The technical field of the present invention relates to cilostazol composition wherein 90% of cilostazol particles have a particle size less than about 50 µm, and to a process for preparing it.
Cilostazol, described in US Pat. No. 4,277,479 is commercially available as 50 and 100 mg oral tablets, marketed by Otsuka under the trade mane PLETAL. It shows not only 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. Cilostazol is practically insoluble in water and thus result in poor bioavailability of the drug.
Low solubility drugs often exhibit the drawback of insufficient dissolution in gastric fluids that prejudices obtaining plasmatic concentration sufficient to achieve the therapeutic effects. Much work has been undertaken worldwide, to achieve a sufficient plasmatic concentration necessary to reach the desired therapeutic effects. Some of the frequently used approaches involve one or more of milling, solid dispersion, solid-state modifications, complexation etc.
Cilostazol is a low solubility drug, and requires well-defined solubility improving approaches, to achieve desired dissolution profile from cilostazol compositions. US Patent application No. 20030166937 discloses pharmaceutical composition of cilostazol, comprising milled cilostazol wherein 90% of the particles either have a diameter of about 60 µm or less than about 15 µm.
There is a need for cilostazol compositions, which would be bioequivalent when compared to the existing marketed compositions such as PLETAL, and which would be easier to manufacture, and have reproducible performance, compared to the existing compositions. None of the above prior art documents teaches or suggests the instant invention.
We have now discovered that cilostazol compositions having desired dissolution may be prepared by using milled cilostazol wherein at least 90% cilostazol particles, have a particle size less than about 50 µm. The desired particle size may be achieved by processing cilostazol alone, or with a carrier to form a co-milled mass.
Hence, in one general aspect there is provided a pharmaceutical composition of cilostazol wherein at least 90% cilostazol particles have a particle size less than about 50 µm.
In another general aspect there is provided, a pharmaceutical composition of cilostazol wherein at least 25% cilostazol particles have a particle size greater than about 15 µm.
In another general aspect there is provided, a pharmaceutical composition of cilostazol wherein at least 90% cilostazol particles have a particle size less than about 50 µm and at least 25% cilostazol particles have a particle size greater than about 15 µm.
In another general aspect there is provided, a pharmaceutical composition comprising cilostazol co-milled with a carrier.
In another general aspect there is provided, a pharmaceutical composition comprising cilostazol co-milled with a carrier wherein at least 90% particles of the co-milled mass have a particle size less than about 50 µm.
In another general aspect there is provided, a pharmaceutical composition comprising cilostazol co-milled with a carrier wherein at least 25% particles of the co-milled mass have a particle size greater than about 15 µm.
In another general aspect there is provided, a pharmaceutical composition comprising cilostazol co-milled with a carrier wherein at least 90% particles of the co-milled mass have a particle size less than about 50 µm and at least 25% particles of the co-milled mass have a particle size greater than about 15 µm.
In another general aspect there is provided, a process for the preparation of co-milled mass of cilostazol and a carrier comprising the steps of blending cilostazol and carrier; feeding into a milling equipment; and milling to obtain a co-milled mass of desired particle size.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending milled cilostazol
and one or more pharmaceutical^ inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 90% cilostazol particles have a particle size less than about 50 µm.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending milled cilostazol and one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 25% cilostazol particles have a particle size greater than about 15 µm.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending milled cilostazol and one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 90% cilostazol particles have a particle size less than about 50 µm and at least 25% cilostazol particles have a particle size greater than about 15 µm.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending co-milled mass of cilostazol and a carrier with one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 90% particles of the co-milled mass have a particle size less than about 50 µm.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending co-milled mass of cilostazol and a carrier with one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 25% particles of the co-milled mass have a particle size greater than about 15 µm.
In another general aspect there is provided, a process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending co-milled mass of cilostazol and a carrier with one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 90%
particles of the co-milled mass have a particle size less than about 50 µm and at least 25% particles of the co-milled mass have a particle size greater than about 15 µm.
The term "particle size" as used herein refers to the average particle diameter of the particle on conversion of its volume into a sphere. The percentages of cilostazol or co-milled mass particles as used herein refers to percentage volume of the total volume. The size of particles was measured using Malvern Mastersizer.
The term "cilostazol" as used herein includes cilostazol and its pharmaceutically acceptable salts.
The term "solid dosage form" as used herein includes conventional solid dosage forms such as tablet, capsule, sachet, and the like.
Cilostazol is poorly soluble in water and its bioavailability is limited by the rate of dissolution of cilostazol into the surrounding media. Reduction of particle size results in an increase in the effective exposed surface to the dissolution media, aiding in solubility and consequently the bioavailability of cilostazol from the dosage form. Uncontrolled size reduction to a very fine range results in excessive drug losses during processing, besides hindering smooth processing of dosage forms. In addition, use of fine particles would also increase the risk of re-agglomeration. Pharmaceutical compositions of the instant invention comprises cilostazol particles of a particular size range i.e. at least 90% of cilostazol particles would have a particle size less than about 50 µm and/or at least 25% of cilostazol particles would have a particle size greater than about 15 µm. In particular, at least 90% of cilostazol particles would have a particle size less than about 45 µm and at least 25% would have a particle size greater than about 15 µm. More particular, at least 90% of cilostazol particles would have a particle size less than about 45 µm and at least 50% would have a particle size greater than about 15 µm.
Cilostazol particles of the desired size range may be obtained by the process of milling using conventionally used mechanical mills such as cad mill, fitz mill, multi mill, impact mill, and ball mill; or air jet mill. In particular, a mechanical mill may be used. The particle size of the final product in a mechanical mill is dependent on the speed of rotation, aperture size and shape, and configuration of the screen/sieve used. These parameters can be easily
adjusted/selected and maintained throughout the milling process, and thereby these mills would produce reproducible results. Advantageously, the particle size of the final product is not drastically affected by the initial particle size distribution and feed rate. These ensure reproducible particle size distribution of the final product, lowering variability in dissolution and consequently the bioavailability. Above all, mechanical milling is a fast and commercially feasible process.
Alternatively, cilostazol may be blended with a carrier and then milled to form a co-milled mass. During co-milling cilostazol particles get adhered to the carrier surface in fine particulate form. By virtue of such adhering, static charges generated during the milling process are neutralized, thereby reducing chances of re-agglomeration of cilostazol particles besides improving the flow properties. Co-milling also helps in wetting of cilostazol during dissolution, enhancing dissolution further. In embodiments wherein a term "co-milled mass" is used, the particle size and respective percentages of cilostazol as above, would refer to the particles of the co-milled mass.
Examples of carriers used for co-milling include all substances that are physiologically acceptable, compatible with cilostazol and other pharmaceutically inert excipients, and have a capacity to adhere to cilostazol particles. Specific examples include cellulose derivatives such as microcrystalline cellulose, and calcium carboxymethylcellulose; sugars such as lactose; and starch. The weight ratio of cilostazol and carrier may vary from about 1:1 to about 1:0.1. In particular, starch may be used in the weight ratio of 1:0.3 (cilostazol: starch).
According to one of the embodiments, pharmaceutical composition of cilostazol may comprise milled cilostazol or co-milled mass and pharmaceutically inert excipients. Pharmaceutically inert excipients include all physiologically inert excipients used in the pharmaceutical art of dispensing. Examples include binders, diluents, surfactants, disintegrants, lubricants/glidants, coloring agents, and the like.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose,
polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol -20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol -20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, palmitoyl carnitine; and the like.
Specific examples of disintegrants include low-substituted hydroxypropylcellulose L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Coloring agents include any FDA approved colors for oral use.
In one of the embodiments, cilostazol tablet may be prepared by blending milled cilostazol or co-milled mass of cilostazol and a carrier with pharmaceutically inert excipients; and directly compressing into tablet.
In another embodiment, cilostazol tablet may be prepared by blending milled cilostazol or co-milled mass of cilostazol and a carrier with intragranular pharmaceutically inert excipients; wet granulating the blend with a granulating fluid or solution/dispersion of binder in granulating fluid; drying and sizing the granules; blending with extragranular pharmaceutically inert excipients; lubricating the blend; and compressing the blend into tablets.
In another embodiment, cilostazol tablet may be prepared by blending milled cilostazol or co-milled mass of cilostazol and a carrier with intragranular pharmaceutically inert excipients; dry granulating the blend by roller compaction or slugging; sizing the granules; blending with extragranular excipients; lubricating the blend; and compressing the blend into tablets.
Specific examples of solvents used as granulating fluid and for preparing solution/dispersion of binder include methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and the like.
Optionally, tablets prepared in any of the embodiments above may be further coated with one or more functional and/or non-functional coating layer, as desired.
The invention is further illustrated by the following examples, which is for illustrative purpose and should not be construed as limiting the scope of the invention in any way.
(Table Removed)
Procedure (Example 1):
1. Cilostazol was sifted through sieve #25 (BSS) and milled in a Fitz mill, so that 90% particles are less than 44 µm and 30% are greater than 15 µm.
2. Starch, calcium carboxymethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose were sifted separately through sieve #25 (BSS).
3. Sifted calcium carboxymethylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, and half of the quantity of starch of step 2 were blended with the milled particles of step 1 in a rotary mixer granulator to form a blend.
4. The blend of step 3 was granulated using purified water as granulating fluid, to form granules.
5. The granules of step 4 were dried in a fluidized bed dryer and sized by sifting through sieve #25 (BSS).
6. Sized granules of step 5 were blended with the remaining half quantity of starch (of step 2) and magnesium stearate, and compressed into tablets using suitable toolings.
Procedure (Example 2):
1. Cilostazol and starch were sifted through sieve #25 (BSS) and co-milled in a Fitz mill, that 90% particles are less than 44 µm.
2. Calcium carboxymethylcellulose, hydroxypropyl methylcellulose and microcrystalline cellulose were sifted separately through sieve #25 (BSS).

3. The sifted ingredients of step 2 were blended with the co-milled mass of step 1 in a rotary mixer granulator to form a blend.
4. The blend of step 3 was granulated using purified water as granulating fluid, to form granules.
5. The granules of step 4 were dried in a fluidized bed dryer and sized by sifting through sieve #25 (BSS).
6. Sized granules of step 5 were blended with magnesium stearate and compressed into tablets using suitable toolings.
Comparative in vitro release of cilostazol from tablets as per composition of Example 1 and 2, and the marketed Pletal® (100 mg) tablets was studied in 900 ml water containing 0.3% sodium lauryl sulphate, using USP II dissolution apparatus, at a paddle speed of 75 rpm. The results of the study are given in Table 1.
Table 1. In vitro release of cilostazol from tablets prepared according to Example 1 and Pletal® tablets (Table Removed)

WE CLAIM:
1. A pharmaceutical composition of cilostazol wherein at least 90% cilostazol particles are less than about 50 µm.
2. A pharmaceutical composition of cilostazol wherein at least 25% cilostazol particles are greater than about 15 µm.
3. The pharmaceutical composition according to claim 1 and 2 wherein at least 90% cilostazol particles are less than about 50 µm and at least 25% cilostazol particles are greater than about 15 µm.
4. The pharmaceutical composition according to claim 3 wherein at least 90% cilostazol particles are less than about 45 urn and at least 25% cilostazol particles are greater than about 15 µm.
5. The pharmaceutical composition according to claim 4 wherein at least 90% cilostazol particles are less than about 45 urn and at least 50% cilostazol particles are greater than about 15 µm.
6. The pharmaceutical composition according to any of the preceding claims wherein cilostazol particles of the desired particle size are prepared by the process of milling.
7. The pharmaceutical composition according to claim 6 wherein cilostazol is blended with carrier and milled to form a co-milled mass of the desired particle size.
8. The pharmaceutical composition according to claim 7 wherein carrier is selected from the group consisting of cellulose derivatives, sugars and starch.
9. The pharmaceutical composition according to claim 8 wherein weight ratio of cilostazol and carrier may vary from about 1:1 to about 1:0.1.
10. The pharmaceutical composition according to claim 8 wherein carrier is starch.
11.The pharmaceutical composition according to claim 10 wherein weight ratio of cilostazol and starch is 1:0.3.
12. The pharmaceutical composition according to claim 6 wherein milling is carried out in a mechanical mill or air jet mill
13. The pharmaceutical composition according to claim 12 wherein milling is carried out in a mechanical mill selected from the group consisting of cad mill, fitz mill, multi mill, impact mill, and ball mill.
14. The pharmaceutical composition according to claim 13 wherein milling is carried out in a fitz mill.
15. A pharmaceutical composition of cilostazol wherein at least 90% cilostazol particles are less than about 50 µm, achieved by milling cilostazol in a mechanical mill.
16. A pharmaceutical composition of cilostazol comprising cilostazol wherein at least 25% cilostazol particles are greater than about 15 µm, achieved by milling cilostazol in a mechanical mill.
17. The pharmaceutical composition according to claim 15 and 16 wherein at least 90% cilostazol particles are less than about 50 µm and at least 25% cilostazol particles are greater than about 15 µm.
18. The pharmaceutical composition according to claim 17 wherein at least 90% cilostazol particles are less than about 45 µm and at least 25% cilostazol particles are greater than about 15 µm.
19. The pharmaceutical composition according to claim 18 wherein at least 90% cilostazol particles are less than about 45 µm and at least 50% cilostazol particles are greater than about 15 µm.
20. The pharmaceutical composition according to claim 15 or 16 wherein mechanical mill is selected from the group consisting of cad mill, fitz mill, multi mill, impact mill, and ball mill.
21. The pharmaceutical composition according to claim 20 wherein mechanical mill is fitz mill.
22. The pharmaceutical composition according to any of the preceding claims wherein cilostazol is selected from cilostazol and its pharmaceutically acceptable salts.
23. The pharmaceutical composition according to any of the preceding claims wherein it further comprises one or more pharmaceutically inert excipients.
24. The pharmaceutical composition according to claim 23 wherein pharmaceutically inert excipient is selected from the group consisting of binders, diluents, surfactants, lubricants/ glidants, and coloring agents.
25. A process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending milled cilostazol or a co-milled mass of cilostazol
with one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 90% cilostazol particles are less than about 50 µM.
26. A process for the preparation of pharmaceutical composition of cilostazol comprising the steps of blending milled cilostazol or a co-milled mass of cilostazol with one or more pharmaceutically inert excipients; optionally granulating the blend; and processing into a solid dosage form, wherein at least 25% cilostazol particles are greater than about 15 µm.
27. The process according to claim 25 and 26 wherein at least 90% cilostazol particles are less than about 50 µm and at least 25% cilostazol particles are greater than about 15 µm.
28. The process according to claim 27 wherein at least 90% cilostazol particles are less than about 45 µm and at least 25% cilostazol particles are greater than about 15 urn.
29. The process according to claim 28 wherein at least 90% cilostazol particles are less than about 45 µm and at least 50% cilostazol particles are greater than about 15 µm.
30. The process according to claim 25 or 26 wherein blend of cilostazol or a co-milled mass of cilostazol with one or more pharmaceutically inert excipients is granulated.
31. The process according to claim 30 wherein granulation is carried out by wet granulation or dry granulation technique.
32. The process according to claim 31 wherein granulation is carried out by wet granulation technique.
33. The process according to claim 25 or 26 wherein solid dosage form is selected from the group consisting of tablet, capsule, sachet, pill and granule.
34. The process according to claim 33 wherein solid dosage form is tablet.