INTRODUCTION:

Buccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming the disadvantages associated with the latter mode of dosing. Problems such as first pass metabolism and drug degradation in the harsh gastrointestinal environment can be circumvented by administering drug via buccal route. Moreover, the oral cavity is easily accessible for self medication and can be promptly terminated in case of toxicity just by removing the dosage form from buccal cavity. It is also possible to administer drugs to patients who cannot be dosed orally via this route.^1-4

The dizziness associated with vertiginous disorder is often accompanied with nausea and vomiting. Retention of the administered anti-emetic oral dose and its subsequent absorption during anti-emetic therapy is critically affected by recurrent emesis and various physiological processes like impaired gastric emptying and other GI disturbances. One such anti-emetic drug, domperidone after oral dosing undergoes extensive gastric and hepatic first pass metabolism resulting in low bioavaibality (15%) which therefore, may not minimize the rate of vomiting.⁵

In the present investigation, an attempt has been made to design efficacious and prolonged release mucoadhesive tablets of domperidone using various polymers to avoid first pass metabolism, to reduce dosing frequency and to improve patient compliance.

MATERIAL AND METHODS:

Materials:

Domperidone was obtained from Dr. Reddy’s Lab Hyderabad, HPMC K-4M and HPMC E-15LV (Nulife Pharmaceuticals, Pune) were used. Chitosan was obtained from Unichem Labs ltd., Mumbai.

Preparation of mucoadhesive tablets:

Mucoadhesive tablets of domperidone were prepared by direct compression techniques using different grades of polymer with varying concentration (Table1). The tablets were prepared using Carbopol 934P, HPMC K4M and HPMC E15LV as primary polymers and chitosan used as secondary polymer as a penetration enhancer.⁶ The effect of secondary polymer on drug release and mucoadhesion was studied. The tablets were compressed using 8mm flat faced punch on a single stroke punching machine.^7,8

Determination of physicochemical parameters:

Twenty tablets were weighed individually and the percentage weight was determined. Percentage deviation was calculated and checked for weight variation. Thickness was measured using vernier calipers. Five tablets of each formulation were taken and the amount of drug present in each tablet was determined. The surface pH of the tablets was determined in order to investigate the possibility of any irritation in the oral cavity. The tablets were kept in contact with simulated saliva fluid for 2h and pH was noted by bringing the electrode in contact with surface of the formulations.

Bioadhesive strength of the tablets were measured on a modified physical balance using method described by Gupta et al.⁹ Sheep buccal mucosa was used as model mucosal membrane and simulated saliva fluid as moistening fluid. (Fig 1)

Fig.1. Developed Balance for Determination of Detachment Stress.

Swelling studies:

The swelling properties of the tablets were evaluated by determination of % swelling. Each tablet was weighed (W₁₎ and immersed in a simulated saliva fluid at pH6.8 for predetermined times. After immersing the formulation for specified time, the tablets were wiped off to remove excess of surface water by using filter paper and weighed (W₂).^{10, 13}

% Swelling = (W₂) – (W₁₎ X 100

(W₁₎

Table I. Composition of buccoadhesive tablets

Ingre dients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Dom peri done	20	20	20	20	20	20	20	20	20
Chito san	90	60	120	90	60	120	90	60	120
Carb opo l934p	90	120	60	-	-	-	-	-	-
HPMC K4M	-	-	-	90	120	60	-	-	-
HPMC E15LV	-	-	-	-	-	-	90	60	120
Magnesium Stearate	01	01	01	01	01	01	01	01	01

In-vitro release studies:

In-vitro release studies of domperidone bioadhesive tablets were determined using USP Dissolution Testing Apparatus II (Paddle type). The dissolution test was performed using 500 ml of 6.8 phosphate buffer, at 37 ± 0.5°C at 50 rpm. Aliquot (5 ml) of the solution was collected from the dissolution apparatus hourly for 8 hours and were replaced with fresh dissolution medium. Aliquots were withdrawn at one hour interval from a zone midway between the surface of dissolution medium and the top of rotating paddle not less than 1 cm apart from the vessel wall.^11,12The aliquots were filtered, and the absorbance was measured at 283nm spectrophotometrically.

Fig. 2.FTIR Spectra of the optimized formulation (F4).

RESULTS AND DISCUSSION:

The average weight of the tablet was found to be 199mg to 203mg with the maximum % deviation of ±0.265 for all the formulation. The tablets showed thickness in the range of 1.20 to 1.50 mm (±0.34).

The percentage drug content of all the formulation was found to be 91 to 97% (±0.75). Thus the entire tablet complies with that of the standard.

Surface pH of all the formulation was found to be 5.9 to 6.4. These results reveal that all the formulation provide an acceptable pH in the range of salivary pH (5.5 to 7.0).It was also observed that they did not produce any local irritation to the mucosal surface.

Table 2 shows the mucoadhesive strength, swelling index and %matrix erosion of different formulations. The strength of tablet was dependent on the property of mucoadhesive polymers, which adheres to the mucosal surface and also on the concentration of polymer used.

The buccal tablets were prepared by using Carbopol 934P, HPMC K-4M and HPMC 15 LV as primary polymers. Chitosan was used as the secondary polymer. The buccal tablet containing polymers in various ratios were evaluated for the bioadhesive strength, swelling index and drug release in order to obtain an optimized formulation.

In the trial 200mg was set as target weight of single tablet. The polymers in the concentration of 80% were necessary to achieve 8 hrs bioadhesion. The decrease in the polymer concentration resulted in decrease in bioadhesive time. The primary and secondary polymer in the ratio of 1:1, 1:2, 1:3 were used for preparing tablets.

Fig. 3. Release Profile of the formulations F1, F2, and F3.

HPMC K- 4M and Chitosan in 1:1 ratio has been selected as optimum concentration magnesium stearate was selected was a lubricant.

The in-vitro release of domperidone from mucoadhesive tablet was found to vary according to the type and ratio of matrix forming polymer used. The release of domperidone was decreased with increasing concentration of Carbopol 934P, HPMC K-4 M and HPMC E-15 LV. The percentage of the drug released from the formulation F1, F2, and F3 was found to be 53.58%, 42.30%, 57.05% respectively containing different concentration of chitosan in combination with Carbopol 934P. The possible reason for reduction in the total release of drug may be due to the interaction between two oppositely charged bioadhesive polymers i.e. cationic chitosan and anionic Carbopol 934P.It may be expected that inter polymer complex between carboxylic group of chitosan will be formed and the dissolution rate retarded by complex formation which leads to decrease dissolution.¹⁴

Table II. Bioadhesive Strength of Various Mucoadhesive Tablets

Formulation code	Bioadhesive strength	Swelling index
F1	18.1±0.45	196±3.05
F2	25.7±1.21	150±5.29
F3	18.2 ±1.22	200±12.58
F4	23.39±1.80	145.2±5
F5	20.6±0.20	136.7±11.48
F6	17.5±0.50	193±10.14
F7	18.29±0.8	130±15.27
F8	16.9±0.65	105±7.63
F9	16.2±1.36	148±6.18

It was observed that, decreasing the concentration of polymer HPMC the release of the drug from the formulation become faster. Formulations F7 to F9 released their contents before the designated time period and hence were discarded from study. Formulation F4 shown statistically significant percentage release and was selected for further studies. Increasing the concentration of chitosan showed an increase percentage release due to its penetration enhancing effect.

Bioadhesion study:

The highest bond strength was possessed by the formulation F2 containing chitosan and Carbopol 934P in the ratio of 1:2. Decreasing the content of the Carbopol 934P resulted in decreased adhesion force. Increasing the concentration of chitosan increases the bond strength. The bond strength of F9 was followed by batch F6 which were composed of chitosan: HPMC K-15M and Chitosan: HPMC E-15 LV IN the ratio of 2:1.

Swelling Index:

Swelling index was determined with respect to time. The swelling index of the tablets was increased with increasing concentration of chitosan. The polymer absorbed large volumes of water rapidly and swells to its maximum hydrated size without dissolving in aqueous media. The uptake of water by HPMC is a slower process compared with chitosan. HPMC is a hydrophilic polymer which swells slowly to form a gel which then dissolves in the presence of water. The gelling property of this polymer will provide the binding strength to oppose bursting effect of chitosan. Hence the integrity of tablet was maintained for further period of time until most of HPMC was dissolved.

Fig.4. Release Profile of the formulations F4, F5, and F6.

Assessment of duration of bioadhesion:

The duration of bioadhesion decreased with decreasing concentration of HPMC. The duration of bioadhesion of the formulated bioadhesion tablets were determined and found to be around 8 hours except the formulation F5 and F8. Less duration of bioadhesion of F5and F8 may be due to lesser quantity of chitosan which might be insufficient to maintain the integrity of the formulations.

CONCLUSION:

The present work was aimed to develop the mucoadhesive drug delivery system for domperidone with prolonged effect and to avoid first pass metabolism. From the study, it is observed that formulation F4 was best in terms of drug release, bioadhesive performance and physicochemical properties.

Therefore it can be concluded that stable formulation could be developed by incorporating chitosan and HPMC K-4M in the ratio of 1:1 for the sustained release of domperidone from mucoadhesive tablet with adequate bioadhesiveness and swelling properties without the risk of mucosal damage.

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