Formulation and Evaluation of Gastro-retentive Drug Delivery Systems of Cinnarizine

Introduction

Out of all drug delivery systems available, oral drug delivery is the popular route of administration.¹ Recent studies have shown that a novel drug delivery system prolongs the gastric residence time and also predicts the release profile in GI tract by gastro retention techniques and these systems are called ‘Gastro retentive systems’ (GRDDS).² These systems increase the gastric residence time, bioavailability and also improve the solubility of the drugs insoluble in high pH environment.^3,4

Cinnarizine is an anti-histamine drug and calcium channel blocker, which is also a piperazine derivative used for treatment of vertigo and vomiting. It has poor bioavailability and has a half-life of 3.4 hours. Cinnarizine solubility in alkaline pH is very low. It is a labyrinthitis sedative which acts by interfering the signal transmission between the inner ear and hypothalamus by its calcium blocking ability.^5,6 Since drugs like cinnarizine have low solubility and low dissolution rate in gastrointestinal tract, this causes the main problem for systemic circulation after oral administration. On

this basis, cinnarizine was selected for sustained floating release system. In the present study, using synthetic and natural polymers, cinnarizine effervescent floating tablets were formulated with the aim of achieving 24- hour drug release and floating.

Materials and Methods

Materials

Cinnarizine was procured from Seva Fine Chem., Ahmedabad. Hydroxypropyl Methylcellulose K5M (HPMC K5M) and polyox were obtained from The Dow Chemical Company and sodium carboxy methyl cellulose, sodium bicarbonate, guar gum, citric acid, xanthan gum, magnesium stearate were purchased from S.D. Fine Chem. Pvt. Ltd., Mumbai

Method

Effervescent floating tablets of cinnarizine were prepared by direct compression method.

Preparation of cinnarizine floating tablet

Sufficient quantities of drug, polymers with all other excipients were weighted and passed though #44 sieve (355 mm) as mentioned in Table 1 and these were mixed well in a polyethylene bag. This mixture was blended with 1% magnesium stearate and talc. Then the granules were compressed into tablets using “Remik mini press – 1” tablet punching machine (9 mm diameter).

Evaluation of powder blends ^7-14

Preformulation studies such as bulk and tapped density, angle of repose, compressibility index and Hausner’s ratio were evaluated and results are tabulated in Table 2.

Evaluation of floating tablet formulations ^15,16

Post-compression parameters such as friability, thickness and hardness were evaluated using Roche Friabilator, Vernier calipers and Monsanto hardness tester, respectively. The results are tabulated in Table 3.

Drug content uniformity

Tablet containing 50 mg of Cinnarizine was taken in 100 mL volumetric flask and the volume was made up using pH 1.2 buffer. Dilution was done using 1 mL of stock solution with pH 1.2 in 100 mL volumetric flask. Schimadzu UV-visible double beam spectrophotometer was used to estimate the drug content at 253 nm in triplicates.

In-vitro dissolution studies

The tablets were evaluated using USP Apparatus II, Paddle type for dissolution. About 900 mL of pH 1.2 buffer was used as the dissolution medium and the paddle speed was maintained at 50 RPM and the temperature at 37±0.5ºC, respectively. At each pre-determined time intervals, 5 mL samples were withdrawn and replaced with fresh buffer. The samples were diluted for determining the drug release using Schimadzu UV-visible double beam spectrophotometer at 253 nm and the experiments were conducted in triplicates. The graph was plotted against the % drug release vs time to study the release profile of the drug.

In-vitro buoyancy studies

The tablets were evaluated for the time required to rise and float on the surface using pH 1.2 buffer simulated gastric fluid. The floating lag time is tabulated in Table 3.

Analysis of release mechanism ^17,18

Tables 4a and 4b present the percentage cumulative release profile of F1 to F14 formulations. The release mechanisms such as Zero order, First order, Higuchi and Kosermeyer model for formulated cinnarizine floating tablets were determined for formulation F5. The results are tabulated in Table 5.

Results

The cinnarizine floating tablets F1 to F14 were formulated by using different types of polymers like sodium carboxymethyl cellulose (CMC), guar gum, xanthan gum, guar, polyox and HPMC K5M along with effervescent materials such as sodium bicarbonate and citric acid. All the pre-formulation parameters and the post formulation parameters were within the limits. The floating lag time varied between 27.23±0.31 to 158.13±0.12. In vitro release pattern and total floating time to 24 hour with optimum lag time was observed. Thus, the drug with HPMC K5M in ratio of 1:2 was found as the optimized formula.

Discussion

The measured hardness of floating tablets ranged between 4 to 5 kg/cm2 . The friability was less than 1% in all formulations ensuring that the tablets were mechanically stable. All the tablets passed weight variation test as the percent weight variation was within the pharmacopoeia limits of ±5% of the weight range.

The release profiles of the formulations are shown in Figure 1. All the formulations showed floating lag time ranging between 27.23±0.31 sec to 158.03±0.12 sec. All the formulations maintained their integrity but formulation F4, F7 and F8 remained buoyant for 20, 16 and 12 h, respectively and showed drug release within those hours. Other formulations F1, F2, F3, F9, F10, F11, F12, F13 and F14 remained buoyant for 24 h, but formulation F5 showed 98.75% of drug release at the end of 24 h. So, formulation F5 was selected as the optimized formulation as all the other formulations showed drug release for more than 24 h.

For the optimized formulation F5, the model that fits the data was zero order model (R2 = 0.993) and n value was found to be 1.013 indicating that it follows case II transport as shown in Table 5. Hence it was concluded that the floating tablets of Cinnarizine (F5) provided slow and complete drug release spread over 24 h.

Conclusion

The tablets of cinnarizine were prepared for gastroretentive floating sustained release by direct compression based on effervescent approach. HPMC K5M, polyox, xanthan gum, sodium CMC, and guar gum were used as polymers. Citric acid and sodium bicarbonate were used as gas-generating agents, which also influenced the floating time. As the drug-polymer ratio increased, the release of the drug decreased. Based on mechanism of drug release, F5 was found to be the best formulation as zero order (R2 = 0.993) with 98.75% by the end of 24 hours.

Conflict of Interest

Nil

Acknowledgement

The authors are thankful to the management of Nargund College of Pharmacy, Bengaluru, for giving the opportunity and providing required necessary facilities for carrying out this work in their college