Provided is a cilostazol preparation which comprises incorporating a fine powder of cilostazol into a dispersing and/or solubilizing agent thereby to enhance the dispersibility and/or solubility. Further, provided is a process for improving absorbability of a slightly soluble drug such as cilostazol even at the lower portion of the digestive tract, wherein said drug is hard to be absorbed at the lower portion of the digestive tract when a conventional method is used. According to the present invention, cilostazol is absorbed enough even at the lower portion of the digestive tract to have an effect as thrombolytic drug, cerebral circulation improving drug or the like.

DISCLOSURE OF INVENTION

The present inventors have invented the preparation capable of remarkably increasing absorption of cilostazol even at the lower portion of the digestive tract, by incorporating a dispersing and/or solubilizing agent to a fine powder of cilostazol according to a simple apparatus and an easy operation without adjusting the powder to average particle size of less than about 400 nm.

One of objects of the present invention is to provide a novel preparation wherein absorption of cilostazol even at the lower portion of the digestive tract is improved.

Further, another object of the present invention is to provide a method of improving absorbability of a slightly soluble drug such as cilostazol, which is hard to be absorbed at the lower portion of the digestive tract.

Further, another object of the present invention is to provide a sustained release preparation of cilostazol, which contains a cilostazol preparation capable of releasing cilostazol even at the lower portion of the digestive tract.

In the present invention, the upper portion of the digestive tract is a digestive organ exemplified by stomach or small intestine and the like, and the lower portion of the digestive tract is a digestive organ exemplified by large intestine and the like.

If cilostazol can be absorbed widely ranging from small intestine to large intestine at the lower portion of the digestive tract, it can be absorbed for a long time by a single oral administration. Therefore, blood concentration capable of continuously exerting a desired drug efficacy can be obtained and it becomes possible to suppress the above unfavorable side effects such as headache.

The present inventors have intensively studied to obtain a preparation capable of accelerating absorption of cilostazol at the lower portion of the digestive tract. As a result, they have found that the absorption is drastically improved by forming cilostazol as an active ingredient into a fine powder and further improving the dispersibility and/or solubility of the fine powder. More specifically, they have found that the absorption from the lower portion of the digestive tract can be drastically improved by adding a dispersing and/or a solubilizing agent thereby to improve the dispersibility and/or solubility of the fine cilostazol powder in comparison with the case where a bulk or fine powder of cilostazol is used alone or the bulk cilostazol powder is merely mixed with a dispersing and/or solubilizing agent. Thus, the present invention has been completed.

Thus, the present invention relates to the following inventions:

1. A cilostazol preparation having a capability of dissolving cilostazol even at the lower portion of the digestive tract, which comprises incorporating a fine powder of cilostazol as an active ingredient into a dispersing and/or solubilizing agent.

2. The cilostazol preparation according to the item 1, wherein said dispersing and/or solubilizing agent is selected from the group consisting of a water-soluble polymer, a surfactant and a mixture thereof.

3. The cilostazol preparation according to the item 2, wherein said fine powder of cilostazol is a fine powder having average particle diameter of about 10 .mu.m or less.

4. The cilostazol preparation according to the item 3, wherein said dispersing and/or solubilizing agent is incorporated within a range from 0.005 to 50 parts by weight based on 1 part by weight of cilostazol.

5. The cilostazol preparation according to the item 3 or 4, wherein said dispersing and/or solubilizing agent is selected from the group consisting of a water-soluble polymer, a surfactant and a mixture thereof.

6. The cilostazol preparation according to the item 5, wherein said dispersing and/or solubilizing agent is a surfactant.

7. The cilostazol preparation according to the item 6, wherein said surfactant is an alkyl sulfate salt.

8. The cilostazol preparation according to the item 5, wherein said fine powder of cilostazol is a fine powder having average particle diameter of about 7 .mu.m or less.

9. The cilostazol preparation according to the item 8, wherein said dispersing and/or solubilizing agent is incorporated within a range from 0.01 to 10 parts by weight based on 1 part by weight of cilostazol.

10. The cilostazol preparation according to the item 8, wherein said fine powder of cilostazol is a fine powder having average particle diameter of about 5 .mu.m or less.

11. The cilostazol preparation according to the item 8, wherein said dispersing and/or solubilizing agent is a surfactant.

12. The cilostazol preparation according to the item 11, wherein said fine powder of cilostazol is a fine powder having average particle diameter of about 5 .mu.m or less.

13. The cilostazol preparation according to the item 12, wherein said surfactant is an alkyl sulfate salt.

14. The cilostazol preparation according to the item 13, wherein said alkyl sulfate salt is a sodium lauryl sulfate.

15. A process for improving absorbability of a slightly soluble drug which is hard to be absorbed at the lower portion of the digestive tract, which comprises forming said slightly soluble drug as an active ingredient into a fine powder and improving dispersibility and/or solubility of said slightly soluble drug.

16. The process for improving the absorbability at the lower portion of the digestive tract according to the item 15, wherein a dispersing and/or solubilizing agent is incorporated into said slightly soluble drug thereby to improve the dispersibility and/or solubility of said slightly soluble drug.

17. The process for improving the absorbability at the lower portion of the digestive tract according to the item 15, wherein said slightly soluble drug as an active ingredient is cilostazol.

18. The process for improving the absorbability at the lower portion of the digestive tract according to the item 17, wherein a dispersing and/or solubilizing agent is incorporated into said slightly soluble drug thereby to improve the dispersibility and/or solubility of said slightly soluble drug.

19. The process for improving the absorbability at the lower portion of the digestive tract according to the item 17, wherein said fine powder of cilostazol is a fine powder having average particle diameter of about 10 .mu.m or less.

20. A sustained release preparation of cilostazol which contains any one of cilostazol preparations described in the items 1 to 14.

21. The sustained release preparation according to the item 20, which has a capability of releasing cilostazol even at the lower portion of the digestive tract.

22. The sustained release preparation according to the item 21, wherein the cilostazol preparation is coated with a sustained release material.

23. The sustained release preparation according to the item 21, which is a dry coated tablet comprising a sustained release outer layer portion containing cilostazol, and a sustained release core tablet containing a cilostazol preparation, wherein a solubility of said core tablet is more rapid than that of said outer layer portion.

24. The sustained release preparation according to the item 21, which is a tablet containing core granules wherein sustained release core granules containing a cilostazol preparation are coated with an enteric material and further said sustained release core granules are compressed with an outer layer portion containing cilostazol.

25. The sustained release preparation according to the item 21, which is a capsule comprising granules coated with an enteric material wherein said granules contain a cilostazol preparation and rapid release powders or tablets containing cilostazol.

26. The sustained release preparation according to the item 21, which is a multiple-unit type preparation wherein at least more than 2 of sustained release small tablets containing a cilostazol preparation are contained.

27. A fine powder of cilostazol having average particle diameter of about 10 .mu.m or less, which is for a starting material of a sustained release preparation of cilostazol.

28. The fine powder of cilostazol according to the item 27, which has an average particle diameter of about 5 .mu.m or less.
 

Claim 1 of 19 Claims

1. A cilostazol preparation for oral administration which is capable of dissolving at the lower portion of a human digestive tract, comprising a fine powder of cilostazol having an average particle diameter of from 2 to 10 .mu.m as an active ingredient, wherein said fine powder has been incorporated into a surfactant as a dispersing and/or solubilizing agent and wherein the preparation is in the form of powder, a granule, a pill, a tablet or a capsule for orally administering the preparation to a human.

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