DILTIAZEM CONTROLLED RELEASE FORMULATION AND METHOD OF MANUFACTURE

• US 20010007681A1
• Filed: 07/20/1998
• Published: 07/12/2001
• Est. Priority Date: 07/20/1998
• Status: Active Grant

• Current Assignee: Andrx Pharmaceuticals LLC (Abbvie Incorporated)
• Original Assignee: Andrx Pharmaceuticals LLC (Abbvie Incorporated)
• Inventors: CHEN, CHIH-MING, CHENG, XIU XIU, JAN, STEVE
• Granted Patent: US 6,524,620 B2
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077

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.

Claims

1. A controlled release pharmaceutical dosage formulation comprising a plurality of active pellets coated with an extended release coating wherein the active pellets consist essentially of:

(i) 10-30% of the total weight of the active pellets of a pharmaceutically acceptable inert seed;

(ii) 50-85% of the total weight of the active pellets of diltiazem or a pharmaceutically acceptable salt thereof; and

(iii) 1-15% of the total weight of the active pellets of a binder;

and the extended release coating comprises;

(i) 60-85% of the total weight of the coating of a water insoluble water permeable polymer;

(ii) 0.5-5% of the total weight of the coating of a channeling agent;

(iii) 10-40% of the total weight of the coating of a lubricant; and

(iv) optionally less than 1% of the total weight of the coating of a surfactant.

2. The controlled release dosage formulation as defined in

claim 1

wherein the diltiazem or pharmaceutically acceptable salt is micronized.

3. The controlled release dosage formulation as defined in

claim 1

wherein the binder employed in the active pellets is selected from the group consisting of polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, ethylcellulose or mixtures of the foregoing.

4. The controlled release dosage formulation as defined in

claim 1

wherein the binder employed in the active pellet is a combination of a water soluble binder and a water insoluble binder.

5. The controlled release dosage formulation as defined in

claim 4

wherein the ratio of water soluble binder to water insoluble binder is about 1:

1 to about 1;

3.

6. The controlled release dosage formulation as defined in

claim 5

wherein the ratio of water soluble binder to water insoluble binder is about 1:

2.

7. The controlled release dosage formulation as defined in

claim 5

wherein the water soluble binder is polyvinyl pyrrolidone and a water insoluble binder is ethylcellulose.

8. The controlled release dosage formulation as defined in

claim 5

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.

9. The controlled release dosage formulations as defined in

claim 1

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.

10. The controlled release dosage formulation as defined in

claim 9

, wherein the water insoluble water permeable polymer is a poly(ethylarcylate methylmethacrylate) copolymer.

11. The controlled release dosage formulation as defined in

claim 1

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 pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, sucrose, drug itself or any combination of the foregoing.

12. The controlled release dosage formulation as defined in

claim 11

wherein the channeling agent is hydroxypropyl methylcellulose.

13. The controlled release coating as defined in

claim 1

wherein the lubricant is selected from the group consisting of talc, magnesium stearate, silicon dioxide, kaolin or a mixture of the foregoing.

14. The controlled release dosage formulation as defined in

claim 13

wherein the lubricant is a mixture of talc and magnesium stearate.

15. The controlled release formulation as defined in

claim 14

wherein the ratio of talc to magnesium stearate is about 1:

2 to about 2;

1.

16. The controlled release dosage formulation as defined in

claim 1

wherein the surfactant is not optional and is polysorbate 80.

17. The controlled release dosage formulation as defined in

claim 1

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°

C.;

after 2 hours 0-30% of the diltiazem is released;

after 4 hours 10-50% of the diltiazem is released;

after 8 hours 30-85% of the diltiazem is released;

after 12 hours 45-90% of the diltiazem is released;

not less than 60% of the diltiazem is released after 16 hours;

and not less than 70% of the diltiazem is released after 20 hours.

18. The controlled release dosage formulation as defined in

claim 17

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°

C.;

after 2 hours 5-25% of the diltiazem is released;

after 4 hours 15-45% of the diltiazem is released;

after 8 hours 45-80% of the diltiazem is released;

after 12 hours 60-85% of the diltiazem is released;

not less than 70% of the diltiazem is released after 16 hours;

and not less than 75% of the diltiazem is released after 20 hours.

19. The controlled release dosage formulation as defined in

claim 1

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated gastric fluid (SGF) and at 37°

C.;

after 2 hours 0-30% of the diltiazem is released;

after 4 hours 10-50% of the diltiazem is released;

after 8 hours 25-80% of the diltiazem is released;

after 12 hours 50-90% of the diltiazem is released;

not less than 55% of the diltiazem is released after 16 hours;

and not less than 65% of the diltiazem is released after 20 hours.

20. The controlled release dosage formulation as defined in

claim 19

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 ml of simulated gastric fluid and at 37°

C.;

after 2 hours 5-25% of the diltiazem is released;

after 4 hours 15-45% of the diltiazem is released;

after 8 hours 40-75% of the diltiazem is released;

after 12 hours 55-85% of the diltiazem is released;

not less than 65% of the diltiazem is released after 16 hours;

and not less than 70% of the diltiazem is released after 20 hours.

21. The controlled release dosage formulation as defined in

claim 1

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 100 rpm in 900 ml of 0.1 N HCl and at 37°

C.;

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.

22. The controlled release dosage formulation as defined in

claim 21

that exhibits the following dissolution profile when tested in a USP 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.

23. A controlled release pharmaceutical dosage formulation consisting essentially of a plurality of active pellets coated with an extended release coating wherein the active pellets consist essentially of:

(i) 10-30% of the total weight of the active pellets of a pharmaceutically acceptable inert seed;

(ii) 50-85% of the total weight of the active pellets of diltiazem or a pharmaceutically acceptable salt thereof;

(iii) 0.25-5% of the total weight of the active pellets of a water soluble binder; and

(iv) 0.75-10% of the total weight of the active pellet of a water insoluble binder;

and the extended release coating consists essentially of;

(i) 60-85% of the total weight of the coating of a water insoluble water permeable polymer;

(ii) 0.5-5% of the total weight of the coating of a channeling agent;

(iii) 5-20% of the total weight of the coating of talc;

(iv) 5-20% of the total weight of the coating of magnesium stearate; and

(v) optionally less than 1% of the total weight of the coating of a surfactant.

24. The controlled release dosage formulation as defined in

claim 23

wherein the active pellets consist essentially of:

(i) 15-25% of the total weight of the active pellets of a pharmaceutically acceptable inert seed;

(ii) 65-85% of the total weight of the active pellets of diltiazem or a pharmaceutically acceptable salt thereof;

(iii) 1-3.4% of the total weight of the active pellets of a water soluble binder; and

(iv) 3-6.6% of the total weight of the active pellet of a water insoluble binder;

and the extended release coating consists essentially of;

(i) 65-80% of the total weight of the coating of a water insoluble water permeable polymer;

(ii) 0.75-2% of the total weight of the coating of a channeling agent;

(iii) 7.5-15% of the total weight of the coating of talc;

(iv) 7.5-15% of the total weight of the coating of magnesium stearate; and

(v) optionally less than 0.5% of the total weight of the coating of a surfactant.

25. The controlled release dosage formulation as defined in

claim 24

wherein the water insoluble binder employed in the active pellet is polyvinyl pyrrolidone and the water insoluble binder employed in the active pellet is ethylcellulose.

26. The controlled release dosage formulation as defined in

claim 23

that exhibits the following dissolution profile when tested in a USP 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.

27. 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.

28. The process as defined in

claim 27

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 is not optional and comprises 5-43% of the total weight of the active pellets to be coated.

29. The process as defined in

claim 28

wherein the first allotment of active pellets comprise 65-80% of the total weight of active pellets to be coated, the second allotment of active pellets comprise 5-15% of the total weight of the active pellets to be coated and the third allotment of active pellets comprises 15-25% of the total weight of the active pellets to be coated.

30. The process as defined in

claim 27

wherein the first amount of extended release coating comprises 10-33% of the total amount of extended release coating to be applied to all the active pellets, the second amount of extended release coating comprises 34-80% of the total amount of extended release coating to be applied to all the active pellets and the third amount of extended release coating is not optional and comprises 10-40% of the total amount of extended release coating to be applied to all the active pellets.

31. The process as defined in

claim 30

wherein the first amount of extended release coating comprises 15-25% of the total amount of extended release coating to be applied to all the active pellets, the second amount of extended release coating comprises 50-75% of the total amount of extended release coating to be applied to all the active pellets and the third amount of extended release coating comprises 15-30% of the total amount of extended release coating to be applied to all the active pellets.

32. 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 seed 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;

b) coating the first allotment of active pellets with a first amount of extended release coating 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) optionally 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 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 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 comprises 10-30% of the total amount of extended release coating to be applied to all the active pellets, the second amount of extended release coating comprises 34-80% of the total amount of extended release coating to be applied to all the active pellets and the third amount of extended release coating comprises 10-40% of the total amount of extended release coating to be applied to all the active pellets.

33. The process as defined in

claim 32

wherein the first allotment of active pellets comprise 65-80% of the total weight of active pellets to be coated, the second allotment of active pellets comprise 5-15% of the total weight of the active pellets to be coated and the third allotment of active pellets comprises 15-25% of the total weight of the active pellets to be coated and the first amount of extended release coating comprises 15-25% of the total amount of extended release coating to be applied to all the active pellets, the second amount of extended release coating comprises 50-75% of the total amount of extended release coating to be applied to all the active pellets and the third amount of extended release coating comprises 15-30% of the total amount of extended release coating to be applied to all the active pellets.

34. A product prepared according to the process defined in

claim 32

that exhibits the following dissolution profile when tested in a USP type 2 apparatus at 100 rpm in 900 ml of 0.1 N HCl and at 37°

C.;

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.

35. The product as defined in

claim 34

that exhibits the following dissolution profile when tested in a USP 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.