Dextran derivatives for controlled-release of active compounds in the small intestine; methods for preparing such derivatives; and enteric polymers containing such derivatives.

Abstract

This invention involves a dextran derivative for controlled release. Intestinal active compounds containing at least one substituent of 1,2-cyclohexanedicarboxyl. (1,2-cyclohexanedicarboxyl) with a substitution percentage ranging from 20 to 70 percent of the number of hydroxyl groups. In addition to dextran, dextran derivatives also contain succinyl substituents. Percentage substitution ranging from 25 to 80 percent of the number of hydroxyl groups in dextran. Dextran derivatives accordingly. This invention exhibits specific solubility in aqueous solutions. The pH ranges from 5 to 7. This invention also involves enteric polymers. Pharmaceutical components and pharmaceutical formulations for oral administration containing derivatives. The aforementioned dextran.

Claims

------30 / 03 / 2569------(OCR)OCR09WP1. A dextran derivative for controlled release of active compounds in the small intestine, containing 1,2-cyclohexanedicarboxyl substituents with a percentage substitution of 20 to 70 percent of the number of hydroxyl groups in dextran, and succinyl substituents with a percentage substitution of 25 to 80 percent of the number of hydroxyl groups in dextran. Dextran derivatives are soluble in aqueous solutions at pH 5 to 6.

52. Dextran derivatives under claim 1 have a 1,2-cyclohexanedicarboxyl substitution percentage of 46 to 54% of the total hydroxyl groups in dextran, a succinyl substitution percentage of 25 to 29% of the total hydroxyl groups in dextran, and a specific minimum pH for complete solubility in aqueous solution of 6.53.Dextran derivatives under claim 1 with a 1,2-cyclohexanedicarboxyl substitution percentage of 44 to 50% of the total number of hydroxyl groups in dextran, a succinyl substitution percentage of 31 to 35% of the total number of hydroxyl groups in dextran, and a specific minimum pH for complete solubility in aqueous solution of 64. Dextran derivatives under claim 1 with a 1,2-cyclohexanedicarboxyl substitution percentage of 30 to 46% of the total number of hydroxyl groups in dextran, a succinyl substitution percentage of 31 to 35% of the total number of hydroxyl groups in dextran, and a specific minimum pH for complete solubility in aqueous solution of 64. The dextran derivatives under claim 1.1 have a 1,2-cyclohexanedicarboxyl substitution percentage of 20 to 30 percent of the total number of hydroxyl groups in dextran, a succinil substitution percentage of 70 to 80 percent of the total number of hydroxyl groups in dextran, and a specific minimum pH for complete solubility in aquatic solution of 5.55.Any dextran derivative under claims 1 through 5 that is made into fibrous, particle, powder, granule, film or tablet form; 7. Any dextran derivative under claim 6 in which the particle or fibrous size has an average range from 200 to 1,000 nanometers (nm); 8. Any method for preparing any dextran derivative under claims 1 through 7 which includes the following steps: a. Esterification reaction between dextran and a mixture of 1,2-cyclohexanedicarboxylicanhydride; a. Separation of dextran derivatives from the reaction mixture of step a.

9. Method according to claim 8 in which the esterification reaction is performed using a mole ratio of 1,2-cyclohexanedicarboxylic anhydride to hydroxyl groups of dextran in the range of 1-1.7:

110. Method according to claim 9 in which the mole ratio of 1,2-cyclohexanedicarboxylic anhydride to hydroxyl groups of dextran in the range of 1.25-1.7:111.Method according to claim 8 in which the esterification reaction is performed using a molar ratio of succinic anhydride to the hydroxyl group of dextran in the range of 0.1-1.5:

112. Method according to claim 11 in which the molar ratio of succinic anhydride to the hydroxyl group of dextran in the range of 0.25-1.25:

113. Method according to claim 8 in which the esterification reaction is performed using a molar ratio of 1,2-cyclohexane dicarboxylic anhydride to succinic anhydride to the hydroxyl group of dextran. The method according to claim 13, in which the molar ratio of 1,2-cyclohexanedicarboxylic anhydride to succinic anhydride to hydroxyl groups of dextran is in the range of 1.1-1.4:0.1-0.4:1, 1.1-1.4:0.3-0.7:1, 1.1-1.4:

0. 6-1.2:1 or 1.1-1.4:1.1-1.4:

115. Method according to claim 14 in which the molar ratio of 1,2-cyclohexanedicarboxylic anhydride to succinic anhydride to the hydroxyl group of dextran is 1.25:0.25:1, 1.25:0.5:1, 1.25:0.75:1, 1.25:1:1 or 1.25:1.25:116.

17. Any of the methods under claims 8 through 16 in which the esterification reaction is carried out with a base catalyst.

18. Any of the methods under claim 17 in which the catalyst is lithium chloride or triethylamine.

19. Any of the methods under claim 8 through 16 in which the esterification reaction is carried out with a base catalyst.

20. Any of the methods under claims 8 through 19 in which the esterification reaction is carried out by reflux at a temperature ranging from 100 to 130 degrees Celsius.

21. Any of the methods under claim 8 through 19 in which the esterification reaction is carried out for a time ranging from 12 to 24 hours.

22. Any of the methods under claim 8 in which the separation of dextran derivatives is carried out by precipitation, crystallization, filtration, centrifugation, or dialysis.The method under claim 21, in which the separation of dextran derivatives is carried out by dialysis, consists of the following steps: - precipitation of dextran derivatives by placing the reaction mixture obtained from step a into a dialysis bag and immersing it in distilled water while continuously stirring to precipitate the dextran derivatives in the dialysis bag, and - drying of the precipitated dextran derivatives by freeze-drying to obtain dry powder dextran derivatives.

23. The method under claim 22, in which the precipitation of dextran derivatives uses a dialysis bag. The cyst has a pore size of 500-12000 Daltons (MWCO500-12000Da).

24. Any one of the methods for forming dextran derivatives under claims 1 to 7, which includes: a. The provision of a solution of dextran derivatives obtained by dissolving dextran derivatives in a solvent using a weight ratio of dextran derivatives to solvent in the range of 0.2-0.6:1, and b. The formation of fibers from the solution of dextran derivatives obtained in step a.

25. The forming method under claim 24, which also includes the provision of a solution of dextran derivatives obtained in step a.

26. The forming method under claim 24 or 25, which also includes the mixing of additional components of a choice from the group of active ingredient, excipient, adjuvant, carrier and mixtures thereof into the dextran derivative solution before the forming of the dextran derivative solution.

27. One of the forming methods under claim 24 to 26 in which the formation of the dextran derivative solution is carried out by electrospinning.

28. The forming method under claim 27 in which the electrospinning is carried out using a needle size between 27G and 18G.

29. The forming method under claim 27 in which the electrospinning is carried out using a flow rate of the dextran derivative solution in the range of 1 to 2 ml per hour. 30.

31. Forming method according to claim 27 in which the electrospinning method is performed using an electrical potential difference between the metal needle and the metal support in the range of 10 to 30 kV.

32. Forming method according to claim 24 or 27 in which the resulting fibers have an average size between 200 and 1,000 nanometers.

33. Enteric polymer composed of any one of the dextran derivatives according to claims 1 to 7, which includes 1,2-cyclohexanedicarboxyl substituents with a percentage substitution of 20 to 70 percent of the total number of hydroxyl groups in dextran and succinyl substituents with a percentage substitution of 25 to 80 percent of the total number of hydroxyl groups in dextran, in which the enteric polymer is soluble in aqueous solution at a pH of 5 to 6.5.Enteric polymer according to claim 33 in which the dextran derivative has a percentage substitution of 1,2-cyclohexanedicarboxyl substituents of 46 to 54 of the total number of hydroxyl groups in dextran, a percentage substitution of succinyl substituents of 25 to 29 of the total number of hydroxyl groups in dextran, and has a specific minimum pH for complete solubility in aqueous solution of 6.

535. Enteric polymer according to claim 33 in which the dextran derivative has a percentage substitution of 1,2-cyclohexanedicarboxyl substituents of 44 to 50 of the total number of hydroxyl groups in dextran. The enteric polymer according to claim 33, where the dextran derivative has a 1,2-cyclohexanedicarboxyl substitution of 30 to 46 of the total number of hydroxyl groups in dextran, a succinil substitution of 46 to 67 of the total number of hydroxyl groups in dextran, and a specific minimum pH for complete solubility in aquatic solution of 636.Enteric polymer according to claim 33 in which the dextran derivative has a percentage substitution of 1,2-cyclohexanedicarboxyl substituents of 20 to 30 percent of the total number of hydroxyl groups in dextran, a percentage substitution of succinyl substituents of 70 to 80 percent of the total number of hydroxyl groups in dextran, and has a specific minimum pH for complete solubility in aqueous solution of 538. Any one of the enteric polymers according to claims 33 to 37 is made into fibrous or particulate form.

39. Enteric polymers under claim 38 in which the particles or fibers have an average size ranging from 200 to 1,000 nanometers.

40. Enteric polymers under any of claims 33 to 39 for controlled release of active substances in the small intestine.

41. Pharmaceutical components for oral administration containing any dextran derivative under claims 1 to 7 or any enteric polymer under claims 33 to 40. 42.Oral pharmaceutical components coated with dextran derivatives as per any of claims 1 to 7 or enteric polymers as per claims 33 to 40; 43. Oral pharmaceutical components as per claim 41 or 42 which also contain an active agent; 44. Oral pharmaceutical components as per any of claims 41 to 43 which also contain an additive of choice from a group of fillers, adjuvants, carriers and mixtures thereof.

5. Pharmaceutical formulations for oral administration under any of the claims 41 to 44 in the form of fibers, particles, powder, granules, films, tablets, pills, seeds, pellets, or capsules.

46. Pharmaceutical formulations for oral administration under claim 45 in which the particles or fibers have an average size ranging from 200 to 1,000 nanometers.

47. Pharmaceutical formulations for oral administration containing any of the dextran derivatives under claims 1 to 7 or any of the enteric polymers under claims 33 to 40. 48.Oral pharmaceutical formulations coated with dextran derivatives as per any of claims 1 to 7 or enteric polymers as per claims 33 to 40.