Introduction

Cancer chemotherapy causes lot of adverse effects, of which nausea and vomiting is prime one. This can be clearly seen with model anticancer drug cisplatin, which is first line drug in many types of cancers. Hence anti emetic drugs like ondansetron, granisetron are administered one hour prior to the administration of anticancer drug ₁ . But this becomes a major patient non compliance in the case of children, elderly and bed ridden patients for whom swallowing tablets causes inconvenience ₂ . Among the dosage forms developed to facilitate ease of medication, the rapid disintegrating tablet (RDT) is one of the most widely employed commercial products ₃ . Hence in this article an attempt is made to improve patient compliance by formulating antiemetic drug granisetron in the form of mouth dissolving tablets.

Mouth dissolving tablets get disintegrate within one minute due to incorporation of super disintegrants ₄ . Hence onset of action can be minimized. Also first pass effect of drugs can be minimized significantly due to pre gastric absorption through buccal, sublingual routes. Hence oral bioavailability is also increased. The major disadvantage of this system is unpalatable and bitter drugs should be taste masked properly. This can be done by either adding a sweetening agent or by coating with a polymer ₅ .

Many technologies have come up for fast dissolve tablets like Zydis, Orasolv, Durasolv, Flashtab and Wowtab ₆ . Technologies like Zydis and Flashtab have resulted in tablets with very low disintegration time, but poor mechanical strength. On the other hand Orasolv, Durasolv have resulted in better mechanical strength, but longer disintegration times ₇ .

Materials And Methods

Granisetron was obtained as a gift sample from Health biotech India pvt ltd, chandigarh. Excipients for tablet were gifted by Signet chemical corporation, Mumbai. All solvents used were of analytical grade and were purchased from S.D. Fine chemicals, ltd, Mumbai.

Granisetron is an anti emetic, generally prescribed in cancer chemotherapy to control nausea and vomiting. It is an selective 5 HT-3 antagonist and binds to receptor and stops vomiting ₈ .

Formulation of mouth dissolving tablets:

The tablets were prepared by wet granulation technique ₉ . Granisetron along with diluent were granulated with PVP K-32 in Isopropyl alcohol. The wet mass is screened through 16 mesh and dried at 60°c for 30 min. The dried granules were then screened through 40 mesh. Finally talc, magnesium stearate, aerosol and flavour were added to the granules and blended in twin shell blender for 30 min. All the excepients were passed previously from 60 mesh. The blend was then compressed on a Cadmach single-stroke punch machine. The different optimized formulations are shown in Table 1.

Figure 1

Table 1: Formulation of granisetron mouth dissolving tablets with various super disintegrants.

Evaluation of mouth dissolving tablets:

The tablets were evaluated for various quality control parameters like appearance, texture ₁₀ , taste ₁₁ , mouth feel, hardness ₁₂ , friability ₁₃ , weight variation, disintegration time ₁₄ , drug content, and drug release ₁₅ . Hardness of the tablets was determined by Monsanto hardness tester. Friability was determined by Roche's friabilator. The results of evaluation of different formulations are depicted in table 2.

Figure 2

Table 2: Evaluation of granisetron mouth dissolving tablet formulations

Wetting Time and Water Absorption Ratio ₁₆ :

A piece of tissue paper folded twice was kept in a culture dish (internal diameter 5.5 cm) containing ~6 mL of purified water. A tablet having a small amount of amaranth powder on the upper surface was placed on the tissue paper. The time required to develop a red color on the upper surface of the tablet was recorded as the wetting time. The same procedure without amaranth was followed for determining the water absorption ratio. The wetted tablet was weighed and the water absorption ratio, R, was determined according to the following equation, R = {(W a ? W b) W b} × 100 where, W_b and W_a were the weights of the tablet before and after study.

Drug content is determined by placing 20 tablets in mortar and crushed. The quantity of powder equivalent to 1mg of granisetron was taken in a 100ml volumetric flask, and dissolved in distilled water. Five milliliters of the solution is taken and filtered. Then it is suitably diluted with distilled water and assayed for drug content at 210 nm, using double beam UV/Vis spectrophotometer (Shimadzu, model-1601).

Disintegration testing (6 tablets) was performed by using modified method. After placing the tablet in #10 basket, the test was carried out in 25 ml distilled water at temperature of 370 and agitation speed of 40 shakes/min, using a mechanical shaker (Neolab reciprocating shaker). In vitro dissolution studies were carried out using USP XXIII Dissolution apparatus I (basket type). The release profile was studied in both phosphate buffer (pH 6.8) and acid buffer (pH1.2).

Results

The different formulations of granisetron were mainly varied in the ingredients used for disintegration. In F1, F2, F3 super disintegrants were used, and in F4 Micro crystalline cellulose (Avicel PH 101) is used. All the tablets showed smooth texture. Weight variation and friability was within limits. Hardness of all tablets was between 3-4 kg/cm ² . Due to addition of aspartame and saccharin sodium, all tablets showed non bitter taste.

By addition of flavour, the mouth feel was pleasant. In vitro disintegration time of all the tablets was within 60 seconds. Drug content of all the formulations was within limits and drug release was more than 80% within 30 min. The release profile of granisetron from different formulations in phosphate buffer (pH 6.8) (Fig 1) and acid buffer (pH 1.2) (Fig 2) are depicted.

Figure 3

Figure 1: Cumulative percent release of Granisetron from various formulations at pH 6.8

Figure 4

Figure 2: Cumulative percent release of Granisetron from various formulations at pH 1.2

Discussion

The main aim of formulating mouth dissolve tablets was to achieve instantaneous dispersion without the aid of water. By seeing in vitro dispersion time and disintegration, it can be clearly stated that, the objective has been achieved. Of all the formulations, F4 showed a little bit longer disintegration time, because it lacked super disintegrant in the formulation. Due to the presence of super disintegrants, water uptake is good, hence wetting time and water absorption ratio are high, thereby leading to faster disintegration. Above all, most of the formulation showed 80% drug release within 30 min, hence decreasing the lag time for absorption. By seeing this, it can be clearly seen that there is more chance for pre gastric absorption, thereby reducing first pass metabolism. Therefore overall oral bioavailability can be increased. As the target patients are children and elderly, the addition of sweeteners and flavour increased the appeal and patient compliance.

Acknowledgement

Correspondence to

Dr R C Doijad, Professor and Head, Department of Pharmaceutics, KLES College of pharmacy, Belgaum, Karnataka, India – 590 010. Phone : +91 9845178402 e-mail : rcdoijad1@rediffmail.com