Dipyricamole sustained release forms comprising lacquer-coated particles and the preparation thereof

• US 4,367,217 A
• Filed: 12/31/1980
• Issued: 01/04/1983
• Est. Priority Date: 01/12/1980
• Status: Expired due to Term

• Current Assignee: KARL Thomae GmbH Dr
• Original Assignee: Boehringer Ingelheim GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: Gruber, Peter, Brickl, Rolf, Bozler, Gerhard, Stricker, Herbert
• Primary Examiner(s): Rose, Shep K.
• Application Number:
  US06/221,834
• Time in Patent Office: 734 Days
• Field of Search: 424/19-22, 424/32, 424/33, 424/35, 427/3
• US Class Current: 424/494
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5078 with drug-free core
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

This invention relates to a composition for the sustained release of dipyridamole which comprises (i) spheroid particles comprised of dipyridamole or crystallized salts thereof and pharmacologically acceptable acid or acid substance, and (ii) a coating surrounding said spheroid particles, said coating being comprised of from about 50 to 100 percent by weight of acid-insoluble lacquers soluble in intestinal juices and from about 0 to 50 percent by weight of lacquers insoluble in gastric and intestinal juices and said coating being present in an amount of from about 3 to 30 percent by weight, based on the weight of the spheroid particles, and to the preparation of such a composition.

Claims

1. A composition for the sustained release of dipyridamole which comprises (i) spheroid particles comprised of (a) dipyridamole or acid addition salts thereof and (b) at least one pharmacologically acceptable acid or acid substance, the total amount of acid from acid addition salts present and the acid or acid substance being in a ratio of at least 1 acid equivalent to 1 mol of dipyridamole, said particles having a diameter of from about 0.1 to 3 mm, and (ii) a coating surrounding said spheroid particles, said coating being comprised of from about 50 to 100 percent by weight of acid-insoluble lacquers soluble in intestinal juices and from about 0 to 50 percent by weight of lacquers insoluble in gastric and intestinal juices and said coating being present in an amount of from about 3 to 30 percent by weight, based on the weight of the spheroid particles.

2. The composition of claim 1, wherein the spheroid particles contain dipyridamole as component (a) and the acid or acid substance and dipyridamole are present in a ratio of at least 1 acid equivalent to 1 mol of dipyridamole.

3. The composition of claim 2, wherein the ratio is from about 1 to 30 acid equivalents to 1 mol of dipyridamole.

4. The composition of claim 1, wherein the spheroid particles contain acid addition salts of dipyridamole as component (a) and the acid or acid substance and acid addition salts are present in amounts such that the total amount of acid or acid substance and acid from the acid addition salts is in a ratio of at least 1 acid equivalent to 1 mol of dipyridamole.

5. The composition of claim 1, wherein the acid is selected from the group consisting of fumaric acid and tartaric acid.

6. The composition of claim 1, wherein the coating comprises from 0 to about 14 percent by weight of ethylcellulose.

7. The composition of claim 1, wherein the spheroid particles comprise rounded granulates or pellets and have a diameter of from about 0.8 to 1.5 mm.

8. The composition of claim 1, wherein the coating contains lacquers insoluble in gastric and intestinal juices.

9. The composition of claim 1, wherein the acid-insoluble lacquers soluble in intestinal juices are selected from the group consisting of methacrylic acid/methacrylate copolymers (acid number 180 to 200), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropylmethylcellulose succinate, cellulose acetate succinate, hydroxypropylmethylcellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose trimellitate, methacrylic acid/methacrylate copolymer (acid number 300 to 330), and mixtures of one or more thereof.

10. The composition of claim 9, wherein the lacquer soluble in intestinal juices comprises from about 90 to 50 percent by weight of methacrylic acid/methacrylate copolymer (acid number 180 to 200) and of from about 10 to 50 percent by weight of hydroxypropylmethylcellulose phthalate.

11. The composition of claim 10 which contains an additional outer coating comprising a lacquer soluble in intestinal juices.

12. The composition of claim 1, wherein the spheroid particles comprise a core consisting essentially of acid or acid substance and said core has a coating of a retarding lacquer component.

13. The composition of claim 1, wherein coated spheroid particles are contained in conventional hard gelatin capsules.

14. The composition of claim 1, wherein the coated spheroid particles have diameters of up to 1.5 mm and are contained with conventional excipients in tablet form.

15. The composition of claim 1, wherein the spheroid particles have cores and the cores are comprised of an acid or acid substance different from the acid or acid substance in admixture with dipyridamole.

16. The composition of claim 1, wherein the acid-insoluble lacquer soluble in intestinal juices is soluble at a pH of about 4.5 or greater.

17. A method for treatment of cardiovascular disorders in a host in need of such treatment which comprises administering to said host a cardiovascularly effective amount of a composition of claim 1.

18. The composition of claim 1, wherein the coating is comprised of 100 percent by weight of acid-insoluble lacquers soluble in intestinal juices.

19. A hard gelatin capsule which contains an effective amount of a composition of claim 1 wherein the dipyridamole or acid addition salts thereof are present in an amount of from about 50 to 500 mg.

20. The capsule of claim 19, wherein the dipyridamole or acid addition salts thereof are present in an amount of from about 150 to 250 mg.

21. A tablet which comprises a compressed mixture of an effective amount of a composition of claim 1, wherein the coated spheroid particles thereof have a particle size of up to 1.5 mm and conventional pharmaceutical excipients and wherein the dipyridamole or acid addition salts thereof are present in an amount of from about 50 to 500 mg.

22. The tablet of claim 21, wherein the dipyridamole or acid addition salts thereof are present in an amount of from about 150 to 250 mg.

23. The method of claim 17, wherein the spheroid particles contain dipyridamole as component (a) of the composition and the acid or acid substance and dipyridamole are present in a ratio of at least 1 acid equivalent to 1 mol of dipyridamole.

24. The method of claim 23, wherein the ratio is from about 1 to 30 acid equivalents to 1 mol of dipyridamole.

25. The method of claim 17, wherein the spheroid particles contain acid addition salts of dipyridamole as component (a) of the composition and the acid or acid substance and acid addition salts are present in amounts such that the total amount of acid or acid substance and acid from the acid addition salts is in a ratio of at least 1 acid equivalent to 1 mol of dipyridamole.

26. The method of claim 17, wherein the acid is selected from the group consisting of fumaric acid and tartaric acid.

27. The method of claim 17, wherein the coating comprises from 0 to about 14 percent by weight of ethylcellulose.

28. The method of claim 17, wherein the spheroid particles comprise rounded granulates or pellets and have a diameter of from about 0.8 to 1.5 mm.

29. The method of claim 17, wherein the coating contains lacquers insoluble in gastric and intestinal juices.

30. The method of claim 17, wherein the acid-insoluble lacquers soluble in intestinal juices are selected from the group consisting of methacrylic acid/methacrylate copolymers (acid number 180 to 200), hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, ethylcellulose phthalate, hydroxypropylmethylcellulose succinate, cellulose acetate succinate, hydroxypropylmethylcellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, hydroxypropylmethylcellulose trimellitate, methacrylic acid/methacrylate copolymer (acid number 300 to 330), and mixtures of one or more thereof.

31. The method of claim 30, wherein the lacquer soluble in intestinal juices comprises from about 90 to 50 percent by weight of methacrylic acid/methacrylate copolymer (acid number 180 to 200) and of from about 10 to 50 percent by weight of hydroxypropylmethylcellulose phthalate.

32. The method of claim 31 which contains an additional outer coating comprisng a lacquer soluble in intestinal juices.

33. The method of claim 17, wherein the spheroid particles comprise a core consisting essentially of acid or acid substance and said core has a coating of a retarding lacquer component.

34. The method of claim 17, wherein the coating is comprised of 100 percent by weight of acid-insoluble lacquers soluble in intestinal juices.

35. The method of claim 17, wherein coated spheroid particles are contained in conventional hard gelatin capsules.

36. The method of claim 17, wherein the coated spheroid particles have diameters of up to 1.5 mm and are contained with conventional excipients in tablet form.

37. The method of claim 17, wherein the spheroid particles have cores and the cores are comprised of an acid or acid substance different from the acid or acid substance in admixture with dipyridamole.

38. The method of claim 17, wherein the acid-insoluble lacquer soluble in intestinal juices is soluble at a pH of about 4.5 or greater.

39. A process for the preparation of a sustained release dipyridamole composition which comprises the steps of:

(a) uniformly spraying rounded starter cores having an average diameter of from about 0.3 to 1 mm with an alcoholic polyvinyl pyrrolidone solution;

(b) mixing the sprayed starter cores from step (a) with a mixture of dipyridamole or acid addition salts thereof and a sufficient amount of acid substance to make the dipyridamole component water-soluble until the starter cores thus treated roll freely;

(c) drying the treated cores from step (b), steps (a) to (c) being repeated until the treated cores obtain a size of from about 0.1 to 3 mm; and

(d) applying to the treated cores from step (c) a lacquer coating comprising from about 50 to 100 percent by weight of pharmacologically acceptable acid-insoluble lacquers soluble in intestinal juices and from 0 to about 50 percent by weight of pharmacologically acceptable lacquers insoluble in gastric and intestinal juices, said coating being present in an amount of from about 3 to 30 percent by weight, based on the weight of the spheroid particles.