IL42459A

IL42459A - Medicament formulations having controlled residence time in the gastric region

Info

Publication number: IL42459A
Application number: IL42459A
Authority: IL
Original assignee: Purdue Research Foundation
Priority date: 1972-06-09
Filing date: 1973-06-07
Publication date: 1976-12-31
Also published as: IE38151L; NL7307737A; FR2187290A1; ZA733897B; SE395609B; GB1428426A; IE38151B1; PL90109B1; ES415624A3; HU167947B; DD109309A5; AU5935773A; BE800637A; RO64146A; CH582002A5; IL42459A0; CA1040533A; DD112354A5; FR2187290B1; AU5682673A

Claims

424S -2 - 56 - 118-3324 CLAIMS:

1. A sustained release medicament formulation with prolonged gastric residence comprising a) a medicament core or a core comprising a diagnostic aid, and b) a pharmaceutically acceptable coating on said core comprising. (1) a pharmaceutically acceptable cross-linked polymeric component which comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, the prepolymer being a copolymer of (1) 20-90 parts by weight of a substituted or unsubstituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms , said polymeric film being water-hydratable , water-permeable and swellable in the presence of gastric fluids, ..424i£>"S- - 563-- 118-3324 r a d , optionally , (2) a pharmaceutically acceptable, substantially water-insoluble polymeric component.

2. A sustained release medicament formulation with prolonged gastric residence comprising a) a medicament core, and b) a pharmaceutically acceptable coating on said core comprising a cross-linked polymeric film which comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, the prepolymer being a copolymer of (i) 20-90 parts by weight of a substituted or unsubstituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms , said polymeric film being water-hydratable, water- permeable and swellable in the presence of gastric fluids. - 57 - 118-3324

3. A formulation according to Claim 2, in which the polymeric film comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 1.5 parts by weight of cross-linking agent.

4. A formulation according to Claim 2 or 3"j in which the prepolymer contains repeating units of formula I , in which one of and R? is hydrogen and the other is hydrogen, chlorine, fluorine, hydroxy, alkyl of 1 to 16 carbon atoms, aryl, aralkyl or -SO^H, and R is dimethylene, optionally substituted by alkyl of 1 to 4 carbon atoms, phenyl,- or alkoxy of 1 to 12 carbon atoms , or is -CH -CH=CH-CH„-. - 58 - 118-3324

5. A formulation according to Claim 4, in which the prepolymer contains repeating units of formula I, in which each of and R2 is hydrogen, and R is dimethylene optionally substituted by phenyl or methoxy.

6. A formulation according to Claim 5, in which the prepolymer contains repeating units of formula I, in which each of ^ and R2 is hydrogen and R is dimethylene substituted by methoxy.

7. A formulation according to any one of Claims 2 to 6, in which the average molecular weight of the prepolymer is from 100,000 to 5,000,000.

8. A formulation according to Claim 7,. in which the average molecular weight is 250,000 to 2,000,000.

9. A formulation according to any one of Claims 2 to 7, in which the prepolymer is that knov/n under the trade name Gantrez AN-119, Gantrez AN-139, Gantrez AN-149, Gantrez AN-169 or Gantrez AN-179 , as hereinbefore defined.

10. A formulation according to any one of Claims 2 to 9, in which the cross-linking agent is an alk lene diol, a polyalkylene glycol, a long-chain dihydric compound, a diamine, or a triol.

11. A formulation according to Claim 10, in which the cross-linking agent is 1 , 3-propylene diol, 42459-2 - 59 - 118-3324 diethylene glycol, glycerine, polyethyleneglycol, poly-tetramethylene glycol, methoxypolyethylene glycol, a poly-oxyethylene sorbitan ether, ethylene diamine, triethylene tetramine, pentaethylene hexamine or 1,2 ,3-but.ane-triol.

12. A formulation according to Claim 11, in which the cross-linking agent is an alkylene diol or poly-oxyethylene sorbitan ether.

13. A formulation according to any one of Claims 10 to 12, in which the cross-linking agent is polyoxy-ethylene sorbitan monooleate or monolaurate.

14. A formulation according to any one of Claims 2 to 13, in which the polymeric film incorporates a plasticiser.

15. A formulation according to any one of Claims 2 to 14, in which the prepolymer is cross-linked in the presence of a plasticiser, which is present to the extent of 8 parts by weight of prepolymer to 1 to 10 parts by weight of plasticiser.

16. A formulation according to Claim 15, in which the plasticiser is present to the extent of 8 parts by weight of polymer to 1 to 7 parts by weight of plasticiser. - 60 - 118-3324

17. A formulation according to Claim 16, in which the plasticiser is present to the extent of 8 parts by weight of prepolymer to 4 to 5 parts by weight of plasticiser.

18. A formulation according to any one of claims 14 to 17, in which the plasticiser is glyceryltri-acetate, ethylacetate , diethyl phthalate or dibutyl-phthalate.

19. A formulation according to Claim 18, in which the plasticiser is glyceryl triacetate.

20. A formulation according to any one of Claims 2 to 19, in which the polymeric film incorporates a material which is soluble in gastric fluids to provide for film opening.

21. A formulation according to Claim 20, in which the material is finely divided calcium carbonate.

22. A sustained release medicament formulation with prolonged gastric residence, comprising a) a medicament core and b) a pharmaceutically acceptable coating on said core comprising a binary polymeric film including 1) a , harmaceutically acceptable, substantially water-insoluble, polymeric component 42459-2 - 61 - 118-3324 ·♦'· and 2) a pharmaceutically acceptable cross- linked polymeric component which comprises a prepolymer cross-linked with a cross-linking agent at a ratio of 8 parts by weight of prepolymer to 0.15 to 4 parts by weight of cross-linking agent, the prepolymer being a copolymer of i) 20 to 90 parts by weight of a substituted or unsubstituted unsaturated dicarboxylic acid or acid anhydride having 1 to 3 carbon atoms between the two carboxylic groups, and (ii) 10-80 parts by weight of an alkene of 2 to 6 carbon atoms, styrene or an alkyl vinyl ether in which the alkyl radical contains 1 to 16 carbon atoms, said polymeric component being water-hydratable , water-permeable and swellable in the presence of gastric fluids.

23. A formulation according to Claim 22, in which the substantially insoluble polymeric component is a carboxyl containing or carboxylate copolymer. 42459-2

24. A formulation according to claim 23, in which the substantially water-insoluble polymeric component is a polyacrylate.

25. A formulation according to claim 24, in which the polyacrylate is poly (methylmethacrylate) or poly (ethylmethacrylate) .

26. A formulation according to any one of claims 22 to 25, in which the second polymeric component is a prepolymer defined in any one of claims 3 to 8.

27. A formulation according to any one of claims 22 to 26, in which the binary polymeric film comprises the first and second polymeric components in a ratio of from 90:10 to 10:90 by weight.

28. A formulation according to claim 27, in which the ratio is 60:40 to 10:90.

29. A formulation according to any one of the preceding claims, in which the medicament core is in the form of a tablet or capsule.

30. A formulation according to any one .of the preceding claims, in which the medicament core is in the form of a tablet.

31. A formulation according to any one , of the preceding claims, in which only part of the medicament core is coated with the polymeric film. $ 2 59-2 - 63 - 118-3324

32. A formulation according to claim 31, in which the medicament core comprises a multilayer tablet having a first layer comprising a water-insoluble drug and a second layer comprising a water-soluble drug, the second layer but not the first layer being coated with the polymeric film.

33. A formulation according to Claim 32, in which the tablet has an intermediary film bonding layer, the film being coated on the second layer and the intermediary layer.

34. A formulation according to claim 33, in which the intermediary bonding layer comprises stearic acid, glyceryl monostearate , spermacetti , cetyl alcohol or an acetylated monoglyceride .

35. A formulation according to claim 34, in which the intermediary bonding layer, additionally comprises a polymeric component comprising a prepolymer according to any one of claims 3 to 8.

36. A formulation according to any one of the preceding claims, in which the medicament core comprises tetracycline, ampicillin, aspirin, potassium chloride phenylpropanolamine, phenyl butazone, amoxycillin or pehtaerythritol tetranitrate .

37. A sustained release medicament formulation A2459 -2 - 64 - 118-3324 substantially , as herein described with reference to any one of the preceding Examples.

38. A method of producing a formulation according to Claim 2, which comprises a) coating a medicament core with a solution comprising a prepolymer and a cross-linking agent, as defined in Claim 2, and b) subjecting the resulting coated medicament core to cross-linking conditions.

39. A method according to claim 38, for the production of a formulation according to any one of claims 2 to 21, and 29 to 36, (as appendant to claims 2 to 21).

40. A method according to claim 38 or 39, in which the solution is in ethylacetate .

41. A method according to claim 30, 39, or . 40., in which the resulting coated medicament core is subjected to a temperature of from 10° to 90 °C and a relative humidity of from 30 to 95%.

42. A method according to claim 30, 39, 40 or 41, in which the resulting coated medicament core is subjected to a temperature of from 20° to 60°C and a relative humidity of from 40 to 60%.

43. A method according to any one of claims 38 42459-2 - 65 - 118-3324 to 42, in which the resulting coated medicament core is cross-linked in its shipping container.

44. A method according to claim 38, substantially as herein described with reference ;to any one of the Examples 1 to 7.

45. A formulation according to claim 2, whenever produced by a process according to any one of claims 38 to 44. .

46. A process for the production of a formulation according to claim 22, comprising coating a medicament core with a solution of a binary polymer comprising components 1) and 2), defined in claim 22.

47. A process according to Claim 46, in which the solution is in ethyl acetate.

48. A method according to claim 46 or 47, for the production of a formulation according to any one of claims 22, 28, 29 or 48 (as appendent to claims 22 to 28).

49. A method according to claim 46, substantially as herein described with reference to Example 8.

50. • 50. A formulation according to claim 22, whenever produced by a method according to any one of claims 46 to 49.

51. A method of increasing the potential gastric residence time of an oral dosage form, which comprises 42459-2 - 66 - 118-3324 providing a medicament core with a coating comprising polymeric film defined in any one of claims 1 to 28.

52. A method according to claim 51, substan tially as herein described with reference to any one o the Examples. 3700/MO/HD For the Appl ¾aats