PHARMACEUTICAL COMPOSITION AND PREPARATION METHOD THEREFOR

Abstract

The present invention provides an oral pharmaceutical composition and a usage thereof, comprising a pharmaceutically acceptable acidic medicinal auxiliary material whose surface is modified and dabigatran etexilate or pharmaceutically acceptable salts or aquo-complexes thereof. The present invention further provides a surface modification method for a medicinal auxiliary material.

Claims

1-16. (canceled)

17. An oral pharmaceutical composition, comprising: (i) a first component, wherein the first component comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt or hydrate thereof; and (ii) a second component, wherein the second component comprises: (a) a pharmaceutically acceptable surface-modified acidic auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified acidic auxiliary material comprises a neutral salt layer that comprises: 1) an anion of an acidic medicinal auxiliary material in a powdered form; and 2) a cation of a pharmaceutically acceptable alkaline substance for surface modification; or (b) a pharmaceutically acceptable surface-modified alkaline auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified alkaline auxiliary material comprises a neutral salt layer that comprises: 1) a cation of an alkaline medicinal auxiliary material in a powdered form; and 2) an anion of a pharmaceutically acceptable acidic substance for modification.

18. The oral pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of up to 10%.

19. The oral pharmaceutical composition of claim 18, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.10% to 10%.

20. The oral pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable alkaline substance for modification or pharmaceutically acceptable acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ratio by weight of 0.67% to 4%.

21. The oral pharmaceutical composition of claim 17, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a water solubility of greater than 1 g/250 mL at 20° C., or wherein the alkaline medicinal auxiliary material is a pharmaceutically acceptable alkaline substance having a water solubility of greater than 1 g/250 mL at 20° C.

22. The oral pharmaceutical composition of claim 17, wherein the acidic medicinal auxiliary material is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt; and wherein the pharmaceutically acceptable alkaline substance for surface modification is selected from the group consisting of aqueous ammonia, meglumine, trihydroxymethylaminomethane, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium stearate, potassium stearate, lysine, arginine and histidine, and a hydrate thereof.

23. The oral pharmaceutical composition of claim 17, wherein the alkaline medicinal auxiliary material is selected from the group consisting of lysine, arginine and histidine, and a hydrate thereof; and wherein the pharmaceutically acceptable acidic substance for modification is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt.

24. The oral pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable alkaline substance for modification is selected from the group consisting of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, lysine, arginine and a hydrate thereof.

25. The oral pharmaceutical composition of claim 17, wherein the acidic medicinal auxiliary material or the alkaline medicinal auxiliary material has a particle size of 0.4 to 1.5 mm.

26. The oral pharmaceutical composition of claim 17, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid, and wherein the pharmaceutically acceptable alkaline substance is a carbonate base.

27. The oral pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable organic acid is tartaric acid, and wherein the carbonate base is sodium carbonate.

28. An oral pharmaceutical composition, comprising: (i) a first component, wherein the first component comprises an active pharmaceutical ingredient or a pharmaceutically acceptable salt or hydrate thereof; and (ii) a second component, wherein the second component comprises: (a) a pharmaceutically acceptable surface-modified acidic auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified acidic auxiliary material comprises a neutral salt layer formed by reacting: 1) a powdered form of an acidic medicinal auxiliary material; and 2) an aqueous solution comprising a pharmaceutically acceptable alkaline substance for surface modification, wherein the acidic medicinal auxiliary material is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt thereof, and wherein the pharmaceutically acceptable alkaline substance for modification is selected from the group consisting of aqueous ammonia, meglumine, trihydroxymethylaminomethane, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium stearate, potassium stearate, lysine, arginine and histidine, and a hydrate thereof; or (b) a pharmaceutically acceptable surface-modified alkaline auxiliary material, wherein the surface of the pharmaceutically acceptable surface-modified alkaline auxiliary material comprises a neutral salt layer formed by reacting: 1) a powdered form of an alkaline medicinal auxiliary material; and 2) an aqueous solution comprising a pharmaceutically acceptable acidic substance for modification, wherein the alkaline medicinal auxiliary material is selected from the group consisting of lysine, arginine, histidine, and a hydrate thereof, and wherein the pharmaceutically acceptable acidic substance for modification is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, and an acidic salt.

29. The oral pharmaceutical composition of claim 28, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ration by weight of up to 10%.

30. The oral pharmaceutical composition of claim 29, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ration by weight of 0.10% to 10%.

31. The oral pharmaceutical composition of claim 30, wherein the alkaline substance for modification or acidic substance for modification to the acidic medicinal auxiliary material or alkaline medicinal auxiliary material are present in a ration by weight of 0.67% to 4%.

32. The oral pharmaceutical composition of claim 28, wherein the acidic medicinal auxiliary material or the alkaline medicinal auxiliary material has a particle size of 0.4 to 1.5 mm.

33. The oral pharmaceutical composition of claim 26, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a water solubility of greater than 1 g/250 mL at 20° C., or wherein the alkaline medicinal auxiliary material is a pharmaceutically acceptable alkaline substance having a water solubility of greater than 1 g/250 mL at 20° C.

34. The oral pharmaceutical composition of claim 26, wherein the acidic medicinal auxiliary material is tartaric acid, and wherein the pharmaceutically acceptable alkaline substance for surface modification is sodium carbonate.

Description

DESCRIPTION OF DRAWINGS

[0040] FIG. 1 shows that the drug obtained in Example 2 achieves the same dissolution effect as the prior art product.

[0041] FIG. 2 shows the dissolution results of the capsules of Example 3 which were prepared with the raw material dabigatran etexilate mesylate and the modified tartaric acid in different proportions.

DESCRIPTION OF EMBODIMENTS

[0042] To clearly illustrate the object, the technical solution and the advantages of the present invention, the specific embodiments of the present invention will be described below in detail, with reference to the accompanying drawings.

[0043] The technical solutions in the examples of the present invention will be described below in detail, with reference to the examples of the present invention. Obviously, the examples described herein are merely a part of the examples of the present invention, and do not represent all. On the basis of the examples shown in the present invention, all the other examples which can be obtained by those of ordinary skill in the art without paying any creative efforts are within the scope of the present invention.

[0044] It should be noted that in this context, the terms “comprise”, “include”, and “contain” or any other variants thereof are intended to be nonexclusive, so that a process, method, article or apparatus comprising a series of elements includes not only those elements, but also other elements which are not explicitly listed, or elements which are inherent to such a process, method, article, or apparatus. Meanwhile, in the present invention, the dissolution is tested at 100 rpm and at a temperature of 37° C. by the basket method specified in the Pharmacopoeia, and water is used as the solvent.

[0045] FIG. 1 shows that the drug obtained according to Formula 2 achieves the same dissolution effect as the prior art product. FIG. 2 shows the dissolution results of the capsules prepared with the raw material dabigatran etexilate mesylate and the modified tartaric acid in different proportions.

[0046] The method for surface modification of an acidic medicinal auxiliary material according to the present invention comprises: according to the water solubility of the alkaline substance for modification, formulating an aqueous solution of the pharmaceutically acceptable alkaline substance for modification at a concentration of 5 to 40 wt %; adding the acidic medicinal auxiliary material having a particle size of 0.4 to 1.5 mm, preferably 0.5 mm, to a certain volume of the above formulated aqueous solution of the pharmaceutically acceptable alkaline substance for modification having a concentration of 5 to 40 wt %; alkalizing the surface of powder particles of the acidic medicinal auxiliary material with the above aqueous solution of the alkaline substance for modification, to form a neutral salt layer on the surface of the powder particles of the acidic medicinal auxiliary material. The acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a water solubility of greater than 1 g/250 mL at 20° C., and the organic acid as the acidic medicinal auxiliary material is one selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid, or a hydrate or acidic salt thereof, preferably tartaric acid. The pharmaceutically acceptable alkaline substance for modification as used for alkalization is a pharmaceutically acceptable alkaline substance for modification, and the pharmaceutically acceptable alkaline substance for modification is one of sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium stearate, potassium stearate, lysine, arginine and histidine, or a hydrate thereof, preferably sodium carbonate.

[0047] First, a sodium carbonate aqueous solution having a concentration of 20% (by weight) is formulated; with stirring, 10% of the above formulated sodium carbonate aqueous solution having a formulation concentration of 20% is added to tartaric acid powder particles having a particle size of 0.4 to 1.5 mm, preferably 0.5 mm; and after stirring, the tartaric acid powder particles are dried in a drying apparatus such as a drying oven or a fluidized bed, to yield the modified tartaric acid powder particles.

[0048] Since the sodium carbonate aqueous solution is alkaline, a chemical reaction will occur between the alkaline sodium carbonate and the acidic tartaric acid, forming a neutral salt layer on the surface of the tartaric acid powder particles. The neutral salt layer separates the acidic medicinal auxiliary material tartaric acid from the active drug ingredient which is labile to acids in the formulation that however requires the use of acidic auxiliary materials therein, thereby improving the storage stability of the drug. In addition to sodium carbonate, any weak-acid strong-alkali salts which are alkaline in an aqueous solution can be used in the present invention, without any particular limitation.

Example 1

Formula 1

[0049]

TABLE-US-00001 Dabigatran etexilate mesylate 173.0 mg Tartaric acid 173.5 mg Sodium carbonate  3.54 mg Total   350 mg Control formula: Dabigatran etexilate mesylate 173.0 mg Tartaric acid   177 mg Total   350 mg

[0050] Dabigatran etexilate mesylate, tartaric acid, and sodium carbonate are all commercially available raw materials.

[0051] According to Formula 1, a quantified amount of sodium carbonate was dissolved in 20 mL water; with stirring, tartaric acid powder particles having a particle size of 0.4 to 1.5 mm were added to the sodium carbonate aqueous solution; and after stirring, the tartaric acid powder particles were dried in a drying apparatus such as a drying oven or a fluidized bed, to yield the modified tartaric acid powder particles.

[0052] The modified tartaric acid powder particles were thoroughly mixed with dabigatran etexilate mesylate indicated in Formula 1 and loaded into hydroxypropylmethylcellulose (HPMC) capsules. The capsules were then packed into high density polyethylene (HDPE) bottles containing a desiccant. After being stored at 75° C. and 75% RH for 1 week and 2 weeks, capsule samples were tested by HPLC and the results are shown in the following table.

[0053] According to the control formula, tartaric acid powder particles were thoroughly mixed with dabigatran etexilate mesylate indicated in the control formula and loaded into hydroxypropylmethylcellulose (HPMC) capsules. The capsules were then packed into high density polyethylene (HDPE) bottles containing a desiccant. After being stored at 75° C. and 75% RH for 1 week and 2 weeks, capsule samples were tested by HPLC and the results are shown in the following table.

TABLE-US-00002 TABLE 1 Total amount of decomposition products (%) Storage duration Formula 1 Control formula 0 day 0.27 0.31 1 week 2.9 3.6 2 weeks 4.8 10.9

[0054] As can be seen from the above results, the formulation into which the modified tartaric acid was added exhibits a greatly improved storage stability. As shown in Table 1, it can be seen that as the storage duration changes, the stability is 200% or more relative to the unmodified control.

Example 2

Formula 2

[0055]

TABLE-US-00003 Dabigatran etexilate mesylate 173.0 mg Tartaric acid 166.6 mg Sodium carbonate  3.4 mg HPC  10.0 mg Silica powder  8.0 mg SDS  5.0 mg Lactose  45.0 mg Magnesium stearate  6.0 mg Total 420.0 mg

[0056] According to Formula 2, a quantified amount of sodium carbonate was dissolved in 20 mL water; with stirring, tartaric acid powder particles having a particle size of 0.4 to 1.5 mm were added to the sodium carbonate aqueous solution; and after stirring, the tartaric acid powder particles were dried in a drying apparatus such as a drying oven or a fluidized bed, to yield the modified tartaric acid powder particles.

[0057] Then, dabigatran etexilate mesylate were mixed with the modified tartaric acid powder particles, followed by other pharmaceutically acceptable excipients, and loaded into HPMC capsules to yield the pharmaceutical formulation product.

Example 3

[0058] Dabigatran etexilate mesylate were mixed with the modified tartaric acid powder particles, followed by other pharmaceutically acceptable excipients, and loaded into HPMC capsules to yield the pharmaceutical formulation product. FIG. 2 shows the dissolution results of the capsules prepared with the raw material dabigatran etexilate mesylate and the modified tartaric acid in different proportions. The dissolution was tested at 100 rpm and at a temperature of 37° C. by the basket method specified in the Pharmacopoeia, and water was used as the solvent.

[0059] The results show that the dissolution of the dabigatran etexilate mesylate formulation product into which the modified tartaric acid was added is significantly improved as compared with the dissolution of the formulation into which the modified tartaric acid was not added.

[0060] To sum up, the pharmaceutical composition of the present invention exhibits a superior storage stability, achieves a high solubility, and provides the desired bioavailability. Meanwhile, the method for surface modification of a medicinal auxiliary material performs the modification of the surface of the acidic medicinal auxiliary material by only an one-step reaction, and thus has a simple process and achieves low production costs.

[0061] The specific embodiments described above are merely illustrative of the spirit of the present invention, and the scope of the present invention is not limited thereto. It will be apparent to those skilled in the art that, other embodiments can be readily made by way of modifications, replacements or variations according to the technical contents disclosed in the present Description, and all of the other embodiments are intended to be within the scope of the present invention.