INTRODUCTION:

Most of the orally administered dosage forms have several physiological limitations, such as GI transit time, incomplete drug absorption due to incomplete release of drug from the devices and too short residence time of the dosage forms in the absorption region of GI tract. To overcome these limitations many attempts have been made by scientists by designing various drug delivery systems. Among these systems, Floating drug delivery systems (FDDS) is one of the approaches which remain buoyant due to their lower density that that of the GI and intestinal fluids. Both single and multiple unit systems have been developed^1,2

Prolonged gastro retention of the therapeutic moiety may offer numerous advantages, including improvement of bioavailability, therapeutic efficiency and possible reduction of dose^3,4,5. It has been reported that prolonged local availability of antibacterial agents may augment their effectiveness in treating H. Pylori infections⁶.

FLOATING DRUG DELIVERY SYSTEMS (FDDS)

FDDS have a bulk density lower that gastric fluid and thus remains buoyant in stomach for prolonged period of time without affecting gastric emptying time. They are also referred to as hydro dynamically balanced systems (HBS) as they are able to maintain their low density. Based on mechanisms of floating, two different technologies i.e., Effervescent FDDS and Non-effervescent FDDS were attempted to release drug. Incase of effervescent systems, when they reach he stomach CO₂is liberated by the acidity of gastric content and is entrapped in jellified hydro colloid. When the liberated gas is expelled from the dosage form it creates pores through which water can easily pass and helps in wetting of the polymers. The CO₂ generated compounds like sodium bicarbonate, calcium carbonate, citric acid/tartaric acid mixtures can be used^7-10.

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of less than 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form.

Atorvastatin calcium is a HMG-CoA reductase inhibitor used in the treatment of hyperlipidaemia¹¹. It has a oral bioavailability of less than 12%. It also undergoes high first pass metabolism. It is highly soluble in acidic pH and absorbed more in the upper part of the GIT¹². In order to improve the absorption and its oral bioavailability, we have attempted to formulate a floating drug delivery systems using Atorvastatin calcium as the model drug with HPMC K4M and Ethyl cellulose as polymers.

MATERIALS AND METHODS:

Materials

Atorvastain calcium was obtained as a gift sample from M/s. Caplin point, Pondicherry. HPMC K4M, Ethyl cellulose was purchased from Merck Chemicals, Germany. Other reagents and solvents used were of analytical grade

Methods

1. Preparation of Floating tablets by Melt granulation technique

Required quantity of bees wax was weighed and melted in a large china dish over a water bath. The drug was added to the molten wax and mixed well. Previously weighed quantities of HPMC K4M, Ethyl cellulose and sodium bi carbonate were added to the drug-wax mixture and mixed well. After thorough mixing the china dish was removed from water bath and cooled. The coherent mass was then scrapped from the china dish and was passed through sieve no.60. the granules were then lubricated with talc and magnesium stearate was added. The lubricated granules were then passed through sieve no.100. The granules were then compressed using a single punch tablet machine (Cadmach, Ahmedabad)

TABLE-1: Formulation

Ingredients	F1	F2	F3	F4
Atorvastatin Calcium	40mg	40mg	40mg	40mg
HPMC K4M	40mg	30mg	20mg	10mg
Ethyl cellulose	0	10mg	20mg	30mg
NaHCO3	30mg	30mg	30mg	30mg
Beeswax	40mg	40mg	40mg	40mg
Mag. Stearate	5mg	5mg	5mg	5mg
Talc	5mg	5mg	5mg	5mg

2. Evaluation of granules

Angle of repose

Flow property of the granules was evaluated by determining the angle of repose and the compressibility index. Static angle of repose was measured according to fixed funnel method and free standing cone method of Banker and Anderson¹³. The angle of repose was calculated using the equation, Tan θ = h/r ….(1) where is the angle of repose.

Bulk density

Loose bulk density (LBD) and Tapped bulk density (TBD) were determined for the prepared granules. LBD and TBD was calculated using the formula,

LBD = Wt of Powder / Vol. of Powder …………..(2)

TBD = Wt of Powder / Tapped Vol. of Powder… .(3)

Compressibility Index

Carr’s Compressibility Index¹⁴ for the prepared granules was determined by the equation,

Carr’s Index(%) = TBD – LBD/TBD x 100 … …(4)

TABLE-2: Granule Properties of all formulations

Formulation	Angle of Repose (θ)	LBD (g/ml)	TBD (g/ml)	Compressibility Index (%)
F1	34⁰.99’	0.475	0.586	18.94
F2	32⁰.82’	0.442	0.574	22.99
F3	30⁰.37’	0.482	0.604	20.19
F4	35⁰.35’	0.468	0.578	19.03

3. Evaluation of Tablets

Tablets from all the five formulations were evaluated for its various properties like thickness and diameter using vernier calipers, hardness by using Monsanto hardness tester (Cadmach), friability by using Roche Friabilator, and weight variation by using a electronic balance (Anamed). The results were given in Table 2.

Drug content estimation

Five tablets were taken and amount of drug present in each tablet was determined. The tablets were crushed in a mortar and the powder equivalent to 40mg of drug was transferred to 100ml standard flask. The powder was dissolved in 5ml of Methanol and made up to volume with 0.1N HCl. The sample was mixed thoroughly and filtered through whatman filter paper. The filtered solution was diluted suitably and analyzed for drug content by UV spectrophotometer at a max of about 245nm

In Vitro Buoyancy studies

In Vitro buoyancy studies was performed for all the four formulations as per the method described by Rosa et al¹⁵. The randomly selected tablets from each formulation was kept in a 100ml beaker containing simulated gastric fluid, pH 1.2 as per USP. The time taken for the tablet to rise to the surface and float was taken as floating lag time. The overall floating time was calculated during the dissolution studies

In Vitro Dissolution studies

The in vitro dissolution studies was carried out in 0.1N HCl using USP XXII Dissolution test apparatus employing paddle stirrer. One tablet was placed inside the dissolution medium and the paddle was rotated at 75rpm. 5ml samples were withdrawn at specific time intervals and the same volume was replaced to maintain sink conditions. The samples were analyzed for drug content spectrophotometrically at 245nm.

TABLE-4: In vitro Buoyancy studies

Formulation	Lag time (sec)	Floating time (hrs)
F1	22	>12hrs
F2	26	>12hrs
F3	39	>8hrs
F4	51	3-4hrs

Drug release kinetics

To analyze the mechanism of drug release from the prepared formulations, the data obtained from in vitro release studies were subjected to Higuchi’s model, Zero order model and Korsmeyer’s model.

Stability studies

The promising formulation was tested for a period of 8 weeks at different temperatures of 25⁰C and 40⁰C with 60%RH and 75% RH, for their drug content.

RESULTS AND DISCUSSIONS:

The formulations showed good flow property and compressibility index (Table). Angle of repose ranged from 30.37 to 35.35 and the compressibility index ranged from 18.94 to 22.91. The LBD and TBD of the prepared granules ranged from 0.442 to 0.492 and 0.578 to 0.604 respectively. The results of angle of repose indicates good flow property of the granules and the value of compressibility index further showed support for the flow property.

The shape of the tablets of all formulations remained circular with no visible cracks. The thickness ranged from 2.7mm to 3.0mm and the average percentage weight variation of 20 tablets from each formulation remained within +- 5%. The hardness and percentage friability of all batches remained within the range of 6.0kg/cm3 and 0.524% respectively. The drug content estimations showed values in the range of 98.65% to 103.07% which reflects good uniformity in drug content among different formulations.

All the formulations showed values within the prescribed limits for tests like hardness, friability and weight variation which indicate that the prepared tablets are of standard quality.

In Vitro Dissolution studies

The data obtained from in vitro dissolution studies of all the four formulations was given in Table. Tablets of F1, F2, F3 and F4 released 36.88%, 34.77%, 42.17% and 48.51% respectively at the end of 8hrs. These

TABLE-5: In vitro Drug release studies

Time (hrs)	Cumulative percentage of drug release (%)*
Time (hrs)	F1	F2	F3	F4
1	14.05 ± 1.00	8.97 ± 0.07	10.56 ± 0.06	10.97 ± 1.01
2	21.03 ± 1.15	11.83 ± 0.99	11.83 ± 0.98	15.78 ± 0.98
3	27.90 ± 1.15	16.27 ± 1.08	16.37 ± 1.00	19.41 ± 1.01
4	32.12 ± 1.23	21.13 ± 1.23	21.03 ± 1.23	26.31 ± 1.23
5	37.73 ± 2.05	26.84 ± 1.54	25.03 ± 1.23	32.22 ± 1.89
6	41.64 ± 2.45	29.59 ± 1.20	29.06 ± 1.21	36.78 ± 1.98
7	45.44 ± 2.17	32.97 ± 1.27	31.17 ± 1.29	39.52 ± 1.93
8	48.52 ± 2.65	36.88 ± 2.12	34.75 ± 2.21	42.17 ± 2.18

± standard deviation, *n=3.

TABLE-6: In vitro release kinetic data for the prepared formulations

Formulation	Zero order plot R²	Higuchi’s Plot R²	Korsmeyers Plot R²
F1	0.9853	0.9686	0.7300
F2	0.9727	0.9968	0.6820
F3	0.9734	0.9695	0.6945
F4	0.9498	0.9935	0.6370

formulations vary in the amount and type of polymers used. All the formulations contained equal amount of gas generating agent (sodium bi carbonate) and bees wax.

The formulations were prepared mainly with HPMC K4M and Ethyl cellulose polymers. Both polymers were chosen as they are well established in the similar studies and have great swelling and sustained release properties respectively. Sodium bi carbonate is added to the formulation as gas generating agent. The formulation up on contact with HCl liberates CO2 and expels from the dosage from creating pores through which water can penetrate into dosage form and the rate of wetting of polymer increases. The results of in vitro percentage release at different time intervals is plotted against time to obtain release profile (Fig.1)

From the in vitro drug release studies, it was concluded that formulation having only HPMC showed more release when compared to other formulations where part of HPMC was replaced with ethyl cellulose (F1 against F2, F3 and F4). This is due to less permeability of water to ethyl cellulose. When the amount of ethyl cellulose was increased the drug release was found to be decreased which shows the sustained release effect of ethyl cellulose. In formulation F4, which contained maximum amount of ethyl cellulose and minimum of HPMC, drug release was found to be more than F2 and F3 but less than F1 which may be due to rupture of tablets at the end of 3hrs leading to increased drug release. Hence it was concluded that F3 was the best among the four formulations with a sustained release of 34.77% at the end of 8hrs.

TABLE-7: Result of Stability studies

Time in weeks	F3 - Drug Content (%)
Time in weeks	25⁰C/65% RH	25⁰C/70% RH	40⁰C/65% RH	40⁰C/70% RH
2	98.90	98.84	99.46	99.10
4	98.68	98.39	99.39	99.39
6	98.40	98.71	99.12	99.27
8	98.10	98.20	98.86	98.84

Release Kinetics Analysis

The drug release data were fitted to various models like Higuchi’s model (cumulative percent release against square root to time), Zero order model (cumulative percent release against time) and Korsmeyer’s model (log cumulative percent release against time) kinetics to know the release mechanism. The data were processed for regression analysis usins MS EXCEL statistical function.

The kinetic data (Table-6) showed that the release of drug followed diffusion controlled mechanism for the formulations. Diffusion is related to transport of drug from the dosage form in to the in vitro fluid depending up on the concentration. As the gradient varies the drug is released and the distance for diffusion increases. In the present study, in vitro release profiles could be best expressed by Higuchi’s equation as all formulations showed good linearity (R²: 0.9586 to 0.9935) indicates that diffusion is dominant mechanism of drug release with these formulations.

Stability studies

The percentage drug content at different temperature after every 2 weeks is given in table.7. Dissolution studies of selected formulation (F3) were carried out after subjecting the formulation for stability study. From the data (not shown), the formulation was found to be stable under the conditions mentioned before since there was no significant change in percentage amount of drug content.

Fig-1: In vitro Drug release profiles of all formulations.

CONCLUSION:

The present study was aimed at developing an oral floating system for Atorvastatin calcium with the use of a swellable polymer, release retardant and an alkalizing agent which proved to be an ideal formulation, as it released the drug in a controlled manner for extended period of time by maintaining the buoyancy. This formulation may overcome the problem of poor solubility and its associated problems. Since the formulation showed sufficient release for prolonged period, the dose can be reduced and possible incomplete absorption of the drug can be avoided.

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Received on 27.10.2008 Modified on 12.11.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008; Page 492-495

Formulation	Thickness (mm)	Hardness (kg/cm²)	Diameter (mm)	Friability (%)	Weight variation(mg)	Drug content (%)
F1	2.9±0.001	5.5	8	0.481	172.2±1.35	102.12
F2	3.0±0.04	6.0	8	0.524	169.4±2.62	98.65
F3	2.9±0.02	6.0	8	0.321	174.3±1.68	99.60
F4	2.7±0.01	5.5	8	0.426	176.9±1.35	103.07