FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 43)
TITLE OF THE INVENTION:
"NOVEL COMPOSITION OF CILOSTAZOL"
APPLICANT:
(a) NAME: TITAN LABORATORIES PRIVATE LIMTED
(b) NATIONALITY: An Indian Company Incorporated Under The Companies Act, 1956
(c) ADDRESS: 102, Titan House, 60 Feet Road, Ghatkopar (E),
Mumbai: 400077, Maharashtra, India.
PREAMBLE TO THE DESCRIPTION:
COMPLETE
The following specification describes the invention

Field of Invention:
The present invention relates to a novel Cilostazol composition. More particularly, the invention relates to a novel sustained release formulation of Cilostazol, which is essentially devoid of any release controlling agent, and the process for formulation thereof.
Background of Invention:
Cilostazol is prescribed for treatment of claudicatio intermittens, that is, intermittent muscle pain usually in people suffering from peripheral artery disease. Cilostazol acts by inhibiting platelet aggregation and dilating the arteries thereby increasing the blood flow to the affected area in turn increases oxygen supply to affected tissue thereby reducing pain/spasm.
As a consequence, of phosphodiesterase III enzyme inhibition by Cilostazol, both in platelets and arterial walls, the degradation of cAMP is also inhibited. As a result, cAMP accumulation in platelets prevents there aggregation and accumulation in arterial walls leads to dilation of arteries. Both inhibition of platelet aggregation and dilation of arteries lead to an increased blood flow hence increased oxygen supply which alleviates the pain.
Cilostazol was first described in US4277479 of Otsuka Pharmaceutical Co., Ltd. Chemically Cilostazol is termed as 6-[4-(l-cyclohexyl-lH-tetrazol-5-yl)butoxy]-3,4-dihydro-2(lH)-quinolinone. The chemical structure of the same is as follows:


Cilostazol is intended to be prescribed as a dose of 100 mg twice daily, which would mean two tablets need to be administered daily. As such, being on medication is an out-of-ordinary act hence patient compliance to the prescribed therapy is generally accepted norm. One way of keeping this non-compliance in check is to use such formulations which can function as depot formulations or formulations which can release the drug over an extended period of time, also known as sustained release (SR) formulations. The SR formulations are designed to release a drug at a predetermined rate by maintaining a constant drug level for a specific period of time with minimum side effects.
Cilostazol SR formulations are subject matters of various patents/patent applications, exemplified as 5895/DELNP/2009 of Amorepacific Corporation/Pacific Pharmaceutical Co. Ltd. Said Patent Application specifically relates to a controlled release formulation of Cilostazol. As per the disclosure of 5895/DELNP/2009, the invention relates to a controlled release formulation of Cilostazol which comprises Cilostazol particles dispersed in a hydrogel matrix.

Another modified release formulation of Cilostazol is described in US Patent No. 7144585. Said patent relates to a Cilostazol preparation for oral administration which is capable of dissolving at the lower portion of a human digestive tract. The Cilostazol as claimed in the invention is a fine powder of Cilostazol having an average particle diameter of from 2 to 10 μm .It further claims a sustained release Cilostazol preparation comprising coating materials like enteric coating materials.
US20110091535 of Otsuka Pharmaceutical Co., Ltd. discloses a sustained release formulation comprising of pre-gelatinized starch and an enteric ingredients along with Cilostazol.
From the current technology scenario, it can be inferred that, the sustained release formulations which are commercially available in market usually comprise of a release controlling agent, which can be cellulose derivatives, methacrylic acid copolymers, vinyl polymers or gums or the like.
The process involved in production of conventional sustained release formulations tends to be difficult, at times intricate, based on which approach is used for sustaining the release of Cilostazol.
The processing intricacies and the cost involved in designing a sustained release formulations is well depicted in the prior art WO 2003/092660 Al of Ranbaxy

Laboratories Ltd. which claims a mono compartment osmotic controlled drug delivery system comprising a poorly soluble drug and at least one alginic acid derivative. The invention is made illustrious by quoting examples of poorly soluble drugs one amongst them is Cilostazol.
The Osmotic drug delivery systems employed in designing sustained /controlled drug delivery systems are the most promising strategies for designing a controlled release dosage forms. However the process of manufacturing if not followed intricately would set in disadvantages such as dose dumping which would subsequently lead to adverse effects.
The coating process involved in manufacturing such Osmotic drug delivery systems have to be well controlled to avoid film defects. Second intricate parameter is the diameter of the orifice which has to be drilled onto the surface to enable the drug release. The diameter or size of the orifice drilled is critical and would require finesse in manufacturing. The diameter of the orifice has to be optimized; if too large it would lead to solute diffusion and if too small would lead to dosage form deformities due to buildup of hydrostatic pressure which would result in the erratic and uncontrolled drug release.
Literature reveals certain clinical trial studies (Clin Ther. 2011 Dec; 33(12):2038-53. Epub 2011 Nov 29) which had been carried out for Pharmacokinetic comparison of sustained- and immediate-release oral formulations of Cilostazol in healthy Korean subjects: a randomized, open-label, 3-part, sequential, 2-period,

crossover, single-dose, food-effect, and multiple-dose study. The findings of the study suggested that in the select group of healthy Korean volunteers, the SR formulation of Cilostazol was not significantly different in AUC compared with that of the IR formulation, although it did display a significantly lower C (max) per dose in both the single- and multiple-dose groups. Food significantly increased the bioavailability of the SR formulation. The Cilostazol SR and IR formulations were well tolerated in all parts of the study, with no serious adverse events reported. (ClinicalTrials.gov identifier. NCT01455558.)
Therefore keeping the entire prior art specifics in mind there is a need to develop a novel ,economic and safe approach for production of sustained release formulations of Cilostazol.
The present inventors have developed a novel approach for production of sustained release formulation for Cilostazol which is devoid of any release controlling agent and the same being safe and highly economic.
Summary of Invention:
Accordingly, the present invention provides a novel stable sustained release formulation for Cilostazol which is devoid of any release controlling agent.
In another aspect, the invention provides a safe and economical process for manufacturing a sustained release dosage form of the invention.

Brief Description of Drawings:
Fig. 1 depicts the process flow chart for the process adapted for manufacturing of
the formulation of the invention.
Detailed Description of Invention:
The present invention will be explained with further details by the following embodiments and examples. However, they are only portrayed to perceive the present invention, and should not be construed to limit the scope of the present invention in any way.
For the purpose of current description, the term 'pellet' would refer to granules, beads, spheroids, spherules and the like and their process of preparation.
For description purposes, the term "pellet" refers to an extruded spheronized pellet which consists of the therapeutically effective amount of active agent, that is, Cilostazol in combination with pharmaceutically acceptable ingredients.
In accord with the aforesaid objects of invention, described herein is a novel sustained release formulation for Cilostazol, wherein the formulation is devoid of any release controlling agent.
The formulation of the invention exhibits a sustained release profile even in absence of a release controlling agent.

The present invention does not attribute to the extra investment in the machinery as required for dosage forms in the desired category namely sustained release dosage forms or the like. As apparent from prior art the sustained release or once a day (OD) formulations as available involve the Osmotic pump technology which involves intricacy and cost, certain other processes require micronization of the active unlike this the present invention does not involve any complicated machinery and the processing is not intricate.
The formulation of invention typically comprises Cilostazol or any pharmaceutically acceptable salt thereof.
Sustained release preparation of Cilostazol typically contains the active, diluent, disintegrant, binder and lubricant in the desired proportion.
The composition essentially contain the active ingredient in the therapeutic dosage range along with the diluent Miorocrystalline Cellulose , disintegrant Croscarmellose Sodium , binder hydroxypropyl methyl cellulose and Talc which functions as a lubricant.
The Cilostazol SR preparation of the present invention can be prepared by blending Cilostazol along with the other excipients including the binder and granulating the blend using purified water. The wet mass thus obtained is further subjected to extrusion and spheronization and dried to yield the desired pellets.

An alternate method of processing also could be preparing the binder solution and then granulating the blend of the active along with the excipients to yield the wet mass which can be further followed by the extrusion spheronization process. The wet mass can be alternatively screened through the desired screen size and further spheronized to get the end pellets.
The size of the pellets can range from a size range of micro pellets to macro pellets depending upon the final dosage form in which the pellets have to be administered.
In another embodiment the pellets obtained from any of the processes above can be further film coated for aesthetic appeal or product differentiation.
Excipients essential for formulating said formulations can be added in case, the Cilostazol SR pellets are to be further formulated in dosage form such as tablets, capsules, solutions or suspensions.
Modifications of aforementioned embodiments and below mentioned examples in a desired manner readily apparent to a person skilled in art would be construed to fall within the scope and limit of this invention as defined by the appended claims.

Example 1:
Cilostazol SR Pellets 50% w/w Labe claim: Each 400 mg pellet contains 200 mg of Cilostazol Pellets size: 16- 20# Formula: Table 1 :

Sr.No Ingredients Qty
1 Cilostazol 50
2 Microcrystalline cellulose 33
3 Croscarmellose Sodium 15
4 HPMC E-5 1
5 Talc 1
6 Purified Water Q.S
Procedure:
1. Process for manufacturing of formulation of Example 1:
1. Mixing Cilostazol, microcrystalline cellulose, Croscarmellose sodium, hydroxypropylmethyl Cellulose and Talc.
2. Sifting the mixture of Step 1
3. Mixing the blend
4. Granulating the blend of Step 3 using purified water ;
5. Extruding the wet mass of Step 4 to form pellets;
6. Spheronizing the pellet of Step 5 at suitable speed, and
7. Drying the pellets of Step 6
The formulation thus obtained was subjected to dissolution testing using United States Pharmacopeia Type II dissolution apparatus at 75 rpm. The dissolution media used was 0.3% Sodium Lauryl Sulfate.

Dissolution was also carried out using 0.5% SLS+0.71% Sodium Chloride. The results of dissolution testing are presented in Table 2.
Results:
Dissolution: Table 2

Time Dissolution

(0.3% SLS) (0.5% SLS+0.71% NaCl)
1HR 6.70 4.5
2HR 10.60 7.70
3HR 13.90 11.20
4HR 21.6 0 15.60
6HR 31.70 25.30
8HR 41.10 37.30
10HR 53.70 49.90
12HR 66.50 62.0.
16HR 89.80 89.30
20 HR 93.60 89.70

Claims:
1. A sustained release pharmaceutical composition of Cilostazol in pellet form
comprising:
a. A therapeutically effective amount of active
b. Diluents which aid pelletization
c. 0% release rate controlling or sustaining agents.
2. The pharmaceutical composition as claimed in claim lvvhich is devoid of any sustaining or release controlling coating.
3. The pharmaceutical composition of claim 1, in which the Cilostazol containing pellets are manufactured using the process of extrusion-spheronization.
4. A pharmaceutical composition as claimed in the preceding claims which essentially comprise of active, atleast one diluent, atleast one disintegrant, atleast one binder and atleast one lubricant.
5. A pharmaceutical composition as claimed in the preceding claims which essentially comprises Cilostazol, Microcrystalline cellulose, Croscarmellose Sodium, Hydroxypropylmethyl cellulose and Talc.
6. A method of preparing a sustained release pharmaceutical composition of Cilostazol in pellet form wherein the core is prepared by the steps comprising: (a) blending a therapeutically effective amount of a medicament along with the
pelletization aiding diluents and excipients such that the solid mass equals to 100% when it is not film coated after pelletization.

(b) adding a granulating liquid to form a wet mass.
(c) passing the wet mass through art extruder to obtain an extrudate; and
(d) forming pellets from the extrudate by spheronization.

7. The method of manufacturing of Cilostazol sustained release pellets as claimed in preceding claims wherein the granulating liquid does not comprise of any solid content.
8. The method of manufacturing of Cilostazol sustained release pellets as claimed in preceding claims wherein the granulating liquid is Purified water.
9. A pharmaceutical composition of Cilostazol sustained release pellets as claimed in preceding claims wherein the pellets are further optionally film coated further or the uncoated or coated pellets are further filled into capsules or compressed to tablets.
10. A pharmaceutical composition of Cilostazol sustained release pellets as
claimed in preceding claims for suspension wherein the coated or uncoated
pellets are optionally dispensed with additional excipients and further
reconstituted for use with purified water.