Stabilized pharmaceutical compositions

• US 6,153,223 A
• Filed: 06/05/1998
• Issued: 11/28/2000
• Est. Priority Date: 06/05/1998
• Status: Expired due to Term

• Current Assignee: Allergan Sales LLC (Abbvie Incorporated)
• Original Assignee: Watson Pharmaceuticals, Inc. (Abbvie Incorporated)
• Inventors: Parikh, Nilesh H., Iyer, Raman, Apelian, Vahe Henry
• Primary Examiner(s): Spear, James M.
• Application Number:
  US09/092,388
• Time in Patent Office: 907 Days
• Field of Search: 424/464, 424/465, 424/468, 424/469, 424/489, 424/452, 514/970
• US Class Current: 424/489
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats

Abstract

The present invention pertains to a stabilized pharmaceutical composition which comprises a mixture of (a) a pharmaceutical agent unstable at a pH above about 3.5; and (b) a stabilizing amount of an acidic pharmaceutically acceptable carrier to stabilize the pharmaceutical agent. The acidic pharmaceutically acceptable carrier is a dried premixture of a pharmaceutically acceptable carrier and an aqueous solution of an acid. The stabilized pharmaceutical composition has a pH value of less than about 3.5, and when stored at a temperature of about 50° C. for about 4 weeks at about 27% relative humidity, retains at least about 80% of the pharmaceutical agent. This invention also pertains to sustained-release forms of the stabilized pharmaceutical compositions as well as to novel methods for preparing and using the stabilized pharmaceutical compositions and to stabilized pharmaceutical compositions made by the novel method.

Claims

1. A method for stabilizing a pharmaceutical composition which comprises the step of:

a) premixing a pharmaceutically acceptable carrier and an aqueous solution of an acid;

b) drying the premixture from step a) to form an acidic pharmaceutically acceptable carrier; and

c) admixing a stabilizing amount of the dried acidic pharmaceutically acceptable carrier from step b) with a pharmaceutical agent unstable at a pH above about 3.5 to form a stabilized pharmaceutical composition, wherein

the acidic pharmaceutically acceptable carrier provides an acidic stabilizing microenvironment around the pharmaceutical agent.

2. The method for stabilizing a pharmaceutical composition according to claim 1, wherein the stabilized pharmaceutical composition has a pH value of less than about 3.5, and when stored at a temperature of about 50°

C. for about 4 weeks at about 27% relative humidity, retains at least about 80% of the pharmaceutical agent.

3. The method according to claim 2, wherein the pharmaceutical agent is unstable at a pH above about 4.5.

4. The method according to claim 2, wherein the pharmaceutical agent, when stored in aqueous solution at a pH above about 3.5 at about 45°

C. for about 40 days, retains less than about 90% of the pharmaceutical agent.

5. The method according to claim 2, wherein the pharmaceutical agent is selected from the group consisting of bupropion hydrochloride, diethylpropion hydrochloride, and ticlopidine hydrochloride.

6. The method according to claim 5, wherein the pharmaceutical agent is bupropion hydrochloride.

7. The method according to claim 2, wherein the pharmaceutically acceptable carrier is selected from the group consisting of microcrystalline cellulose, powdered cellulose, lactose, and starch.

8. The method according to claim 2, wherein the aqueous solution of an acid is selected from the group consisting of hydrochloric acid, nitric acid, sulfuric acid, and phosphoric acid.

9. The method according to claim 2, wherein the acidic pharmaceutically acceptable carrier is a dried premixture of microcrystalline cellulose and hydrochloric acid.

10. The method according to claim 2, wherein the stabilized pharmaceutical composition has a pH value from about 2.5 to about 3.5.

11. The method according to claim 2, wherein the stabilized pharmaceutical composition, when stored at a temperature of about 50°

C. for about 4 weeks at about 27% relative humidity, retains at least about 90% of the pharmaceutical agent.

12. A stabilized pharmaceutical composition prepared by a method which comprises the step of:

(a) premixing a pharmaceutically acceptable carrier and an aqueous solution of an acid;

(b) drying the premixture from step (a) to form an acidic pharmaceutically acceptable carrier; and

(c) admixing a stabilizing amount of the dried acidic pharmaceutically acceptable carrier from step (b) with a pharmaceutical agent unstable at a pH above about 3.5 to form a stabilized pharmaceutical composition;

wherein the stabilized pharmaceutical composition has a pH value of less than about 3.5, and when stored at a temperature of about 50°

C. for about 4 weeks at about 27% relative humidity, retains at least about 80% of the pharmaceutical agent.