Process for the production of stable liquid form of beta-blocker-containing medicaments with controlled release of the active constituent for oral administration

• US 5,484,776 A
• Filed: 10/14/1993
• Issued: 01/16/1996
• Est. Priority Date: 03/13/1992
• Status: Expired due to Fees

• Current Assignee: Synepos AG
• Original Assignee: Synepos AG
• Inventors: Racz, Istvan, Marton, Sylvia
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US08/135,992
• Time in Patent Office: 824 Days
• Field of Search: 514/58, 514/54, 514/59, 514/782, 514/965
• US Class Current: 514/54
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006

Abstract

This invention relates to a process for the production of optimally stable orally administrable solution forms of medicaments containing high-molecular polysaccharides, with controlled release of drugs having beta-blocking action, this process consisting of the reacting of 1 to 20 parts (w/w) of beta-blocking agent (oxprenolol, pindolol, sotalol, metoprolol, alprenolol, acebutolol, atenolol, bopindolol, practolol, nadolol or propranolol) in 100 parts of an aqueous solution with 0.001 to 10.0 parts of a polysaccharide polymer, advantageously with Xanthan Gum having beta-1,4-glucan chain, or dextran, or amylodextrin, or carboxymethylamylum. The reaction is allowed to take place in the course of 20 minutes at a pH adjusted no 2.0-4.5, with vigorous stirring at 80° C. temperature. Following the usual method of the pharmaceutical practice, the system is then formulated by the addition of water to obtain a solution suitable for oral administration.

Claims

1. A process for the production of a stable pharmaceutical for oral administration that provides controlled released of a β

-adrenergic blocker active component, which comprises reacting 1 to 20 parts by weight of the β

-adrenergic blocker in 100 parts of water with 0.001 to 10 parts of a polysaccharide to obtain a mixture, and adjusting the pH of the mixture to between pH 2 and 4.5 with a buffer.

2. A process according to claim 1, wherein the polysaccharide is a carbohydrate polymer with a β

-1,4-glucan chain.

3. A process according to claim 2, wherein the polysaccharide is Xanthan Gum.

4. A process according to claim 1, wherein the temperature of the solution is maintained at about 80°

C. for 20 minutes.

5. A process according to claim 1, wherein the buffer is phosphate-citrate, Sorensen, Walpoe, Clark-Lubs, Britton-Robinson or McIlvain.

6. A process according to claim 1, which further comprises adding an antioxidant to the solution.

7. A process according to claim 6, wherein the antioxidant is sodium pyrosulphite or sodium hydrogen sulphite.

8. A process according to claim 1, which further comprises adding a preservative to the solution.

9. A process according to claim 8, wherein the preservative is sorbate or an ester of a phenylcarboxylic acid.

10. A process according to claim 1, wherein the polysaccharide is present in a final concentration of about 0.1% by weight.

11. A process according to claim 1, wherein the polysaccharide is dextran having an average molecular weight of about 60,000 present in an amount of 0.1-0.6 parts by weight.

12. A process according to claim 1, wherein the polysaccharide is amylodextrin present in an amount of 0.1-10 parts by weight.

13. A process according to claim 1, wherein the polysaccharide is carboxymethylamylum present in an amount of 0.1-10 parts by weight.

14. A process according to claim 1, wherein the β

-adrenergic blocker is metoprolol tartrate.

15. A process according to claim 1, wherein the β

-adrenergic blocker is oxprenolol HCl present in an amount of 0.1-10 parts by weight.

16. A process according to claim 1, wherein the β

-adrenergic blocker is pindolol HCl present in an amount of 0.5-1.5 parts by weight.

17. A process according to claim 1, wherein the β

-adrenergic blocker is sotalol HCl present in an amount of 1-20 parts by weight.

18. A process according to claim 1, wherein the β

-adrenergic blocker is acebutolol HCl present in an amount of 0.5-20 parts by weight.

19. A process according to claim 1, wherein the β

-adrenergic blocker is atenolol HCl present in an amount of 1-10 parts by weight.

20. A process according to claim 1, wherein the β

-adrenergic blocker is bopindolol HCl present in an amount of 0.1-1 parts by weight.

21. A process according to claim 1, wherein the β

-adrenergic blocker is nadolol HCl present in an amount of 1-10 parts by weight.

22. A process according to claim 1, wherein the β

adrenergic blocker is alprenolol HCl present in an amount of 0.1-10 parts by weight.

23. A process according to claim 1, wherein the β

-adrenergic blocker is propranolol HCl present in an amount of 0.1-10 parts by weight.

24. A process according to claim 1, wherein the polysaccharide has a molecular weight of about 15,000.

25. A pharmaceutical prepared in accordance with claim 1.