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. An oral pharmaceutical composition comprising: a) a pharmaceutically acceptable surface-modified acidic medicinal auxiliary material, b) ethyl 3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate that is also called as dabigatran etexilate, or a pharmaceutically acceptable salt or hydrate thereof.

2. The pharmaceutical composition according to claim 1, comprising 10 to 80% by weight of dabigatran etexilate or a pharmaceutically acceptable salt or hydrate thereof; and 20 to 90% by weight of the surface-modified acidic medicinal auxiliary material.

3. The pharmaceutical composition according to claim 1, wherein the salt of dabigatran etexilate is dabigatran etexilate mesylate.

4. The pharmaceutical composition according to claim 1, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable water-soluble acidic solid.

5. The pharmaceutical composition according to claim 4, wherein the acidic medicinal auxiliary material is a pharmaceutically acceptable organic acid having a solubility of greater than 1% in water at 20° C.

6. The pharmaceutical composition according to claim 4, wherein the pH of 1% aqueous solution formulated with the acidic medicinal auxiliary material should be less than or equal to 5.

7. The pharmaceutical composition according to claim 1, wherein the acidic medicinal auxiliary material is one of pharmaceutically acceptable water-soluble organic acids such as tartaric acid, fumaric acid, succinic acid, citric acid, lactic acid and malic acid etc., or a hydrate or acidic salt thereof.

8. The pharmaceutical composition according to claim 1, wherein the acidic medicinal auxiliary material is one of pharmaceutically acceptable water-soluble acidic amino acids such as glutamic acid and aspartic acid etc., or a hydrate or acidic salt thereof, or acidic salts of other pharmaceutically acceptable water-soluble amino acids such as acidic salts of glycine, alanine and serine etc.

9. The pharmaceutical composition according to claim 1, wherein the acidic medicinal auxiliary material is one of acidic salts of pharmaceutically acceptable water-soluble inorganic acids, including, but not limited to dihydrogenphosphates and bisulfates etc., or a hydrate thereof.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable surface-modified acidic medicinal auxiliary material is obtained by treating the acidic medicinal auxiliary material with an aqueous solution of an alkaline substance for modification.

11. The pharmaceutical composition according to claim 10, wherein the weight ratio of the alkaline substance for modification to the acidic medicinal auxiliary material to be modified is 0.1% to 10%.

12. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is a pharmaceutically acceptable water-soluble alkaline solid or liquid.

13. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is a pharmaceutically acceptable alkaline substance having a solubility of greater than 1% in water at 20° C.

14. The pharmaceutical composition according to claim 10, wherein the pH of 1% aqueous solution formulated with the alkaline substance for modification should be greater than or equal to 9.

15. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is one of pharmaceutically acceptable water-soluble inorganic alkaline substances such as hydroxide salts, water-soluble alkaline carbonates and water-soluble alkaline phosphates etc., or a hydrate thereof.

16. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is one of pharmaceutically acceptable water-soluble organic alkaline substances such as aqueous ammonia, meglumine and trihydroxymethylaminomethane etc., or a hydrate thereof.

17. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is one of alkaline salts of pharmaceutically acceptable water-soluble organic weak acids such as alkaline salts of acetic acid, tartaric acid, fumaric acid, succinic acid, citric acid, malic acid and lactic acid etc., or a hydrate thereof.

18. The pharmaceutical composition according to claim 10, wherein the alkaline substance for modification is one of pharmaceutically acceptable alkaline amino acids such as lysine, arginine, and histidine etc., or a hydrate or alkaline salt thereof, or alkaline salts of other water-soluble amino acids such as alkaline salts of glycine, alanine and serine etc.

19. The pharmaceutical composition according to claim 10, wherein the aqueous solution of the alkaline substance for modification has a concentration in the range of 1 wt % to a saturation concentration, preferably 5 to 40 wt %, more preferably 20 wt %.

20. Use of the composition according to claim 1 in the preparation of an anticoagulant medicament conventionally used for preventing deep venous thrombosis and pulmonary embolism after artificial (knee or hip) arthroplasty; for preventing stroke and thrombosis in a patient with abnormal heart rhythm (atrial fibrillation).

21. A process for preparing the pharmaceutical composition according to claim 1, comprising the step of mixing the pharmaceutically acceptable surface-modified acidic medicinal auxiliary material with dabigatran etexilate or a pharmaceutically acceptable salt or hydrate thereof.

22. The process according to claim 21, wherein the pharmaceutically acceptable surface-modified acidic medicinal auxiliary material is prepared by the following steps: formulating an aqueous solution of a pharmaceutically acceptable alkaline substance for modification; adding the aqueous solution of the alkaline substance for modification to the acidic medicinal auxiliary material; stirring rapidly to distribute the aqueous solution of the alkaline substance for modification uniformly on the surface of the acidic medicinal auxiliary material to be modified; and drying.

23. The process according to claim 21, wherein the pharmaceutically acceptable surface-modified acidic medicinal auxiliary material is prepared by the following steps: formulating an aqueous solution of a pharmaceutically acceptable alkaline substance for modification; and in a fluidized bed, spraying the aqueous solution of the alkaline substance for modification to the surface of the acidic medicinal auxiliary material to be modified, and drying at the same time.

24. A method for surface modification of a medicinal auxiliary material, characterized in that, formulating an aqueous solution of a pharmaceutically acceptable alkaline substance for modification or a pharmaceutically acceptable acidic substance for modification; adding powder particles of an acidic medicinal auxiliary material or an alkaline medicinal auxiliary material to the aqueous solution of the alkaline substance for modification or the acidic substance for modification, to form a neutral salt layer on the surface of the powder particles of the acidic medicinal auxiliary material or the alkaline medicinal auxiliary material, 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., and 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.

25. The method for surface modification of a medicinal auxiliary material according to claim 24, characterized in that the pharmaceutically acceptable organic acid as the acidic medicinal auxiliary material is one of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid, or a hydrate or acidic salt thereof.

26. The method for surface modification of a medicinal auxiliary material according to claim 24, characterized in that the pharmaceutically acceptable alkaline substance as the alkaline medicinal auxiliary material is one of lysine, arginine and histidine, or a hydrate thereof.

27. The method for surface modification of a medicinal auxiliary material according to claim 24, characterized in that 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.

28. The method for surface modification of a medicinal auxiliary material according to claim 26, characterized in that 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.

29. The method for surface modification of a medicinal auxiliary material according to claim 24, characterized in that the pharmaceutically acceptable acidic substance for modification is one of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid, or a hydrate or acidic salt thereof, or one of sodium bisulfate, sodium dihydrogenphosphate and stearic acid, or a hydrate thereof.

30. The method for surface modification of a medicinal auxiliary material according to claim 26, characterized in that the pharmaceutically acceptable acidic substance for modification is one of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid, or a hydrate or acidic salt thereof, or one of sodium bisulfate, sodium dihydrogenphosphate and stearic acid, or a hydrate thereof.

31-35. (canceled)

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.