DESIGN AND EVALUATION OF CHRONOTHERAPEUTIC PULSATILE DRUG DELIVERY SYSTEM OF CILNIDIPINE

At present scenario the drug regimen based on circadian rhythm is recently gaining much attention worldwide by researchers. Justification behind it is that, there are various diseases like asthma, hypertension, and arthritis show circadian variation that demand time scheduled drug release for effective drug action. A chrono delivery system, based on biological rhythms, is a state-of theart technology for drug delivery. The aim of present work is formulate and evaluate a press coated pulsatile release tablets of Cilnidipine using an admixture of hydrophilic polymer i.e. hydroxypropyl methyl cellulose (HPMC) and pH sensitive polymers (ethyl cellulose, eudragit S-100) in order to achieve a predetermined lag time for chronopharmacotherapy of Hypertension. Cilnidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function used for the treatment of hypertension. The tablets prepared were evaluated for different properties like bulk density, tapped density, Angle of repose and Carr’s index), hardness, thickness, weight variation, friability, drug content uniformity and in vitro drug release study.


INTRODUCTION
A pulsatile release profile is characterized by a lag time followed by rapid and complete drug release. Pulsatile drug delivery systems are designed according to the circadian rhythm of the body 1 . Chronomodulated system is also known as pulsatile system or sigmoidal release system related to biological rhythms. Circadian rhythm regulates many functions in human body like metabolism, physiology, behavior, sleep pattern, hormone production. Many diseases such as cardiovascular, asthma, peptic ulcer, arthritis etc. follow the body's circadian rhythm and shows circadian pattern 2 . These conditions could be taken by timing and adjusting the administration of drugs according to the circadian rhythm of the disease. These systems are designed in a manner that the drug is available at the site of action at the right time in the right amount 3 . Disease conditions where constant drug levels are not preferred but need a pulse of therapeutic concentration in a periodic manner acts as a push for the development of pulsatile drug delivery system. A time delayed release profile is characterized by a lag time followed by rapid and complete drug release 4 . Cilnidipine is the novel calcium antagonist accompanied with L-type and N-type calcium channel blocking function. Cilnidipine decreases blood pressure and is used to treat hypertension 5 . Due to its blocking action at the N-type and L-type calcium channel, Cilnidipine dilates both arterioles and venules, reducing the pressure in the capillary bed. Cilnidipine is vasoselective and has a weak direct dromotropic effect, a strong vasodepressor effect, and an arrhythmia-inhibiting effect 6 . Hypertension is the most powerful risk factor for the cardiovascular diseases, including stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic and peripheral arterial diseases. Morning hypertension is a condition characterized by high blood pressure (≥135/85 mm Hg) in the morning and controlled levels throughout the day 7 . Heart attacks and stroke usually occur in the morning because of morning hypertension. Between 4:00AM and noon, the body releases certain hormones ISSN: 2456-8058 that boost energy and increase morning alertness, but this also results in a sharp increase in blood pressure 8 . So for effective treatment such type of drug delivery system required which provide minimum amount of drug release at night highest at morning. Through pulsatile delivery system this type of release can be provide. Thus, this study focus on the development of press coated pulsatile tablets of Cilnidipine for providing the relief from hypertension deliver the drug at specific time as per pathophysiological needs of the disease and improvement of therapeutic efficacy and patient compliance.

MATERIALS AND METHODS
Cilnidipine was obtained from Swiss pharma ltd, Lagos, Nigeria. Lactose was obtained from Givanas Nigerial Ltd, microcrystalline cellulose, Crospovidone, Magnesium stearate and dicalcium phosphate were obtained from Chemiron International Limited, Lagos, Nigeria. HPMC, EC and talc were obtained from Avro Pharma Limited, Lagos, Nigeria Eudragit S 100 was obtained from Archy Pharmaceutical Nigeria Limited. All other chemicals and reagents used were either of analytical or pharmaceutical grades. Tablet Manufacturing Method 1. Formulation of core tablets by direct compression The core tablets containing Cilnidipine were prepared by using the composition shown in Table 1. All excipients were mixed for 25 min and passed through a 40 mesh size sieve and directly compressed in to 70 mg tablets using 6 mm round flat punches on a rotary tablet machine 9 .

Preparation of press coated pulsatile tablets
The core tablets were press coated with polymer blend. Polymer blend was composed of HPMC, EC and Eudragit S 100 in different concentrations. Half of the coating material was placed in the die cavity, the core tablet was carefully positioned in the centre of the die and cavity was filled with the other half of the coating material. Coating materials was compressed around the core tablet using of 10mm punch 10 . The compositions are as shown in Table 2.

. Determination of angle of repose
The angle of repose of blend was determined by the funnel method. The accurately weight blend was taken in the funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the blend. The blend was allowed to flow through the funnel freely on to the surface 11 .

Determination of bulk density and tapped density
Both loose bulk density (LBD) and tapped bulk density (TBD) were determined. A quantity of 2gm of blend previously shaken to break any agglomerates formed, then it was introduced in to 10 ml measuring cylinder. After that the initial volume was noted and the cylinder was allowed to fall under its own weight on to a hard surface from the height of 2.5 cm at second intervals.
Tapping was continued until no further change in volume was noted 12 .

Determination of Compressibility Index
The Compressibility Index of the blend was determined by Carr's compressibility index. It is a simple test to evaluate the LBD and TBD of a powder and the rate at which it packed down 13 . The formula for Carr's Index is as below:

Hausner's Ratio
Hausner's Ratio was determined by following equation 14 : B. Post-compressional studies: 1. Uniformity of thickness Thickness of Cilnidipine tablets were measured using a calibrated dial calipers. Three tablets of each formulation were picked randomly and dimensions determined. It is expressed in mm and standard deviation was also calculated 15 .

Weight variation test
Twenty Cilnidipine tablets were selected randomly from each batch and weighed individually to check for weight variation 16 .

Hardness test
Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. Hardness of Cilnidipine tablets was determined using a validated dial type hardness tester. It is expressed in kg/cm 2 . Three tablets were randomly picked from each batch and analyzed for hardness. The mean and standard deviation were also calculated 17 .

Friability
Twenty Cilnidipine tablets were weighed and placed in the Roche friabilator and apparatus was rotated at 25 rpm for 4 minutes 18 . After revolutions the tablets were weighed again. The percentage friability was measured using the formula, 0.45μ membrane. The absorbance was measured at 291 nm after suitable dilution 17 .

Lag time of coated tablets
The lag time of pulsatile release Cilnidipine tablets is defined at the time when the outer coating starts to rupture. It was determined visually by using USP dissolution testing apparatus II (900ml buffer 37.0± 0.5°C, 50 rpm). Coated Cilnidipine tablets were evaluated for lag time in pH 6.8 and 7.4 phosphate buffer respectively. Coated tablets were placed in 900 ml of above mentioned buffers, agitated at 75 rpm and maintained at 37±0.5 0 C. The time taken for outer coating to rupture was monitored and reported as lag time.

Dissolution studies of the coated tablets
Drug release study of coated Cilnidipine tablets was carried out using USP XXIII dissolution test apparatus I. Initially tablets were placed in 900 ml of 0.1 N HCl for 2 hours maintained at 37±0.5 0 C, 75 rpm followed by pH 6.8 phosphate buffer for 3 hours and pH 7.4 for 5 hours. Aliquots of predetermined quantity were collected manually at definite time intervals replacing with fresh buffer to maintain sink condition and analyzed for drug content using a UV-visible spectrophotometer at λ max of 291 nm 11 .

RESULTS AND DISCUSSION
In the present study, an attempt was made to design pulsatile drug delivery system of Cilnidipine for the effective treatment early morning hypertension. The pulsatile drug release tablets were prepared by compression coating method and consisted of two different parts: a core tablet, containing the active ingredient and an erodible outer coating layer of polymer. Based on preliminary trials, the core tablets of Cilnidipine were prepared by using different ingredients including microcrystalline cellulose, crospovidone, lactose, magnesium stearate, dicalcium phosphate and talc by direct compression technique. Results of the pre-compression parameters performed on the blend for batch ( Generally, compressibility index values up to 15% results in good to excellent flow properties. To obtain desired lag time before drug release, the core tablets were coated with varied ratio of HPMC, EC, Eudragit S 100 polymers to achieve barrier properties by compression coating technique. The compression coated tablets were evaluated for weight variation, thickness, hardness, friability, drug content and lag time. The hardness of tablets of all the formulations ranged between 4.93±0.08 to 5.96±0.11 kg/cm 2 . The formulation CPT1 showed a comparatively high hardness value of 5.96±0.11 kg/cm 2 . This may be due to presence of higher amount of ethyl cellulose, which is generally responsible for more hardness.  ethylcellulose, it may be due to high solubility of EC at pH 6.8. This polymer characteristic gives to the matrix a quick gel erosion rate and a high erosion degree of the overall system. Maximum drug release 94.39% was shown by the tablets of batch CPT1 and lowest release 73.54% by the tablets of batch CPT3 in the 10 hrs studies.

CONCLUSION
A satisfactory attempt was made to develop pulsatile release Cilnidipine tablets using pH sensitive polymers (ethyl cellulose, Eudragit S-100) and swellable hydrophilic polymer (HPMC) to mimic the circadian rhythm. Prepared pulsatile drug delivery systems were evaluated for hardness, friability, weight variation, drug content uniformity, in vitro drug release. Based on different evaluation parameters formulation of batch CPT1 was concluded as an optimum formulation. The system released the drug rapidly after a certain lag time due to the rupture of the polymers film. Pulsatile release Cilnidipine tablets can be taken at bedtime so that the content will be released in the morning hours i.e. at the time of symptoms. From the above results, it can be concluded that the prepared pulsatile drug delivery system can be considered as one of the promising formulation technique for chronotherapeutic management of hypertension.

AUTHOR'S CONTRIBUTION
The manuscript was carried out, written, and approved in collaboration with all authors.