% of the total weight of the active pellets to be coated and the first amount of extended release coating suspension comprises 10-30% of the total amount of extended release coating suspension to be applied to all the active pellets, the second amount of extended release coating suspension comprises 34-80% of the total amount of extended release coating suspension to be applied to all the active pellets and the third amount of extended release coating suspension comprises 10-40% of the total amount of extended release coating suspension to be applied to all the active pellets. - View Dependent Claims (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)
after 2 hours 0-30% of the diltiazem is released;
after 4 hours 5-45% of the diltiazem is released;
after 8 hours 20-70% of the diltiazem is released;
not less than 45% of the diltiazem is released after 12 hours;
not less than 55% of the diltiazem is released after 18 hours;
and not less than 65% of the diltiazem is released after 20 hours.
-
-
9. The product as defined in claim 8 that exhibits the following dissolution profile when tested in a United States Pharmacopoeia type 2 apparatus at 100 rpm in 900 ml of 0.1 N HCL and at 37°
- C.;
after 2 hours 5-25% of the diltiazem is released;
after 4 hours 10-35% of the diltiazem is released;
after 8 hours 35-65% of the diltiazem is released;
not less than 50% of the diltiazem is released after 12 hours;
not less than 60% of the diltiazem is released after 18 hours;
and not less than 70% of the diltiazem is released after 20 hours.
- C.;
-
10. The process as defined in claim 6 wherein the diltiazem or a pharmaceutically acceptable salt is micronized.
-
11. The process as defined in claim 6 wherein the binder employed in the active pellets is selected from the group consisting of polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate and ethylcellulose or a mixture thereof.
-
12. The process as defined in claim 6 wherein the binder employed in the active pellet is a combination of a water soluble binder and a water insoluble binder.
-
13. The process as defined in claim 12 wherein the ratio of water soluble binder to water insoluble binder is about 1:
- 1 to about 1;
3.
- 1 to about 1;
-
14. The process as defined in claim 13 wherein the ratio of water soluble binder to water insoluble binder is about 1:
- 2.
-
15. The process as defined in claim 12 wherein the water soluble binder is polyvinyl pyrrolidone and a water insoluble binder is ethylcellulose.
-
16. The process as defined in claim 12 wherein the water soluble binder comprises about 0.25-5% of the total weight of the active pellet and the water insoluble binder comprises about 0.75-10% of the total weight of the active pellet.
-
17. The process as defined in claim 6 wherein the water insoluble water permeable polymer of the extended release coating is selected from the group consisting of ethylcellulose, cellulose acetate, polyacrylates or mixtures thereof.
-
18. The process as defined in claim 17, wherein the water insoluble water permeable polymer is a poly(ethylacrylate methylmethacrylate) copolymer.
-
19. The process as defined in claim 6 wherein the channeling agent employed in the extended release coating is a water or acid soluble pharmaceutically acceptable substance selected from the group consisting of polyvinyl pyrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methycellulose, polyacrylate, sucrose, diltiazem, a pharmaceutically acceptable salt of diltiazem and any combination of the foregoing.
-
20. The process as defined in claim 19 wherein the channeling agent is hydroxypropyl methylcellulose.
-
21. The process as defined in claim 6 wherein the lubricant is selected from the group consisting of talc, magnesium stearate, silicon dioxide, kaolin and a mixture of the foregoing.
-
22. The process as defined in claim 21 wherein the lubricant is a mixture of talc and magnesium stearate.
-
23. The process as defined in claim 22 wherein the ratio of talc to magnesium stearate is about 1:
- 2 to about 2;
1.
- 2 to about 2;
-
24. The process as defined in claim 6 wherein the surfactant is polysorbate 80.
-
25. The process as defined in claim 8 wherein the inert core is a non-pareil seed of sugar or starch having a diameter ranging from about 15-50 mesh.
-
26. The process as defined in claim 6 wherein the first, second, and third allotment of active pellets are coated with varying number of layers of extended release coating wherein said extended release coating consists of a homogeneous mixture comprising about 60-85% of poly (ethyl acrylate methylacrylate) copolymer and a channeling agent.
Specification