Cilostazol preparation Number:7,144,585 from the United States Patent and Trademark Office (PTO) owispatent 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.<H preparation, Cilostazol, Cilostazol, prep, 7144585.html, Patent, pto, 7144585

Title: Cilostazol preparation

Abstract: 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.

Patent Number: 7,144,585 Issued on 12/05/2006 to Mukai, et al.

Inventors: Mukai; Tadashi (Naruto, JP), Tomohira; Yuso (Tokushima, JP), Toda; Masafumi (Naruto, JP), Yamada; Keigo (Tokushima, JP), Oka; Yoshikazu (Tokushima, JP)
Assignee: Otsuka Pharmaceutical Co., Ltd. (Tokyo, JP)

Appl. No.: 09/555,026

Filed: March 21, 2000

PCT Filed: March 21, 2000

PCT No.: PCT/JP00/01722

371(c)(1),(2),(4) Date: January 18, 2002

PCT Pub. No.: WO00/57881

PCT Pub. Date: October 05, 2000

Foreign Application Priority Data


Mar 25, 1999 [JP]			11/81363
Sep 30, 1999 [JP]			11/279147

Current U.S. Class: 424/452 ; 424/455; 424/463; 424/465; 424/474; 424/489; 424/490; 514/951; 514/952; 514/960; 514/961; 514/962; 514/963; 514/964

Current International Class: A61K 9/14 (20060101); A61K 9/20 (20060101); A61K 9/48 (20060101)

Field of Search: 514/314,312,951,952,960-965 424/452,457,458,465,468,469,470-472,474,489,490

References Cited [Referenced By]

U.S. Patent Documents


4344934	August 1982	Martin et al.
4892741	January 1990	Ohm et al.
4895726	January 1990	Curtet et al.
5145684	September 1992	Liversidge et al.
5202129	April 1993	Samejima et al.
5624683	April 1997	Andoh et al.
5849330	December 1998	Marvola et al.
6117455	September 2000	Takada et al.
6264922	July 2001	Wood et al.
6294192	September 2001	Patel et al.
6825214	November 2004	Mendelovici et al.
2005/0255155	November 2005	Sen et al.

Foreign Patent Documents


0 179 583	Apr., 1986	EP
0 661 045	May., 1995	EP
7-291869	Nov., 1995	JP
10-67657	Mar., 1998	JP
WO 93/05770	Apr., 1993	WO
WO 96/21448	Jul., 1996	WO
WO 97/48382	Dec., 1997	WO
WO PCT 97/18382	Dec., 1997	WO
WO 98/31360	Jul., 1998	WO

Other References

"Pharmacokinetics vol. 13, Supplement (1998), S 169, 11B16-4 Analysis of mechanism on improving mucosa lesion caused by intermediate chain-fatty acid salt according to amino acid," with English translation. cited by other .
"Bronchoprotective Effect of an Intrabronchial Administration of Cilostazol Powder and a Nebulized PDE1 and PDE4 Inhibitor KF19514 in Guinea Pigs," M. Fujimura et al., International Archives of Allergy and Immunology, vol. 116, No. 3, 1998, pp. 220-227. cited by other .
"Pharmazeutisch-technologische," H. Sucker et al.. 1991, Thieme Verlag., Stuttgart XP002145328 189560, pp. 673-675. cited by other .
Carmona-Ibanez, Gisela et al., "Experimental Studies on the Influence of Surfactants on Intestinal Absorption of Drugs", Arzneim.Forsch./Drug Res. 49(I), Nr. 1 pp. 44-50, (1999). cited by other .
Sancho-Chust, V. et al., "Experimental Studies on the Influence of Surfactants on Intestinal Absorption of Drugs", Arzneim.Forsch./Drug Res. 45(I), Nr. 5 pp. 595-601, (1995). cited by other .
Garrigues, T.M. et al., "Absorption-partition Relationships for True Homologous Series of Xenobiotics as a Possible Approach to Study Mechanisms of Surfactants in Absorption. Iv. Phenylacetic Acid Derivatives", International Journal of Pharmaceutics, 79 pp. 135-140, (1992). cited by other.

Primary Examiner: Krass; Frederick
Attorney, Agent or Firm: Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P.

Claims

The invention claimed is:

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.

2. The cilostazol preparation according to claim 1, 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.

3. The cilostazol preparation according to claim 2, wherein said surfactant is one or more selected from the group consisting of polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene castor oil, surcrose ester of fatty acid and alkyl sulfate salt.

4. The cilostazol preparation according to claim 3, wherein said surfactant is one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether and alkyl sulfate salt.

5. The cilostazol preparation according to claim 4, wherein said surfactant is an alkyl sulfate salt.

6. The cilostazol preparation according to claim 3, wherein said fine powder of cilostazol is a fine powder having an average particle diameter of from 2 to 7 .mu.m.

7. The cilostazol preparation according to claim 6, 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.

8. The cilostazol preparation according to claim 6, wherein said fine powder of cilostazol is a fine powder having an average particle diameter of from 2 to 5 .mu.m.

9. The cilostazol preparation according to claim 6, wherein said surfactant is one or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether and alkyl sulfate salt.

10. The cilostazol preparation according to claim 9, wherein said fine powder of cilostazol is a fine powder having an average particle diameter of from 2 to 5 .mu.m.

11. The cilostazol preparation according to claim 10, wherein said surfactant is an alkyl sulfate salt.

12. The cilostazol preparation according to claim 11, wherein said alkyl sulfate salt is sodium lauryl sulfate.

13. A sustained release preparation of cilostazol which comprises any one of the cilostazol preparations of claims 1 12 coated with a sustained release coating material.

14. The sustained release preparation according to claim 13, which is a dry coated tablet comprising a sustained release outer layer portion containing cilostazol, and a sustained release core tablet containing the cilostazol preparation, wherein a solubility of said core tablet is more rapid than that of said outer layer portion.

15. The sustained release preparation according to claim 13, which is a tablet containing core granules wherein sustained release core granules containing the cilostazol preparation are coated with an enteric material and further said sustained release core granules are compressed with an outer layer portion containing cilostazol.

16. The sustained release preparation according to claim 13, which is a capsule comprising granules coated with an enteric material, wherein said granules contain the cilostazol preparation.

17. The sustained release preparation according to claim 13, which is a multiple-unit preparation containing more than two sustained release tablets containing the cilostazol preparation.

18. A sustained release preparation of cilostazol, which comprises 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.

19. A process of administering a cilostazol preparation for oral administration which is capable of dissolving at the lower portion of a human digestive tract, comprising administering to a human a sustained release preparation 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 the human.

Description

This application is a 371 of PCT/JP00/01722, filed Mar. 21, 2000

TECHNICAL FIELD

The present invention relates to a preparation wherein the absorbability of cilostazol, which is commercially available as thrombolytic drug, cerebral circulation improving drug or the like is improved and, more particularly, to a preparation comprising a fine powder of cilostazol as an active ingredient wherein the bioabsorbability, particularly the absorbability at the lower portion of the digestive tract is improved.

BACKGROUND ART

Cilostazol (general name of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydrocarbostyryl) has widely been used as thrombolytic drug, cerebral circulation improving drug, anti-phlogistic drug, anti-ulcer drug, hypotensive drug, drug for asthema, and phosphodiesterase inhibitor because it shows not only a high platelet aggregation supression action but also a phosphodiesterase inhibition action, an anti-ulcer action, a hypotensive action and an anti-phlogistic action. Cilostazol is usually used in the form of a tablet produced by adding excipients and other ingredients and compressing the mixture, and is orally administered. However, since the tablet is quickly disintegrated in the living body when orally administered, a large amount of cilostazol is released in the living body within a short time thereby to cause high concentration in blood, resulting in side effects such as headache, heavy feel in head, or pain. To prevent these side effects, a measure of administering a low-dose tablet in multiple dosing is suggested. However, it is ideal to produce a preparation capable of sustaining mild absorption for a long time by a single administration in order to avoid a complicated administration as much as possible. A fixed concentration of a drug in blood can be maintained by forming a slightly soluble drug into a sustained release preparation. However, since cilostazol is mainly absorbed at the upper portion of the digestive tract when administered orally and the absorption rate at the lower portion of the digestive tract is not sufficient, a single administration has its limits of the duration time of absorption. Accordingly, it becomes possible to maintain the concentration of cilostazol within desirable range in blood for a long time by improving absorption at the lower portion of the digestive tract.

Japanese Laid-open Patent Publication No. 7-291869 discloses that bioavailability of certain pharmaceutical agents is remarkably increased by forming a phosphonic acid diester derivative into a fine powder (average particle diameter of not more than about 10 .mu.m).

However, when cilostazol was simply formed into a fine powder of less than about 10 .mu.m in average particle diameter, its absorption rate at the lower portion of the digestive tract was very low.

U.S. Pat. No. 5,145,684 discloses particles consisting essentially of a crystalline drug substance having a surface modifier absorbed on the surface in amount sufficient to maintain an effective average particle size of less than about 400 nm wherein the bioavailability is increased.

But, this USP does not describe increasing the absorption rate at the lower portion of the digestive tract, of slightly soluble drug which exhibits an extremely low adsorption rate thereat.

WO 96/21448 discloses a resin particle having a particle size of not greater than 2,000 .mu.m, which comprises an ethylene vinyl alcohol copolymer and 5 to 10% by weight of cilostazol incorporated therein. The resin particle, upon being administered orally, allows the concentration of cilostazol in blood to be kept constant over an extended period of time.

However, a production method of the resin particle is attended with many problems that an apparatus is on a large scale and an elevated temperature is required, and so on.

Japanese Laid-open Patent Publication No. 10-67657 discloses a multiple-unit type sustained release preparation, which contains two sustained release small tablets prepared by incorporating hydroxypropylmethylcellulose as a sustained release material into cilostazol. However, when a bulk cilostazol powder having an average particle diameter of about 20 .mu.m is used, the resulting preparation showed a low absorbability at the lower portion of the digestive tube and the absorbability was not improved by adding a dispersing and/or solubilizing agent.

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.

In the present invention, "a dispersing and/or solubilizing agent" is an agent capable of suspending, emulsifying or dissolving a slightly water-soluble drug in water.

In the present invention, "a cilostazol preparation" is a preparation which comprises incorporating at least a fine powder of cilostazol into a dispersing and/or solubilizing agent, which is capable of dissolving cilostazol even at the lower portion of the digestive tract.

In the present invention, "a sustained release preparation" is a preparation which shows a sustained release when orally administered.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing a change in concentration of a drug in plasma after preparations of Example 6, Example 7 and Comparative Example 4 were orally administered to beagle dogs under fasting.

FIG. 2 is a graph showing a relation between the dissolved rate (%) of cilostazol and time (hr) when the dissolution test was carried out in Test Example 7 using dry coated tablets P to U containing cilostazol obtained by Example 38.

FIG. 3 is a graph showing a change in concentration of a drug in plasma after preparations of Example 9 and Reference Example 6 were orally administered to beagle dogs in Test Example 9.

FIG. 4 is a graph showing a relation between cilostazol concentration in plasma and time when sustained release preparations of cilostazol obtained in Example 8 were orally administered to healthy male adults in Test Example 10.

FIG. 5 is a graph showing a relation between cilostazol concentration in plasma and time when sustained release preparations of cilostazol obtained in Example 10 were orally administered to healthy male adults in Test Example 10.

FIG. 6 is a graph showing a relation between cilostazol concentration in plasma and time when sustained release preparations of cilostazol obtained in Example 14 were orally administered to healthy male adults in Test Example 10.

BEST MODE FOR CARRYING OUT THE INVENTION

The desired preparation wherein the absorbability of cilostazol is improved according to the present invention can be obtained by forming cilostazol as an active ingredient into a fine powder and further incorporating a dispersing and/or solubilizing agent thereby to improve the dispersibility and/or the solubility of the fine cilostazol powder. To improve the dispersibility and/or solubility of the cilostazol fine powder, cilostazol and a dispersing and/or solubilizing agent are mixed and finely pulverized, a fine cilostazol powder and a dispersing and/or solubilizing agent are subjected to wet granulation, a cilostazol fine powder is dispersed in a solution of dispersing and/or solubilizing agent and then the resulting dispersion is formed into fine granules or granules by spray drying or freeze-drying, or the resulting dispersion is formed into tablets by compression forming.

The cilostazol preparation of the present invention is obtained by mixing a fine cilostazol powder and a dispersing and/or solubilizing agent with a conventional carrier and forming the mixture into a powder, fine granule, granule, pill, tablet, or capsule.

As the carrier, there can be widely used those which have been conventionally known in this field. Examples thereof include excipients such as lactose, D-mannitol, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, and cilicate; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, sodium carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinyl pyrrolidone; disintegrators such as dry starch, agar powder, calcium carboxymethylcellulose, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, monoglyceride stearate, starch, low substituted hydroxypropylcellulose, sodium carboxymethylstarch, and croscarmellose sodium; lubricants such as purified talc, stearate salt, powdered boric acid, polyethylene glycol, colloidal silicic acid, and hardened oil; and plasticizers such as glycerin fatty acid ester, dioctyl phthalate, dibutyl phthalate, triacetin, polysorbate 80, triethyl citrate, and castor oil. These carriers can be appropriately selected and used.

In addition to the fine cilostazol powder as the active ingredient, a dispersing and/or solubilizing agent can be incorporated into the preparation of the present invention, thereby to enhance the dispersion and/or the dissolution absorbability of the fine cilostazol powder, particularly absorbability at the lower portion of the digestive tract.

The usable dispersing and/or solubilizing agent includes, for example, water-soluble polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and polyacrylic acid; and surfactants such as sodium lauryl sulfate and decaglyceryl monolaurate. Surfactants are preferred.

These dispersing and/or solubilizing agent can be used alone or in combination.

The surfactant used in the present invention includes ionic and nonionic surfactants, for example, polyglycerin fatty acid ester such as decaglyceryl monolaurate and decaglyceryl monomyristate; polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid ester such as polyoxyethylene monostearate; polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid such as sucrose stearate ester and sucrose palmitate ester; and alkyl sulfate salt such as sodium lauryl sulfate and magnesium lauryl sulfate. These surfactants can be used alone or in combination.

As the surfactant used as the dispersing and/or solubilizing agent in the present invention, alkyl sulfate salt is preferred and lauryl sulfate salt is more preferred, and sodium lauryl sulfate is most preferred.

The cilostazol preparation of the present invention characterized in that the dispersibility and/or the solubility of a fine cilostazol powder is improved and capable of dissolving cilostazol even at the lower portion of the digestive tract is prepared by adding a dispersing and/or solubilizing agent to cilostazol, 0.005 to 50 parts by weight, preferably 0.01 to 10 parts by weight, more preferably 0.01 to 5 parts by weight of the dispersing based on 1 part by weight of cilostazol, and 0.1 to 99 parts by weight of the other carrier may be optionally added.

In case that the addition amount of a dispersing and/or solubilizing agent is too small, it results in lowering of the absorption because of lowering dissolution rate. In opposition, the addition of too many amounts is restricted from aspects of preparation form, and toxicity such as mucous trouble or pharmaceutical affairs low depending on kinds of dispersing and/or solubilizing agents.

The dispersing and/or solubilizing agent can be added on pulverization of a bulk cilostazol powder or wet granulation of a pulverized bulk cilostazol powder, or added by dispersing the pulverized bulk cilostazol powder in a solution of the dispersing and/or solubilizing agent and spray-drying the suspension.

A dry powder can also be obtained by dissolving sugar alcohols such as D-mannitol, xylitol, and sorbitol; saccharides such as sucrose and lacrtose; water-soluble substances such as dextrin and dextran; and surfactants such as polysolbate 80, sodium lauryl sulfate and sugar ester in a suspension of cilostazol formed into microgranules by wet pulverization, and spray-drying the resulting solution by a conventional procedure.

The cilostazol preparation of the present invention can be formed into pharmaceutical preparations such as tablets, granules, fine granules, or powders. For example, tablets are prepared from a fine powder of cilostazol using a conventional carrier according to a conventional procedure. Granules or fine granules can be prepared by adding the same carrier to the fine powder of cilostazol and granulating the mixture by using a general process such as high-speed stirring granulation, fluid-bed granulation, stirring fluid-bed granulation, centrifuging flow granulation, or extrusion granulation. Furthermore, powders are prepared by mixing the fine powder of cilostazol with the carrier such as excipient by using conventional procedure, or by a process such as fluid-bed granulation, stirring fluid-bed granulation or extrusion granulation.

In the cilostazol preparation according to the present invention, the average particle diameter of the fine cilostazol powder to be used is usually about 10 .mu.m or less, preferably about 7 .mu.m or less, more preferably about 5 .mu.m or less, and most preferably about less than 4 .mu.m. The fine cilostazol powder can be obtained according to conventional methods using various equipment, for examples, methods described in U.S. Pat. No. 5,145,684 or Japanese Laid-open Patent Publication No. 7-291869, etc. For that purpose, any equipment may be used as far as the desired particle diameter can be attained, and examples thereof include jet mil, hammer mill, rotary ball mill, vibration ball mill, shaker mill, rod mill, and tube mill. When using a ball mill or a beads mill, any of dry pulverization or wet pulverization may be conducted.

Describing in detail, pulverization using a jet mill can be carried out, for example, by spraying a compressed air at about 6 kg/cm.sup.2 thereby causing collision between a raw crystal and a ceramic collision plate, or by collision between granules, and classifying and recovering the resulting fine powder using a cyclone adjusted previously to a predetermined clearance.

Process for improving the dispersibility of the fine cilostazol powder includes, for example, process for adding a dispersing as described above, and mixing with a carrier and pulverization, kneading with an excipient, flow, stirring flow and melt granulations, and spray drying or freeze-drying after forming into a suspension, or mixing with a carrier for a long time. Process for improving the dispersibility of the fine cilostazol sometimes accords to process for improving the solubility of the same.

The cilostazol preparation according to the present invention, which is capable of dissolving cilostazol even at the lower portion of the digestive tract, can also be formed into a sustained release preparation of the present invention by sustained release coating. That is, the sustained release preparation is obtained by coating cilostazol-containing fine granules, granules, pills or tablets with a sustained release coating material.

The sustained release coating material includes, for example, enteric materials such as cellulose acetate terephthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, and methacrylic acid copolymer; and insoluble materials such as ethylcellulose and waxes. Plasticizers such as these materials, triethyl citrate, monoglyceride and polyethylene glycol; and usually incorporated additives such as talc and titanium oxide can be selected and used.

A sustained release preparation can also be obtained by preparing a hydrogel type matrix using a high-viscosity water-soluble polymer as a sustained release material, or preparing a matrix with a water-insoluble material such as wax, but a mechanism of forming into a sustained release preparation is not limited thereto. Preferred sustained release preparation is a sustained release preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract.

As a preferred aspect of the sustained release preparation of the present invention, there can be provided a sustained release preparation in the form of a dry coated tablet, comprising the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract in a sustained release core portion having a larger dissolution rate than that of the outer layer portion, and a sustained release cilostazol in the outer layer portion.

As another preferred aspect, there can be provided a sustained release preparation in the form of a granule-containing tablet, which is obtained by coating core granules containing the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract with an enteric material, and compressing the coated core granules with an outer layer containing cilostazol.

As another preferred aspect, there can be provided a sustained release preparation in the form of a capsule, which contains a sustained release granule obtained by coating core granules containing the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract with an enteric material and a rapid release powder or tablet containing cilostazol.

As another preferred aspect, there can be provided a sustained release preparation, which contains a sustained release preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract and at least one or more of a substance capable of swelling in water and/or a water-soluble substance capable of inducing osmotic pressure which are surrounded by semipermeable membrane having water permeability but substantially possessing no permeability of said water-swelling substance and/or said osmotic pressure inducing substance.

As still another aspect, there can be provided a multiple-unit type sustained release preparation comprising at least two small tablets containing the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract according to the present invention.

More specifically, a dry coated tablet is a sustained release preparation obtained by coating a core tablet, which is obtained by compressing a mixture of a fine cilostazol powder, a dispersing and/or solubilizing agent such as surfactant, a small amount of a hydrophilic gel-forming polymer, and a usually used carrier such as disintegrator according to a conventional procedure, with granules for compressing an outer layer portion, comprising cilostazol, a hydrophilic gel-forming polymer, and a usually used carrier such as lactose.

The core tablet having a capability of releasing cilostazol at the lower portion of the digestive tract preferably contains the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract according to the present invention, a small amount of a hydrophilic gel-forming polymer and a disintegrator in view of the dispersibility and/or solubility and sustained release at the lower portion of the digestive tract.

After the dry coated tablet is orally administered, the outer layer forms a hydrophilic gel, thereby to slowly release cilostazol and deliver the core tablet to the lower portion of the digestive tract while avoiding erosion of the core tablet. At the lower portion of the digestive tract where the amount of water is small and enterokinesis is not positive, the core tablet sufficiently disperse and/or dissolve and release a fine cilostazol powder with an aid of the above dispersing and/or solubilizing agent while slowly releasing cilostazol with an aid of a hydrophilic gel.

The hydrophilic gel-forming polymer includes, for example, hydrophilic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, methylcellulose, and polyethylene oxide; and polymer saccharides such as carrageenan, guar gum and arabic gum; and these hydrophilic gel-forming polymers can be used alone or in combination. Among these hydrophilic gel-forming polymers, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyethylene oxide are preferred, and hydroxypropylmethylcellulose is particularly preferred.

The disintegrator includes, for example, low substituted hydroxypropylcellulose, croscarmellose sodium, cross povidone, and carboxymethyl starch. Among these disintegrators, low substituted hydroxypropylcellulose and croscarmellose sodium are preferred, and low substituted hydroxypropylcellulose is particularly preferred.

The amount of cilostazol to be incorporated into the nulcear tablet is within a range from 10 to 95%, preferably from 20 to 90%, and more preferably from 30 to 80%, based on the amount of cilostazol of the whole dry coated tablet.

The amount of the hydrophilic gel-forming polymer to be incorporated into the core tablet is within a range from 1 to 50%, preferably from 2 to 45%, and more preferably from 3 to 40%, based on the amount of cilostazol of the core tablet.

If necessary, the core tablet may be coated with a usually used enteric polymer or water-soluble polymer.

The outer layer requires enough thickness to avoid erosion of the core tablet, and the thickness is not less than 1 mm, preferably not less than 1.5 mm, and more preferably from 1.5 to 3 mm, at one side.

The amount of the hydrophilic gel-forming polymer to be incorporated into the outer layer is within a range from 5 to 80%, preferably from 10 to 70%, and more preferably from 10 to 60%, based on the whole outer layer. When using hydroxypropylmethylcellulose as the hydrophilic gel-forming polymer, the amount is from 5 to 80%, preferably from 7 to 70%, and more preferably from 10 to 65%.

More specifically, a granule-containing tablet is a sustained release preparation obtained by coating core granules comprising a fine cilostazol powder, a dispersing and/or solubilizing agent such as surfactant, and a usually used carrier with an enteric material and a usually used carrier to form coated granules, and coating the coated granules with an outer layer portion, comprising cilostazol, a hydrophilic gel-forming polymer, and a usually used carrier such as lactose.

The coating granules having a capability of releasing cilostazol at the lower portion of the digestive tract are preferably those obtained by coating, core granules comprising the above cilostazol preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract according to the present invention, and an excipient which mainly dissolves in large intestine, with an enteric material which mainly dissolves in intestines in view of the dispersibility and/or solubility and sustained release at the lower portion of the digestive tract.

After the granule-containing tablet is orally administered, the outer layer forms a hydrophilic gel, thereby to slowly release cilostazol, and also moves in the digestive tract while releasing coated granules. The core granules are delivered to the lower portion of the digestive tract, and cilostazol begins to dissolve when the pH value increases. At the lower portion of the digestive tract where the amount of water is small and enterokinesis is not positive, the core granules sufficiently disperse and/or dissolve and release a fine cilostazol powder with an aid of the above dispersing and/or solubilizing agent.

The excipient which dissolves in large intestine includes, for example, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and methacrylic acid copolymer (e.g. EUDRAGID S). Among these exipients, hydroxypropylmethylcellulose acetate succinate and methacrylic acid copolymer (e.g. EUDRAGID S) are preferred, and hydroxypropylmethylcellulose acetate succinate which is a type dissolving at a lower pH (at the pH of about 5.5) is particularly preferred.

The enteric material includes, for example, conventional enteric materials. Among these enteric materials, hydroxypropylmethylcellulose acetate succinate, cellulose acetate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid copolymer, and methacrylic acid copolymer L are preferred, and hydroxypropylmethylcellulose acetate succinate which is a type dissolving at the pH of about 7 is particularly preferred.

The amount of cilostazol to be incorporated into the core granules is within a range from 10 to 95%, preferably from 20 to 90%, and more preferably from 30 to 80%, based on the amount of cilostazol of the whole granule-containing tablet.

The amount of the enteric material is within a range from 10 to 200%, preferably from 20 to 100%, and more preferably from 20 to 60%, based on the core granules.

As the outer layer portion, the same granules for compressing the outer layer portion as those in the dry coated tablet can be used.

Since the granule-containing tablet is liable to be broken by impact because it contains granules, it may be coated with a usually used coating agent, if necessary.

More specifically, the capsule containing the granule coated with an enteric material is the one which contains the same coated granule as the granule coated with an enteric material in the above granule-containing tablet and, cilostazol and a rapid release powder, granule or tablet prepared from a usually used carrier such as excipient and disintegrator.

After orally administered, the coated granule-containing capsule rapidly dissolve cilostazol from the rapid release granule or the rapid release small tablet and the coated granule transfers the core granule at the lower portion of the digestive tract while spreading over the digestive tract.

The amount of cilostazol to be incorporated into the coated granule is within a range from 10 to 95%, preferably from 20 to 90%, and more preferably from 30 to 80%, based on the amount of cilostazol of the whole coated granule-containing capsule.

Any commonly used carrier can be used as the rapid release portion for containing cilostazol.

In addition, a superior sustained release preparation can be prepared by incorporating an organic acid such as citric acid into the enteric material-containing granule which is contained in the above granule-containing tablet and the above coated granule-containing capsule.

When sodium chloride is incorporated into the core granule for improving solubility of hydroxylpropylmethylcellulose acetate succinate, it is the problem that the granule strength is weakened in process of extrusion granulation. The addition of organic acid prevents from the above problem. The addition of organic acid to the enteric material film improves to be resistant to alkali.

More specifically, a multiple-unit type sustained release preparation is a sustained release preparation containing two or more sustained release small tablets comprising a fine cilostazol powder, a dispersing and/or solubilizing agent such as surfactant, a hydrophilic gel-forming polymer, and a usually used carrier such as lactose.

After the multiple-unit type sustained release preparation is orally administered, plural sustained release small tablets are released from the capsule at an arbitrary dissolution rate. Each sustained release small tablet forms a hydrophilic gel with a proper time lag and moves to the lower portion of the digestive tract in the digestive tract while slowly releasing cilostazol. At the lower portion of the digestive tract where the amount of water is small and enterokinesis is not positive, the sustained release small tablets sufficiently disperse and/or dissolve and release a fine cilostazol powder with an aid of the above dispersing and/or the above solubilizing agent.

The hydrophilic gel-forming polymer includes, for example, the above-described hydrophilic gel-forming polymers. Among these hydrophilic gel-forming polymers, hydroxypropylmethylcellulose is particularly preferred. The amount of the hydrophilic gel-forming polymer is within a range from 10 to 90%, preferably from 20 to 80%, and more preferably from 25 to 75%, based on the whole sustained release small tablet.

When using hydroxypropylmethylcellulose, any commercially available one is used, but those having high viscosity are preferred. The viscosity at 20.degree. C. of an aqueous 2% solution is not less than 400 cps, and preferably from 400 to 200,000 cps.

The sustained release small tablet has a diameter within a range from about 2 to 7 mm, and preferably from about 4 to 6.5 mm. The number of the sustained release small tablets with which a capsule is packed is usually not less than 2, preferably from 2 to 20, and more preferably from 3 to 10.

The multiple-unit type sustained release preparation further may contain a rapid released granule or a rapid release small tablet which is prepared from cilostazol and a usually used carrier such as excipient and disintegrator.

The above respective aspects of the sustained release preparation are intended to illustrate the sustained release preparation having a capability of releasing cilostazol even at the lower portion of the digestive tract, but are not to be construed to limit the scope of the sustained release preparation of the present invention.

The dose of cilostazol as the active ingredient in the preparation of the present invention varies depending on the age, sex, body weight, and conditions of the patient, but is usually within a range from 50 to 300 mg, preferably from 50 to 250 mg, and more preferably from 100 to 250 mg per day. The preparation of the present invention preferably contains cilostazol in the amount within the above range per unit dose to attain a desired effect by administering one time per day.

EXAMPLES

The following Comparative Examples, Examples and Test Examples further illustrate the preparation of the present invention and effect in more detail.

Comparative Example 1

Bulk cilostazol powder having an average particle diameter of about 20 .mu.m.

Comparative Example 2

100 g of a bulk cilostazol (CLZ) powder having an average particle diameter of about 20 .mu.m and 10 g of sodium lauryl sulfate (SLS) were weighed, charged in a polyethylene bag, and then mixed with shaking.

Example 1

100 g of a bulk cilostazol (CLZ) powder having an average particle diameter of about 20 .mu.m and 10 g of sodium lauryl sulfate (SLS) are mixed in a polyethylene bag, and then pulverized by using a jet mill (100AS, manufactured by POWREK Co.) to obtain a cilostazol powdered preparation having an average particle diameter of about 3 .mu.m.

Example 2

300 g of a bulk cilostazol (CLZ) powder having an average particle diameter of about 3 .mu.m pulverized by using a jet mill and 132 g of D-mannitol are mixed and then charged in a fluid-bed granulator (NQ-160, manufactured by Fuji Paudal Co., Ltd.). The mixture is subjected to wet granulation by spraying 400 g of an aqueous solution containing 7.5% sodium lauryl sulfate (SLS) and 4.5% hydroxypropylcellulose (trade name: HPC-SL)(corresponding to a solid of 30 g for SLS and 18 g for HPC), and then dried to obtain a cilostazol powdered preparation.

Example 3

To the powder obtained in Example 2, 1.25% magnesium stearate is added and the mixture was compressed so that one tablet has a weight of 162 mg using a single punch tableting machine (No. 2B, manufactured by KIKUSUI SEISAKUSHO Co.) equipped with a punch having a diameter of 8 mm to obtain tablets containing cilostazol in the amount of 100 mg per tablet.

Example 4

3.3 g of polyvinyl alcohol (PVA), 10 g of D-mannitol and 2 g of sodium lauryl sulfate (SLS) are dissolved in 106 g of water. After 20 g of a bulk cilostazol (CLZ) powder having an average particle diameter of about 3 .mu.m pulverized by using a jet mill is dispersed, this solution is spray-dried to obtain a cilostazol powdered preparation.

Example 5

300 g of a bulk cilostazol (CLZ) powder having an average particle diameter of about 3 .mu.m pulverized by using a jet mill and 162 g of D-mannitol are mixed and then charged in a fluid-bed granulator (NQ-160, manufactured by FUJI POWDAL Co., Ltd.). The mixture is subjected to wet granulation by spraying 400 g (corresponding to a solid of 18 g for HPC) of an aqueous solution containing 4.5% hydroxypropylcellulose (trade name: HPC-SL), and then dried to obtain a cilostazol powdered preparation.

Comparative Example 3

100 g of cilostazol having an average particle diameter of about 20 .mu.m is mixed with 30 g of corn starch, 25 g of crystalline cellulose and 12 g of carboxymethylcellulose calcium. After an aqueous solution containing 1.5 g of hydroxypropylmethylcellulose is added, the mixture is granulated with kneading and sieved to form granules for compression. Then, 1.5 g of magnesium stearate as a lubricant is added and the granules are compressed so that one tablet has a weight of 170 mg using a punch having a diameter of 8 mm to obtain tablets containing cilostazol in the amount of 100 mg per tablet.

Example 6

200 g of cilostazol having an average particle diameter of about 20 .mu.m and 50 g of polyvinyl alcohol (203, manufactured by KURARAY Co., Ltd.) are dispersed and dissolved in 750 g of water, and then pulverized, together with 4000 g of zirconia beads having a diameter of 0.3 mm, in DYNO-MILL having a volume of 1.4 L (manufactured by CIMMAL ENTERPRISES Co.) at 2500 rpm for one hour to obtain a pulverized suspension of cilostazol having an average particle diameter of about 270 nm. This pulverized suspension is suitably diluted to give a 0.25% cilostazol suspension. The average particle diameter of cilostazol is measured by a dynamic light scattering process using an electrophoretic light scattering photometer (ELS-800, manufactured by OTSUKA ELECTRONICS, CO., LTD.).

Example 7

5 g of polysolbate 80 and 25 g of D-mannitol are dissolved in 100 g of the pulverized suspension obtained in Example 6 and 75 g of water is added, and then the mixture is spray-dried by using a spray dryer manufactured by NIRO Co.) under the conditions of an inlet temperature of 200.degree. C., an outlet temperature of 110.degree. C., an atomizer revolution of about 25000 rpm and a liquid rate of 20 g/minute to obtain a powder. Gelatin capsules are packed with 240 mg (corresponding to 100 mg for cilostazol) of this powder to obtain capsules of cilostazol.

Comparative Example 4

A bulk cilostazol powder having an average particle diameter of about 20 .mu.m is suspended in a 0.25% polyvinyl alcohol solution to obtain a 0.25% cilostazol suspension.

Example 8

80 g of a bulk cilostazol powder having an average particle diameter of about 2 .mu.m pulverized by using a jet mill, 20 g of hydroxypropylcellulose, 15 g of low substituted hydroxypropylcellulose (trade name: LH-31) and 15 g of sodium lauryl sulfate as a dispersing and/or solubilizing agent are mixed. After 55 g of an aqueous solution containing 2.75 g of hydroxypropylcellulose (trade name: HPC-L) as a binding solution is added, the mixture is granulated with high sheared mixer, dried and sieved to form granules. Then, 0.3 g of magnesium stearate as a lubricant is added and the granules are compressed so that one tablet has a weight of 133 mg using a punch having a diameter of 7 mm to obtain core tablets containing cilostazol in the amount of 80 mg per tablet.

Separately, 120 g of a bulk cilostazol powder having an average particle diameter of about 2 .mu.m, 80 g of hydroxypropylmethylcellulose, 27 g of hydroxypropylcellulose (trade name: HPC-H) and 270 g of lactose are mixed, granulated with 150 g of purified water, dried and sieved to obtain granules, and then 3.0 g of magnesium stearate is added and mixed. 500 mg of granules for compressing an outer layer portion contain 120 mg of cilostazol.

Core tablets and 500 mg of granules for compressing an outer layer portion are mixed and then compressed by using a punch having a diameter of 11 mm so that one tablet has a weight of 633 mg to obtain dry coated sustain released tablets containing cilostazol in the amount of 200 mg per tablet.

Example 9

In the same manner as in Example 8, except for using 140 g of hydroxypropylmethylcellulose and 210 g of lactose as a granule for compressing an outer layer portion, sustained release dry coated tablets are obtained.

Example 10

400 g of a bulk cilostazol powder having an average particle diameter of about 2 .mu.m pulverized by using a Jet mill, 160 g of hydroxypropylmethylcellulose acetate succinate (trade name: SHINETSU AQOAT AS-LF), 40 g of hydroxypropylmethylcellulose as a binder and 40 g of sodium lauryl sulfate as a dispersing and/or solubilizing agent are charged in a kneader (NSK-150, manufactured by OKADA SEIKO Co., Ltd.) and mixed, and then a proper amount of an aqueous solution containing 20 g of sodium chloride, 20 g of citric acid and 20 g of polysolbate 80 is added to obtain a blend. The blend is taken out, granulated by extruding using an extrusion granulator (DOMEGRAN DG-L1, manufactured by Fuji Paudal Co., Ltd.) equipped with a dome die having holes of 0.8 mm in diameter and then formed into spherical granules using a spheronization granulator (MARUMERIZER QJ-400, manufactured by Fuji Paudal Co., Ltd.). The resulting granules are dried and those having a particle diameter of 710 to 1000 .mu.m are selected and used as core granules for coating. 750 g of a coating solution containing 7.0% hydroxypropylmethylcellulose acetate succinate (trade name: SHINETSU AQOAT AS-HF), 3.5% talc, 2.8% triethyl citrate, 0.21% sodium lauryl sulfate and 0.21% citric acid is sprayed over 600 g of core granules using a rotating flow coater (NEW MARUMERIZER NQ-160, manufactured by Fuji Paudal Co., Ltd.), followed by drying to obtain coated granules. 280 m g of the coated granules contain 100 mg of cilostazol.

Separately, 100 g of a bulk cilostazol powder having an average particle diameter of about 2 .mu.m pulverized by using a jet mill, 75 g of hydroxypropylmethylcellulose, 195 g of lactose and 30 g of D-mannitol are mixed, granulated while adding 110 g of purified water and then dried to obtain granules for compressing an outer layer portion. 400 mg of the granules for compressing an outer layer portion contain 100 mg of cilostazol.

280 mg of coated granules, 400 mg of granules for compressing an outer layer portion and 4 mg of magnesium stearate are mixed and then compressed by using a punch having a diameter of 11 mm to obtain granule-containing sustained release tablets containing cilostazol in the amount of 200 mg per tablet.

Example 11

A coating solution containing 6% hydroxypropylmethylcellulose, 2% polyethylene glycol, 1% talc and 1% titanium dioxide is sprayed over the tablets of Example 10 to obtain coated tablets having a weight of 721.9 mg.

Example 12

In the same manner as in Example 10, except that citric acid is eliminated from the coating solution, granule-containing sustained release tablets are obtained. In the same manner as in Example 11, coated tablets are obtained.

Example 13

800 g of a bulk cilostazol powder having an average particle diameter of about 2 .mu.m pulverized by using a jet mill, 1066 g of hydroxypropylmethylcellulose and 60 g of sodium lauryl sulfate as a dispersing and/or solubilizing agent are mixed. The mixture is subjected to wet granulation with adding 1000 g of purified water, dr