Controlled release formulation and method

• US 4,738,850 A
• Filed: 05/27/1986
• Issued: 04/19/1988
• Est. Priority Date: 05/27/1986
• Status: Expired due to Term

• Current Assignee: ER Squibb & Sons LLC (Bristol-Myers Squibb Company)
• Original Assignee: E R Squibb & Sons Incorporated
• Inventors: Thakur, Ajit B., Jain, Nemichand B.
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US06/867,846
• Time in Patent Office: 693 Days
• Field of Search: 424/19, 424/22, 424/468, 424/469, 424/470
• US Class Current: 424/468
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin

Abstract

In accordance with the present invention, a controlled release formulation is provided from which a drug, selected from the group consisting of angiotensin converting enzyme inhibitors and ascorbic acid, is released at a substantially controlled rate. The controlled release formulation of the invention is comprised of a reactive matrix of from about 5 to about 80 percent by weight of the drug in combination with from about 5 to about 70 percent by weight of poly[(1→4)-2-amino-2-deoxy-β-D-glucose] (also referred to as chitosan herein). Further in accordance with the present invention there is provided a gel-like complex formed of the drug and the chitosan in environments ranging from neutral to acidic.

Claims

1. A controlled release formulation from which a drug selected from the group consisting of angiotensin converting enzyme inhibitors and ascorbic acid is released at a substantially controlled rate in environments which are neutral or acidic consisting of a reactive matrix of from about 5 to about 80 percent by weight of said drug in combination with from about 5 to about 70 percent by weight of poly[(1→

4)-2-amino-2-deoxy-β

-glucose].

2. The formulation of claim 1 comprising from about 10 to about 70 percent by weight of said drug and from about 10 to about 60 percent by weight of said glucose.

3. The formulation of claim 1 wherein said drug and said glucose are in a weight ratio from about 0.1:

1 to about 15;

1.

4. The formulation of claim 3 wherein said drug and said glucose are in a weight ratio from about 0.3:

1 to about 10;

1.

5. The formulation of claim 3 wherein said drug and said glucose are in a weight ratio of about 0.45:

1.

6. The formulation of claim 1 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of substituted proline derivatives, azetidine-2-carboxylic acid derivatives, phosphinylalkanoyl prolines, phosphinylalkanoyl substituted prolines, phosphonamidate substituted amino or imino acids, and carboxyalkyl dipeptide derivatives.

7. The formulation of claim 6 wherein said substituted proline derivative is 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline.

8. The formulation of claim 6 wherein said carboxyalkyl dipeptide derivative is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

14. The formulation of claim 1 in the form of a gel-like complex.

15. A method for the controlled release of a drug selected from the group consisting of angiotensin converting enzyme inhibitors and ascorbic acid in a neutral or acidic environment within a mammalian specie comprising

(a) exposing the formulation of claim 1 or 9 containing an effective amount of said drug to a neutral or acidic liquid, thereby forming a gel-like complex;

and thereafter,

(b) subjecting said complex to said neutral or acidic environment such that the drug is slowly and substantially uniformly released over a period of 8 hours or more.

16. The method of claim 15 wherein step (a) is carried out prior to administration of said formulation to said specie.

17. The method of claim 15 wherein step (a) is carried out after administration of said formulation to said specie.

18. A method of alleviating hypertension in a mammalian specie which comprises administering the controlled release formulation of claim 6 containing an effective amount of said angiotensin converting enzyme inhibitor.

19. The method of claim 18 wherein said angiotensin converting enzyme inhibitor is 1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline.

20. The method of claim 18 wherein said angiotensin converting enzyme inhibitor is N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline.

9. A sustained release tablet formulation consisting of from about 5 to about 80 percent by weight of a drug, selected from angiotensin converting enzyme inhibitors and ascorbic acid, in combination with from about 5 to about 70 percent by weight of poly [(1→

4)-2-amino-2-deoxy-β

-glucose], from about 0 to about 30 percent by weight of a diluent and from about 0.3 to about 8 percent by weight of a lubricant.

10. The formulation of claim 9 wherein said diluent is selected from the group consisting of lactose, sugar, corn starch, modified corn starch, citric acid, mannitol, sorbitol, inorganic salts, or cellulose.

11. The formulation of claim 10 wherein said diluent is lactose.

12. The formulation of claim 9 wherein said lubricant is selected from the group consisting of magnesium stearate, stearic acid, palnitic acid, calcium stearate, talc, or carnauba wax.

13. The formulation of claim 12 wherein said lubricant is magnesium stearate.