Pharmaceutical compositions using thiazepine

• US 5,948,437 A
• Filed: 05/28/1997
• Issued: 09/07/1999
• Est. Priority Date: 05/23/1996
• Status: Expired due to Term

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Parikh, Bhavnish Vinod, Addicks, William Joseph, Timko, Robert Joseph
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/864,306
• Time in Patent Office: 832 Days
• Field of Search: 424/464, 424/401, 514/211, 540/551
• US Class Current: 424/464
• 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 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

The invention relates to sustained release formulations comprising 11- 4- 2-(2-hydroxyethoxy)ethyl!-1-piperazinyl!dibenzo b,f! 1,4!thiazepine or a pharmaceutically acceptable salt thereof, to methods of treating psychotic states and hyperactivity utilizing the sustained release formulations and to a process for preparing the sustained release formulations.

Claims

1. A sustained release formulation comprising a gelling agent and 11 - 4- 2-(2-hydroxyethoxy)ethyl!- 1 -piperazinyl!dibenzo- b,f! 1,4!thiazepine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients.

2. A sustained release formulation according to claim 1 wherein the gelling agent is hydroxypropyl methylcellulose.

3. A sustained release formulation according to claim 2 comprising about 5 to 50% by weight of a hydroxypropyl methylcellulose selected from the group consisting of (a) a hydroxypropyl methylcellulose having a viscosity of about 40 to 60 cps, a methoxy content of about 28 to 30% by weight and a hydroxypropoxy content of from about 7 to less than 9% by weight, (b) a hydroxypropyl methylcellulose having a viscosity of about 3,500 to 5,600 cps, a methoxy content of about 28 to 30% by weight and a hydroxypropoxy content of about 7 to 12% by weight, (c) a hydroxypropyl methylcellulose having a viscosity of about 80 to 120 cps, a methoxy content of about 19 to 24% by weight and a hydroxypropoxy content of from about 7 to less than 9% by weight and (d) a hydroxypropyl methylcellulose having a viscosity of about 3,500 to 5,600 cps, a methoxy content of about 19 to 24% by weight and a hydroxypropoxy content of about 7 to 12% by weight, or mixtures thereof;

with the proviso that if the formulation contains a hydroxypropyl methylcellulose described under (d) above the total amount of hydroxypropyl methylcellulose present in the formulation must be greater than 25.8% by weight.

4. A sustained release formulation according to claim 3 comprising about 5 to 40% by weight of a hydroxypropyl methylcellulose selected from the group consisting of (a)-(d) or mixtures thereof.

5. A sustained release formulation according to claim 4 comprising about 8 to 35% by weight of a hydroxypropyl methylcellulose selected from the group consisting of (a)-(d) or mixtures thereof.

6. A formulation according to claim 5 comprising about 10 to 30% by weight of a hydroxypropyl methylcellulose selected from the groups (a)-(d) or mixtures thereof.

7. A formulation according to claim 6 comprising about 15 to 30% by weight of a hydroxypropyl methylcellulose selected from the groups (a)-(d) or mixtures thereof.

8. A formulation according to claim 7 wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of microcrystalline cellulose, lactose, magnesium stearate, sodium citrate and povidone.

9. A formulation according to claim 8 wherein the one or more pharmaceutically acceptable excipients are selected from the group consisting of (a) about 4 to 20% by weight of microcrystalline cellulose, (b) about 5 to 20% by weight of lactose, (c) about I to 3% by weight of magnesium stearate, (d) about 10 to 30% by weight of sodium citrate and (e) about 1 to 15% by weight of povidone.

10. A formulation according to claim 1 wherein 11 - 4- 2-(2hydroxyethoxy)ethyl!-1-piperazinyl!dibenzo b,f! 1,4!thiazepine is in the form of a hemifumarate salt.

11. A formulation according to claim 1 wherein one of the one or more pharmaceutically acceptable excipients is a pH modifier.

12. A formulation according to claim 11 wherein the pH modifier is sodium citrate.

13. A method of treating psychotic states or hyperactivity in a warm-blooded animal which comprises administering to said warm-blooded animal an effective amount of a formulation according to anyone of claims 1-12.

14. A process for preparing a formulation according to anyone of claims 1 or 2 which comprises mixing 11- 4- 2-(2-hydroxyethoxy)ethyl!-1-piperazinyl!dibenzo b,f! 1,4!thiazepine, or a pharmaceutically acceptable salt thereof, a gelling agent and other excipients.

15. A process for preparing a formulation according to anyone of claims 1 or 2 which comprises:

(a) mixing 11- 4- 2-(2-hydroxyethoxy)ethyl!-1-piperazinyl!dibenzo b,f! 1,4!thiazepine, or a pharmaceutically acceptable salt thereof, a gelling agent and other excipients;

(b) wet granulating the mixed components;

(c) drying the mixture;

(d) milling the dried mixture;

(e) blending the mixture with a lubricant; and

(f) compressing the blended mixture to form tablets.