Background of the Invention Chemically, cilostazol, 6- [4- (l-cyclohexyl-lH-tetrazol-5-yl) butoxy]-3, 4- dihydrocarbostyrl. It not only shows a high platelet aggregation suppression action but also various other kinds of medical actions such as phosphodiesterase inhibition action, an anti-ulcer action, a hypotensive action and an anti-phlogistic action. Therefore, cilostazol is widely used as thrombolytic drug, cerebral circulation improving drug, anti-phlogistic drug, anti-ulcer drug, hypotensive drug, drug for asthma, phosphodiesterase inhibitor and the like.

Cilostazol is practically insoluble in water, and its bioavailability from pharmaceutical compositions is considered to be dissolution rate limited. Well-defined approaches addressing the solubility problem of cilostazol, are therefore needed to improve the dissolution rate, and consequently to achieve the desired bioavailability and therapeutic effects.

Prior art approaches are mainly directed to micronization of cilostazol, prior to use in pharmaceutical compositions, as an aid to improve dissolution. For example, WO 00/57881 discloses a cilostazol preparation, which comprises cilostazol having an average particle diameter of about 3 um or less into a suspending and/or solubilizing agent having capability of dissolving cilostazol even at lower portion of digestive tract.

WO 96/21448 discloses a resin particle having a particle size of not greater than 2000pm, which comprises an ethylene vinyl alcohol copolymer and 5 to 10% by weight of cilostazol. The resin particle, upon being administered orally allows the concentration of cilostazol in blood to be kept constant over an extended period of time.

Summary of the Invention However, there still exists a need for alternate approaches, which would be economically feasible and less time consuming. The inventors have now discovered that

adsorption of cilostazol on inert carriers to form adsorbates, would provide dosage form with improved rates of dissolution.

In one general aspect there is provided cilostazol adsorbates. The cilostazol adsorbates include cilostazol adsorbed on inert carrier.

The inert carriers may include one or more of polymeric carriers like cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium (Ac-Disol), sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and non- polymeric carriers like lactose and cyclodextrins. The inert carrier may also be commercially available inert carriers comprising the above inert carrier material such as non-pareil seed, celphere, and the like. In particular, the super disintegrants, mannitol, polyvinyl pyrrolidone, polyethylene glycol, microcrystalline cellulose, sucrose may be used. The ratio of cilostazol to inert carrier may vary from about 1: 0.1 to about 1: 10 by weight.

In another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of layering on an inert carrier a solution of cilostazol in a solvent; drying; and optionally milling.

In another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of dissolving or suspending cilostazol and an inert carrier in a solvent; evaporating the solvent to give a residue; and optionally milling the resultant residue.

In another general aspect there is provided a process of preparing a cilostazol adsorbate. The process includes the steps of dissolving or suspending cilostazol and an inert carrier in a solvent; adding a miscible anti-solvent to precipitate out cilostazol coated carriers; and optionally milling the precipitate.

In one general aspect there is provided a pharmaceutical composition that includes cilostazol adsorbate and one or more pharmaceutically acceptable inert excipients.

The one or more pharmaceutically acceptable inert excipients may be selected from the group consisting of wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.

In another general aspect there is provided a process for preparing a pharmaceutical composition of cilostazol. The process includes the steps of combining cilostazol adsorbate and one or more pharmaceutical acceptable inert excipients, and processing into a solid dosage form.

In another general aspect there is provided a modified release pharmaceutical composition that includes cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable inert excipients.

In another aspect there is provided a process for preparing a modified release pharmaceutical composition of cilostazol. The process includes the steps of combining cilostazol adsorbate, rate controlling polymer and one or more pharmaceutical inert excipients, and processing into a solid dosage form.

The composition may be formulated in the form of granules filled in capsule, tablet or other suitable dosage form. The tablet formulation may further be coated.

In another general aspect there is provided a method of treating intermittent claudication by administering a pharmaceutical composition to a mammal in need thereof.

The pharmaceutical composition includes cilostazol adsorbate and one or more pharmaceutical inert excipients.

In another general aspect there is provided a method of treating intermittent claudication by administering a modified release pharmaceutical composition to a mammal in need thereof. The modified release pharmaceutical composition includes cilostazol adsorbate, rate controlling polymer, and one or more pharmaceutically acceptable inert excipients.

The details of one or more embodiments of the inventions are set forth in the description below. Other features and advantages of the inventions will be apparent from the description and the claims.

Detailed Description of the Invention The inventors have found that improved dissolution characteristics, and consequently improved bioavailability can be achieved by pharmaceutical compositions that include cilostazol adsorbates. The cilostazol adsorbates can be prepared by adsorption of cilostazol on inert carriers. On oral administration, the cilostazol is released from the adsorbates into the surrounding media, in a highly dispersed form, enhancing dissolution.

The preparation of adsorbates maintains the particulate nature throughout processing and storage, until it is released in the dissolution media/gastrointestinal fluids. It also helps to achieve the reproducible results.

The term"cilostazol"as used herein includes cilostazol and its pharmaceutically acceptable salts.

The term"cilostazol adsorbate"as used herein refers to particles of cilostazol or its pharmaceutically acceptable salts that are closely associated with the carrier in clusters.

However, it is not essential that all of the particles of cilostazol or its pharmaceutically salts may actually be in contact with the carrier particle.

The term"inert carrier"as used herein refers to an organic material having an external surface area on which cilostazol can be adsorbed from solution in fine particle form. Examples of inert carriers include polymeric carriers like cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxy propyl methyl cellulose; starches such as maize, rice, corn and potato starch; super disintegrants such as croscarmellose sodium (Ac-Disol), sodium starch glycolate, and crospovidone; polyvinyl alcohol; polyvinyl pyrrolidone; solid grades of polyethylene glycols; and non-polymeric carriers like lactose and cyclodextrins. The inert carrier may also be commercially available inert carriers comprising the above inert carrier material such as non-pareil seed, celphere, and the like. In particular, the super disintegrants, mannitol, polyvinyl pyrrolidone, polyethylene glycol, microcrystalline cellulose, sucrose may be used. The ratio of cilostazol to inert carrier may vary from about 1: 0.1 to about 1: 10 by weight.

The invention further includes a process of preparing cilostazol adsorbates. In general, the process includes dissolving cilostazol in a solvent to form a solution, and layering the solution on an inert carrier, according to the techniques known in the art, for example, dip coating, spray coating, and compression coating. The coated inert carriers may then be milled to form the adsorbates.

In one aspect, cilostazol adsorbate may be prepared by dissolving cilostazol in a solvent to form a solution, adding inert carrier into the solution to form a suspension, evaporating the solvent to get a residue, drying the resulting residue and milling.

In one aspect, cilostazol adsorbate may be prepared by a) dissolving cilostazol in a solvent to form a solution,

b) adding inert carriers to the solvent to form a suspension, c) combining the solution of step a) and suspension of step b) to form a suspension, d) evaporating the solvent of suspension of step c) to get a residue, and e) drying the resulting residue and milling.

The solvent used to prepare cilostazol solution or inert carrier suspension may be the same or even different. The solution and suspension may be combined in either order; or they may be simultaneously combined into a separate container with constant stirring.

In particular, they may be combined by adding the suspension into the solution.

In one aspect, the cilostazol adsorbate may be prepared by dissolving cilostazol in a solvent to form a solution, adding inert carrier into the solution to form a suspension, adding a miscible anti-solvent to precipitate out cilostazol coated carriers, and drying and milling the precipitate.

The adsorbates prepared in any of the aspects above, may further include one or more pharmaceutically acceptable excipients such as binders, crystal modifiers, wetting agents, and the like.

Suitable solvents for dissolving or suspending cilostazol and carrier include one or more organic solvents, including, for example, ethanol, methanol, isopropanol, tertiary butanol, acetone, dimethyl sulfoxide, dimethylfonnamide, tertahydrofuran, methylene chloride, chloroform, triethylamine, pyridine, ethyl acetate, acetonitrile and the mixtures thereof.

Examples of anti-solvents include one or more of aqueous and/or non-aqueous solvents such as methanol, isopropyl alcohol and water.

The residue obtained on drying of the solvent, or the precipitate separated on addition of anti-solvent may be dried using conventional drying methods such as spray drying, filtration, freeze-drying. In particular, spray drying may be used. Milling of the dried cilostazol adsorbates may be carried out in conventional milling equipments, such as cad mill, air-jet mill, multi mill and the like.

The cilostazol adsorbate prepared by any of the processes above may be used as such or combined with other pharmaceutically acceptable inert excipients to form pharmaceutical compositions formulated as solid dosage forms such as tablet, capsule,

granule and the like. The pharmaceutical composition may be prepared as a conventional immediate release dosage form, or a modified release dosage form. The modified release dosage form in addition to above may also include one or more rate-controlling polymers.

The term"modified release dosage form"as used herein includes any modified release formulation intended for slow release such as sustained release, controlled release, delayed release, timed release etc.; capable of modifying and controlling the release of cilostazol up to a period of about 24 hours.

Examples of rate-controlling polymers include one or more of cellulose derivatives, alginic acid derivatives methacrylic acid derivatives, waxes, polysaccharides, alkylene oxides and the like.

In one aspect, the pharmaceutical composition of cilostazol may be prepared by a process that includes the steps of : blending cilostazol adsorbate with pharmaceutically acceptable inert excipients; optionally granulating the blend; lubricating the blend/granules and processing into a solid dosage form.

In another aspect, modified release pharmaceutical composition of cilostazol may be prepared by a process comprising the steps of : blending cilostazol adsorbate, rate- controlling polymer and pharmaceutically acceptable inert excipients; optionally granulating the blend; lubricating the blend/granules and processing into a solid dosage form.

Cilostazol adsorbates may be granulated with the pharmaceutically excipients using any of the conventional methods used in the art including wet granulation, dry granulation, and extrusion-spheronization. hi the wet granulation method, the dry solids (active ingredients, filler, disintegrant, etc. ) are blended and moistened with the binder solution and then the agglomerates or granules are built up of the moistened solids. Wet massing is continued until a desired homogeneous particle size has been achieved whereupon the granulated product is dried to form dried granules. The dried granules are blended with lubricants and, optionally, a disintegrant and the blend then is compressed into tablets or filled into hard gelatin capsules.

In the dry granulation method, the active ingredient can be compacted alone or together with other pharmaceutically acceptable excipients. The granules then are mixed with extragranular excipients and compressed into tablets or filled into hard gelatin capsules.

Thus, the cilostazol dosage forms can be a tablet dosage form prepared by compression of granules of active ingredient and pharmaceutically acceptable excipients obtained by the wet granulation method or the dry granulation method. The cilostazol dosage forms also can be a capsule prepared by filling granules of active ingredient and pharmaceutically acceptable excipients obtained by the wet granulation method or the dry granulation method in a hard gelatin capsule.

Examples of pharmaceutically acceptable inert excipients include wetting agents, diluents, crystal modifiers, binders, disintegrants, coloring agents, flavoring agents, stabilizers, lubricants/glidants and plasticizers.

Examples of wetting agents may include both ionic and non-ionic wetting agents.

These include polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers known as"poloxamer" ; 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 monosterate, polyoxyethylene alkyl ether such as poluoxyethylene lauryl ether; polyoxyethylene castor oil and hardened castor oil, such as polyoxyethylene hardened castor oil; sucrose ester of fatty acid such as sucrose state ester and sucrose pahnitate ester and alkyl sulfate salt such as sodium lauryl sulfate and magnesium lauryl sulfate; sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate sodium, palmitoyl carnitine ; and the like.

In particular, poloxamer (available in trade name of Lutrol) is used.

Examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and the like and combinations thereof Suitable crystal modifiers may include one or more of polyethylene glycol, poly vinyl pyrrolidone and the like.

Suitable binders may include one or more of polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol and the like.

Suitable disintegrants may include one or more of microcrystalline cellulose, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, sodium starch glycollate and the like.

Suitable lubricants and glidants may include one or more of colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax and the like.

Suitable plasticizers may include one or more of polyethylene glycol, triethyl citrate, triacetin, diethyl phthalate, dibutyl sebacate, and the like.

Suitable stabilizers may include one or more of antioxidants, buffers, acids and the like.

The colors may be selected from any FDA approved colors for oral use.

The solid dosage form may be further coated with one or more functional and/or non-functional layers comprising film-forming materials.

Examples of film forming material may include water soluble coating materials of celluloses such as hydroxy propyl cellulose, hydroxy propyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxy ethyl cellulose; enteric coating material of celluloses such as hydroxy propyl methyl cellulose phthalate, hydroxy propyl methyl cellulose acetate succinate, and cellulose acetate phthalate; and other enteric film coating materials such as methacrylic acid copolymer, shellac and the like.

The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way. Cilostazol Adsorbate Example 1: Amount (gm) Ingredients Example 1A Example 1B Example 1C Cilostazol 1 1 1 Mannitol 1 1 1 Polyvinyl pyrrolidone-0. 1- Polyethylene glycol--0. 1 Methylene chloride q. s. q. s. q. s.

Example 2: Amount (gm) Ingredients Example 2A Example 2B Cilostazol 1 1 Polyvinyl pyrrolidone 1- Polyethylene glycol-1 Methylene chloride q. s. q. s.

Procedure (Examples 1 and 2) : 1. Cilostazol was dissolved in methylene chloride with constant stirring.

2. To the solution formed in step 1, other ingredients were added, with constant stirring to form a suspension.

3. The resultant suspension was transferred to a rotavapor and methylene chloride was evaporated.

4. The resultant solid residue was crushed and passed through #200 BSS to obtain cilostazol adsorbate.

Example 3 : Ingredients Amount (gm) Cilostazol 300 Polyvinyl pyrrolidone 9 Methylene chloride q. s.

Procedure: 1. Cilostazol was dissolved in methylene chloride with constant stirring.

2. To the solution formed in step 1, polyvinyl pyrrolidone was added and dissolved by stirring.

3. The solution of step 2 was layered on non-pareil sugar (NPS) beads (#25/30) using Wurster coating apparatus.

4. The layered beads were then dried, milled and passed through #200 BSS to obtain cilostazol solid dispersion.

Cilostazol tablet Example 4: Amount (%w/w) Ingredients Example Example Example 4B Example 4C 4A 4D Adsorbate* 73.45 69.84 76.07 69.84 Poloxamer 3.45 3.28 3.57 3.28 Methocel K 100 LV 10.34 16. 39 Methocel K4 MCR--8. 93 16.39 Low viscosity-hydroxypropyl 3.45 4.92 5.36 4.92 cellulose Microcrystalline cellulose 5. 86 2.29 2.50 2.30 Polyvinyl pyrrolidone 2.59 2.46 2.68 2.46 Magnesium stearate 0.52 0.49 0.54 0.49 Colloidal silicon dioxide 0. 34 0. 33 0. 36 0. 33 Tablet weight (mg) 580 610 560 610

*Cilostazol adsorbate of Example 3, equivalent to 200 mg cilostazol Procedure: For the preparation of tablets of cilostazol as per Examples 4 A-D, cilostazol adsorbate was blended with other inert excipients, and rate-controlling polymers except lubricant/glidant (magnesium stearate and colloidal silicon dioxide); and granulated with isopropyl alcohol, and dried. The dried granules were blended with lubricant/glidant; and compressed to form sustained release tablets.

In vitro dissolution study Procedure: The tablets were tested for in vitro release of cilostazol, in USP type-1 dissolution apparatus at 100 rpm and a temperature of 370. 5'C, in 900-ml of buffer pH 6. 8 containing 0. 3% of sodium lauryl sulfate. The samples were withdrawn after predetermined time and analyzed for cilostazol content. The results of the study are listed below.

Cumulative percentage of cilostazol released (%) Time (h) Example 4A Example 4B Example 4C Example 4D 0 0.00 0.00 0.00 0.00 1 20. 58 10.27 5. 83 2.76 2 47.55 30.35 15.22 8.09 4 81.02 63.96 34.72 18. 92 6 87.02 84. 38 54.38 30. 78 8 89.34 88. 04 70.34 42.30 10 90.11 87.65 80. 64 51.52 12 89.48 87.53 86.44 57.60 Cilostazol adsorbate Example 5: Amount (gm) Ingredients Example 5A Example 5B Cilostazol 30 30 Microcrystalline cellulose 30 30 Polyvinyl pyrrolidone-1 Methylene chloride q. s. q. s.

Procedure: Same as in Example 1.

1. Cilostazol was dissolved in methylene chloride with constant stirring.

2. To the solution formed in step 1, other ingredients were added, with constant stirring to form a suspension.

3. The resultant suspension was transferred to a rotavapor and methylene chloride was evaporated.

4. The resultant solid residue was crushed and passed through #200 BSS to obtain cilostazol adsorbate.

Cilostazol tablet Example 6: Amount (% w/w) Ingredients Example 6A Example 6B Adsorbate* 74. 48 (Example 5A) 72.59 (Example 5B) Poloxamer 3.45 3.70 Methocel K 100 LV 10.34 11.11 Low-viscosity-hydroxypropyl 3, 45 3. 70 cellulose Mannitol 4.83 5.19 Polyvinyl pyrrolidone 2.59 2.78 Magnesium stearate 0.52 0.56 Colloidal silicon dioxide 0.34 0.37 Tablet weight (mg) 580 540

* Equivalent to 200 mg of cilostazol Procedure: Same as in Example 4.

In vitro dissolution study Procedure: Same as in Example 4. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 6A Example 6B 0 0.00 0.00 1 23. 38 23.42 2 38. 41 38.29 4 62.80 62.52 6 78. 10 85.25 8 88.12 90.59 10 93.40 92.57 12 96.46 94.03 Cilostazol adsorbate Example 7: Ingredients Amount (gm) Example Example Example Example 7A 7B 7C 7D Cilostazol 5 5 5 10 Hydroxypropyl methylcellulose 5--- Sucrose-5-- Polyplasdone--5- Polyvinyl pyrrolidone-0. 15-0. 3 Microcrystalline cellulose---5 Methylene chloride q. s. q. s. q. s. q. s.

Procedure: Same as in Example 1.

Example 8: Amount (gm) Ingredients Example Example Example Example 8A 8B 8C 8D Cilostazol 35 35 35 35 Lactose 35 17. 6-- Cross carmelose sodium--35 17.6 Polyvinyl pyrrolidone 1.05 1.05 1. 05 1. 05 Methylene chloride q. s. q. s. q. s. q. s.

Procedure: Same as in Example 1.

Cilostazol tablet Example 9: Amount (% w/w) Ingredients Example Example Example Example Example 9A 9B 9C 9D 9E Adsorbate of 8A 8B 8C 8D 8C Example Cilostazol 72. 73 66.67 72.73 66.67 66.67 adsorbate* Poloxamer 3.64 4.44 3.64 4.44 3.33 Methocel K 4MCR 7.27 8. 89 7.27 8.89 15.00 Low viscosity- hydroxypropyl 5.45 6.67 5.45 6.67 5.00 cellulose Microcrystalline 7. 27 g. g9 cellulose Lactose--7. 27 8.89 6.67 Polyvinyl 2.73 3.33 2.73 3.33 23.50 pyrrolidone Magnesium stearate 0.55 0.67 0.55 0.67 0.50 Colloidal silicon 0.36 0.44 0.36 0.44 0.33 dioxide Tablet weight (mg) 550 450 550 450 600

*Equivalent to 200 mg of cilostazol Procedure: Same as in Example 4.

In vitro dissolution study Procedure: The tablets were tested for in vitro release of cilostazol, in USP type-2 dissolution apparatus at 75 rpm, and a temperature of 370. 5'C, in 900-ml of buffer pH 6.8 containing 0.5% of sodium lauryl sulfate. The samples were withdrawn after predetermined time intervals, and analyzed for cilostazol content. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 9A Example 9B Example 9C Example 9D Example 9E 0 0.00 0.00 0.00 0.00 0.00 1 10.95 8. 15 33.59 21.79 11.32 2 21.34 17.90 47.69 34.40 16.93 4 41.12 35.79 90. 78 56. 28 29. 37 6 62.02 52.03 98. 52 75.22 43. 24 8 83. 75 66.66 98. 32 97.84 57. 08 10 100.97 82.77 98.07 102.11 70. 78 12 104.70 92.62 98.45 102.10 77.94 Cilostazol adsorbate Example 10: Amount (gm) Ingredients Example 10A Example 10B Cilostazol 504.5 503.0 Cross carmelose sodium 505.8 250.5 Polyvinyl pyrrolidone 15.05 15.06 Methylene Chloride q. s. q. s.

Procedure: Same as in Example 1.

Cilostazol tablet Example 11: Amount (% w/w) Ingredients Example 11A Example 11B Adsorbate of Example 10A 10B Cilostazol adsorbate* 66.89 65.95 Poloxamer 3.29 4.31 Methocel K 4MCR 14.83 8.62 Low viscosity-hydroxypropyl 4.94 6.46 cellulose Lactose 6.59 8.62 Polyvinyl pyrrolidone 2.47 4.74 Sodium stearyl fumarate 0.49 0.65 Magnesium stearate 0.16 0.21 Colloidal silicon dioxide 0.33 0.43 Tablet weight (mg) 607 464

*Equivalent to 200 mg of cilostazol Procedure: For the preparation of tablets of cilostazol, cilostazol adsorbate was blended with other ingredients except magnesium stearate, sodium stearyl fumarate, and polyvinyl pyrrolidone. The blend was then granulated using a solution of polyvinyl pyrrolidone in isopropyl alcohol : water mixture (50: 50), and the wet mass was dried in a fluidized bed dryer. The dried granules were blended with magnesium stearate and sodium stearyl fumarate; and compressed to form sustained release tablets.

In vitro dissolution study Procedure: Same as in Example 9. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 11 A Example 11B 0 0 0 1 13 11 2 20 22 4 35 44 6 51 69 8 66 96 10 80 103 12 95 103 Cilostazol adsorbate Example 12: Ingredients Amount (gm) Cilostazol 100 Cross carmelose sodium 50 Polyvinyl pyrrolidone 3 Methylene chloride q. s.

Procedure: Same as in Example 1.

Cilostazol tablet Example 13: Amount (%w/w) Ingredients Example Example Example Example 12A 12B 12C 12D Cilostazol adsorbate* 63.22 61.94 60.71 59.53 Poloxamer 4.13 4.05 3.97 3. 89 Methocel K 4MCR 12.40 14.17 15. 87 17.51 Low viscosity-hydroxypropyl 6.20 6.07 5.95 5.84 cellulose Lactose 8.26 8. 10 7.94 7. 78 Polyvinyl pyrrolidone 4.55 4.45 4.37 4. 28 Sodium stearyl fumarate 0.62 0.61 0.60 0. 58 Magnesium stearate 0.21 0.20 0.20 0.19 Colloidal silicon dioxide 0.41 0.40 0.40 0.39 Tablet weight (mg) 242 247 252 257

*Adsorbate of Example 12, equivalent to 100 mg of cilostazol Procedure: Same as in Example 4.

In vitro dissolution study Procedure: Same as in Example 9. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 13A Example 13B Example 13C Example 13D 0 0 0 0 0 1 19 15 12 11 2 30 26 21 19 4 54 50 42 39 6 76 73 61 59 8 104 97 79 77 10 105 106 104 100 12 105 105 108 105 Cilostazol adsorbate Example 14: Amount (gm) Ingredients Example 14A Example 14B Example 14C Cilostazol 20 20 20 Cross carmelose sodium 10 10 10 Polyethylene glycol 1-- Poloxamer-1- Sodium lauryl suphate--1 Polyvinyl pyrrolidone 0.6 0.6 0.6 Methanol q. s. q. s. q. s.

Procedure: 1. Cilostazol was dissolved in methanol (at 65°C) with constant stirring.

2. To the solution formed in step 1, other excipients were added with constant stirring.

3. The resultant suspension was stirred at room temperature, and filtered under vacuum.

4. The material collected on the filter was dried overnight, and crushed to obtain cilostazol adsorbate. Cilostazol tablet Example 15: Amount (% w/w) Ingredients Example 15A Example 15B Example 15C Adsorbate of Example 14A 14B 14C Cilostazol adsorbate* 62.70 62.70 62.70 Poloxamer 3.97 3.97 3.97 Methocel K 4MCR 13. 89 13.89 13.89 Low viscosity-hydroxypropyl 5.95 5.95 5.95 cellulose Lactose 7.94 7.94 7.94 Polyvinyl pyrrolidone 4. 37 4.37 4.37 Sodium stearyl fumarate 0.60 0.60 0.60 Magnesium stearate 0.20 0.20 0.20 Colloidal silicon dioxide 0.40 0.40 0.40 Tablet weight (mg) 252 252 252 Equivalent to 100 mg of cilostazol

Procedure: Same as in Example 4.

In vitro dissolution study Procedure: Same as in Example 9. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 15A Example 15B Example 15C 0 0 0 0 1 20 18 23 2 33 30 39 4 60 56 68 6 82 78 90 8 104 106 105 10 104 106 105 12 104 106 107 Cilostazol adsorbate Example 16 : Ingredients Amount (gm) Cilostazol 120 Cross carmelose sodium 60 Polyethylene glycol 6 Polyvinyl pyrrolidone 3.6 Methanol q. s.

Procedure: 1. Cilostazol was dissolved in methanol (at 65°C) with constant stirring.

2. To the solution formed in step 1, other excipients were added with constant stirring.

3. The resultant suspension was stirred at room temperature, and filtered under vacuum.

4. The material collected on the filter was dried overnight, and crushed to obtain cilostazol adsorbate.

Cilostazol adsorbate Example 17 : Ingredients Amount (gm) Cilostazol 120, Cross carmelose sodium 60 Polyvinyl pyrrolidone 3.6 Methylene chloride q. s.

Procedure : 1. Cilostazol was dissolved in methylene chloride with constant stirring.

2. To the solution formed in step 1, other excipients were added with constant stirring.

3. The resultant suspension was transferred to a rotavapor and around 80% of methylene chloride was evaporated.

4. The slurry was filtered under vacuum and the material collected on the filter was dried overnight, and crushed to obtain cilostazol adsorbate. Cilostazol tablet Example 18: Amount (% w/w) Ingredients Example 18A Example 18B Adsorbate of Example 16 17 Cilostazol adsorbate* 61.79 62.99 Poloxamer 4.07 3.94 Methocel K4MCR 14.23 13.78 Low viscosity-hydroxypropyl 6. 10 5. 91 cellulose Lactose 8.13 7.87 Polyvinyl pyrrolidone 4.47 4.33 Sodium stearyl fumarate 0.61 0.59 Magnesium stearate 0.20 0.20 Colloidal silicon dioxide 0.41 0.39 Tablet weight (mg) 246 254

*Equivalent to 100 mg of cilostazol Procedure: Same as in Example 11.

In vitro dissolution study Procedure: Same as in Example 9. The results of the study are listed below. Cumulative percentage of cilostazol released (%) Time (h) Example 18A Example 18B 0 0 0 1 14 13 2 26 24 4 51 49 6 77 72 8 99 100 10 105 101 12 105 102 While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.