INTRODUCTION:

Various attempts have been made to prolong the retention time of dosage forms in the stomach and one of the method is to prepare device that remains buoyant in the stomach content due to its lower density than that of the gastric fluids. Gastro retentive system can remain in the gastric region for several hours and hence significantly prolong the gastric residence time of drugs. Prolong gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in a high pH environment. It has application also for local drug delivery to the stomach and proximal small intestines. Gastroretention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits for patients.

Domperidone is a synthetic benzimidazole compound that acts as a dopamine D2 receptor antagonist. Domperidone is also used as a prokinetic agent for treatment of upper gastrointestinal motility disorders.

It continues to be an attractive alternative to metoclopramide because it has fewer neurological side effects. Patients receiving Domperidone or other prokinetic agents for diabetic gastropathy or gastroparesis should be also managing a diet, lifestyle and other medications to optimize gastric motility.

After oral administration, Domperidone is rapidly absorbed from the stomach and the upper part of the GIT with fewer side effects. The maximum plasma concentration occurs within 30-60 min. and plasma half life ranges from 5-7 hrs. Reported oral bioavailability of Domperidone is about 15% because of solubility characteristics. It is a weak base with good solubility in acidic pH but significantly reduced solubility in alkaline medium. Such a weak base, formulated as an oral sustained release dosage form is exposed to environments of increasing pH with subsequent precipitation of poorly soluble free base within the formulation that is no longer capable of being released from the formulation. Due to this challenge to improve the bioavailability of the drug, to reduce the dosing frequency of drug and to increase the residence time in the stomach floating drug delivery system can be useful.

In the present study floating tablet of Domperidone were prepared by using Hydrophilic sustained release polymers, hydrophobic floating enhancer and gas-generating agent.

MATERIALS AND METHODS:

Materials:

Domperidone was received as a gift sample from Vamsi Lab Limited, Solapur. HPMC K100M, Xanthan gum, Dicalcium phosphate and Sodium bicarbonate were purchased from Loba chemie Pvt. Ltd., Mumbai. Ethyl cellulose were purchased from sigma chemical Mumbai. Magnesium stearate was purchased from Research Lab, Mumbai. Aerosil purchased from Sisco Research Laboratory, Mumbai and Hydrochloric acid from Fine-Chem Ltd, Ahmedabad. All other ingredients were of laboratory grade.

Methods:

Preparation of Floating Tablets of Domperidone:

The composition of different formulation of Domperidone floating tablets is shown in Table 1.Effervescent Floating tablets containing 30 mg Domperidone were prepared by direct compression technique using various concentrations of polymers. The ingredients HPMC K 100M, Xanthan Gum, Ethyl cellulose were weighed accurately and passed through sieve no.60 and mixed for 10 min Then except magnesium stearate all other ingredients were blended uniformly in glass mortar. Magnesium stearate was added as a lubricant and further mixed 2-3 min. Whole bulk of powder was then mixed thoroughly for 15 min. The tablets were compressed using Rotary tablet machine (Fluid pack mini press). The weights of the tablets were kept constant by adding Dicalcium phosphate as filler for all formulations. The tablets were round and flat with an average diameter of 09 mm and a Thickness of 2.02 ± 0.02 to 1.99 ± 0.02mm.

Evaluation of Powder:

The flow properties of powder (before compression) were characterized in terms of angle of repose, flow rate, Carr’s index and Hausner ratio. For determination of angle of repose (θ), the powder were poured through the walls of a funnel, which was fixed at a position such that its lower tip was at a height of exactly 2.0cm above hard surface. The powder was poured till the time when upper tip of the pile surface touched the lower tip of the funnel. The tan^-1 (height of the pile / radius of its base) gave the angle of repose. Bulk density (ρb), Tapped density (ρt), Hausner ratio (HR) and Carrs index (IC) were calculated by pouring the powder gently through a glass funnel into a graduated cylinder cut exactly to 10 ml mark. Excess powder was removed using a spatula and the weight of the cylinder with pellets required for filling the cylinder volume was calculated. The cylinder was then tapped from a height of 2.0cm until the time when there was no more decrease in the volume.

Evaluation of Floating Tablets:

The prepared floating tablets were evaluated for Uniformity of weight using 20 tablets, Hardness (Monsanto tester), Friability using 10 tablets (Roche type friabilator), Drug content, In vitro buoyancy and In vitro dissolution studies. The results are expressed as mean ± S.D. (n=3). The drug content in each formulation was determined by triturating 20 tablets and powder equivalent to 10mg was added in 100ml of 0.1N hydrochloric acid, followed by stirring for 20 minutes on sonicator. The solution was filtered through a 0.45μ membrane filter. The resulting solution further diluted suitably and the absorbance was measured spectrophotometrically at 284nm using 0.1N hydrochloric acid as blank. The in vitro buoyancy was determined by floating lag time, per the method described by Rosa et al. The tablets were placed in a 100 ml beaker containing 0.1N hydrochloric acid. The time required for the tablet to rise to the surface and float was determined as floating lag time. The duration of time the dosage form constantly remained on the surface of medium was determined as the total floating time. The release rate of Domperidone from floating tablets was determined using United States Pharmacopoeia (USP) Dissolution Testing Apparatus 2 Paddle method (DT 6D, Lab India, Mumbai). The dissolution test was performed using 900 ml of 0.1N hydrochloric acid, at 37 ± 0.5°C and 50 rpm. A sample (05 ml) of the solution was withdrawn from the dissolution apparatus hourly for 12 hrs. and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45μ membrane filter. Absorbance of these solutions was measured at 284 nm using a UV/Visible double-beam spectrophotometer (V-550, Jasco, Japan). Cumulative percentage drug release was calculated using an equation obtained from a standard curve.

RESULTS:

Flow Properties of Powder:

The powders prepared for compression of floating tablets were evaluated for their flow properties (Table 1). Angle of repose was in the range of 19.00± 0.62 to 24.30±0.13

Flow rate ranged between 0.81±0.03 to 1.27±0.09gm/min.Bulk density ranged between 0.81±0.03 to 1.27±0.09 gm/cm3. Tapped density ranged between 0.47±0.01 to 0.62±0.04 gm/cm3 .Carr’s index was found to be 7.50±0.28 to 9.75±0.62 and Hausner ratio ranged from 1.041±0.11 to 1.108±0.007 for powders of different formulations. These values indicate that the prepared powders exhibited good flow properties.

Evaluation of Floating Tablets:

The floating tablets of Domperidone were prepared by effervescent technique using hydrophilic polymer HPMC K100M, Xanthan gum, Gas generating agent Sodium bicarbonate and hydrophobic floating enhancer Ethyl cellulose. The magnesium stearate was added as a lubricant, Aerosil as a glidant and Dicalcium Phosphate was added as filler. The compositions of various batches were given in Table No. 2. The weight of the tablet varied between 174.5 to 176 mg for different formulations with low standard deviation values, indicating uniformity of weight. The variation in weight was within the range of ±7.5% complying with pharmacopoeial specifications. The hardness for different formulations was found to be 5 kg/cm² indicating satisfactory mechanical strength. The friability was below 1% for all the formulations, which is an indication of good mechanical resistance of the tablet. The drug content varied between 99.23± 1.02 to 101.27± 0.23 indicating content uniformity in the prepared batches. Floating lag time was in range 110 second to 60 second. Duration of floating was upto 12 hrs. In vitro drug release tests of these tablets indicated sustained release of domperidone and 94.986 – 99.775% released at the end of 12h.

DISCUSSION:

The present work was formulation and evaluation of an oral floating matrix tablet of Domperidone. The investigation aims to develop floating tablets of Domperidone with a view to prolong the residence time within the GI tract with sustained release of drug. The flow properties of powder and evaluation test of tablets were comply with standard and showed good results.

In-vitro buoyancy study showed that Batch S1, S4, S7 contain less amount of ethyl cellulose and more of the xanthan gum concentration thus the results showed that there is decrease in floating lag time Sodium bicarbonate was added as a gas-generating agent. Sodium bicarbonate induced carbon dioxide generation in presence of dissolution medium (0.1 N hydrochloric acid). It was observed that the gas generated is trapped and protected within the gel, formed by hydration of polymer (HPMC K100M), thus decreasing the density of the tablet below 1 and tablet becomes buoyant. The tablet swelled radially and axially during in vitro buoyancy studies. As the concentration of HPMC K100M constant and concentration of xanthan gum increases then the drug retardation increases. Hydrophobic floating enhancer Ethyl cellulose works as a dissolution retardant being insoluble in gastric pH. As compared to xanthan gum ethyl cellulose retarded more drug release. The formulation was optimized on the basis of floating ability, matrix integrity and in-vitro drug release. The resulting formulation produced robust tablets with optimum hardness, consistent average weight and low tablet friability. In vitro drug release tests of these tablets indicated sustained release of domperidone and 94.986 – 99.775% released at the end of 12h. In dissolution study of all formulation it was observed that by increasing concentration of polymer and increasing viscosity of polymer, rate of drug was retarded .Comparative dissolution profile shown that all batches given sustained drug release profile. All formulations remained floating in In vitro evaluation. Batch S ₆ showed 99.77 % drug release at end of 12 hrs. Other batches showed drug release less than Batch S₆. Batch S₆contained Xanthan gum and ethyl cellulose in proportionate manner so tablet showed floating on 12 hrs and drug release was retarded.

CONCLUSION:

The effervescent-based floating drug delivery was a promising approach to achieve in vitro buoyancy. The addition of gel-forming polymer (HPMC K100M), Hydrophilic Polymer Xanthan Gum, Gas-generating agent sodium bicarbonate and Hydrophobic Polymer Ethyl Cellulose was essential to achieve in vitro buoyancy. The drug release from the tablets was sufficiently sustained.

Table no1 Evaluation of Powder

Batch	Angle of Repose	Flow rate g/min	Bulk Density g/cm3	Tapped Density g/cm3	Carr’s Index g/cm3	Housner’s Ratio
S1	24.30±.0.13	1.14±0.05	1.14±0.05	0.49±0.01	8.1±0.35	1.087±0.002
S2	23.95±0.24	1.08±0.05	1.08±0.05	0.53±0.02	7.50±0.28	1.081±0.003
S3	22.90±0.40	1.23±0.03	1.23±0.03	0.56±0.02	9.62±0.94	1.041±0.11
S4	23.10±0.35	0.99±0.06	0.99±0.06	0.51±0.04	8.47±0.46	1.092±0.006
S5	21.62±0.20	1.10±0.05	1.10±0.05	0.58±0.03	9.75±0.62	1.108±0.007
S6	22.68±0.65	1.27±0.09	1.27±0.09	0.62±0.04	9.68±0.46	1.100±0.007
S7	23.93±0.45	0.81±0.03	0.81±.03	0.47±0.01	8.45±0.26	1.092±0.003
S8	23.52±0.52	0.98±0.01	0.98±0.01	0.54±0.04	9.17±0.66	1.094±0.019
S9	19.00±0.62	0.92±0.04	0.92±0.04	0.60±0.01	8.30±0.14	1.090±0.001

Table 2. Composition of Floating Tablets of Domperidone

Ingredients mg/tablet	S1	S2	S3	S4	S5	S6	S7	S8	S9
Domperidone	30	30	30	30	30	30	30	30	30
HPMC 100M	30	30	30	30	30	30	30	30	30
Xanthan gum	30	30	30	40	40	40	50	50	50
Sodium bicarbonate	15	15	15	15	15	15	15	15	15
Ethyl Cellulose	15	30	45	15	30	45	15	30	45
Aerosil	1.75	1.75	1.75	1.75	1.75	1.75	1.75	1.75	1.75
Magnesium stearate	1.75	1.75	1.75	1.75	1.75	1.75	1.75	1.75	1.75
Dicalcium Phosphate	51.5	41.5	31.5	46.5	36.5	26.5	21.5	11.5	1.50

Table 3. Physico-Chemical Characterization of Domperidone Floating Tablets

Code	Uniformity of Weight (mg)	Friability (%)	Drug Content (mg)	Floating Lag Time (S)	Floating Duration (hrs.)	% Avg Drug release
S1	175.2	0.93 ± 0.01	101.0 ± 1.21	110 ± 2	08	96.28±0.24
S2	174.9	0.84 ± 0.04	100.13 ± 0.33	82 ± 6	10	98.28±0.40
S3	175.9	0.57 ± 0.06	100.05 ± 0.75	71 ± 2	>12	98.91±0.81
S4	175.0	0.69 ± 0.04	99.39 ± 0.66	100 ± 2	10	96.08±0.81
S5	175.2	0.85 ± 0.03	100.22 ± 1.20	75 ± 5	>12	98.49±0.58
S6	176.0	0.49 ± 0.04	101.27 ± 0.23	65 ± 5	>12	99.75±0.16
S7	175.2	0.82 ± 0.02	99.88 ± 0.22	90 ± 4	11	97.70±0.34
S8	175.6	0.74 ± 0.03	99.232 ± 1.02	73 ± 3	>12	95.71±0.30
S9	174.5	0.52 ± 0.03	99.42 ± 0.45	60 ± 6	>12	94.98±0.38