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 infections.^[6]

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. In case of effervescent systems, when they reach the stomach CO₂ is 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] The non-effervescent FDDS based on mechanism of swelling of polymer or bio adhesion to mucosal layer in GI tract. The most commonly used excipients in non-effervescent FDDS are gel forming or highly swellable Cellulose type hydrocolloid, polysaccharides and matrix forming material such as polycarbonate, polyacrylate.^[11]

In order to improve the absorption and its oral bioavailability, we have attempted to formulate a floating drug delivery systems using Rosuvastatin 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 Dr. Reddy Lab, Hyderabad. Other reagents and solvents used were of analytical grade.

Methods

I. 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. Formulations and tablet contents were given in table 1.

Table 1: Formulation

Materials for 1tablet(mg)	I	II	III	IV
Rosuvastatin Calcium	40	40	40	40
HPMC k₄m	40	30	20	10
Ethyl Cellulose	0	10	20	30
Sodium Bicarbonate	30	30	30	30
Bees Wax	39	40	40	42
Magnesium Stearate	6	4	5	4
Talc	5	5	5	4

Table-2: Granule properties of all formulations

Formulation	Angle of Repose (θ)	LBD (g/ml)	TBD (g/ml)	Compressibility Index (%)
F1	26˚.10׳	0.454	0.517	12.13%
F2	26˚.56׳	0.475	0.571	16.8%
F3	27˚.87׳	0.500	0.601	16.92%
F4	28˚.36׳	0.417	0.598	30.37%

II. Evaluation Of Granules

i. 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 Anderson^[12]. The angle of repose was calculated using the equation, Tan θ = h/r ….(1) where θ is the angle of repose.

ii. 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)

iii. Compressibility Index

Carr’s Compressibility Index^[13] for the prepared granules was determined by the equation,

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

The values of angle of repose, bulk density and compressibility index were shown in table 2.

III. Evaluation of Tablets

Tablets from all the four 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 electronic balance. The results were given in Table 3.

i. Drug content estimation

Rosuvastatin (100 mg) was accurately weighed and dissolved in 100 ml methanol to form a stock solution (1000 μg/ml). The stock solution was further diluted suitably with methanol to get a working standard solution of concentration 100 μg/ml. This working standard solution was suitably diluted to give a concentration of 15 μg/ml and this was then scanned in UV range.

This showed an absorption maximum at 243.60 nm. Different concentrations were prepared from the stock solution and absorbance was measured using the spectrophotometer. The absorbance measurements of these solutions were carried out against methanol as blank at 244 nm. The values are shown in table 4.

ii. In Vitro Buoyancy studies

In Vitro buoyancy studies was performed for all the four formulations as per the method described by Rosa et al^[14]. The randomly selected tablets from each formulation were 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 and tabulated in table no. 5.

iii. 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. The values were tabulated in table 6. A curve of percentage release of different formulations of rosuvastatin was plotted in fig no. 1.

Table 4: Drug content estimation

S. No.	Concentration (µG/ML)	Absorbance
1	0	0
2	5	0.371
3	10	0.529
4	15	0.807
5	20	1.115
6	25	1.391

Table 5: In Vitro Buoyancy studies

Formulations	Lag time (sec)	Floating time (hrs)
F1	70	>12hrs
F2	40	>12hrs
F3	50	>12hrs
F4	62	>12hrs

Table 6: In vitro Drug release studies

Time (hrs)	Cumulative % Drug Released
Time (hrs)	F1	F2	F3	F4
2	23.39	21.2	23.81	23.81
4	28.48	25.09	25.09	25.51
6	37.42	35.42	28.49	37.42
8	41.1	40.1	32.75	42.1

RESULTS AND DISCUSSIONS:

The formulations showed good flow property and compressibility index (Table 2). Angle of repose ranged from 26.10 to 28.36 and the compressibility index ranged from 12.13 to 30.37. The LBD and TBD of the prepared granules ranged from 0.417 to 0.500 and 0.517 to 0.607 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 1.8 mm to 2.1 mm 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 3.9-4.3 kg/cm3 and 1.3-2.2% respectively. The drug content estimations showed values in the range of 0.371 to 1.391 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 6. Tablets of F1, F2, F3 and F4 released 41.1%, 40.1%, 32.75% and 42.1% respectively at the end of 8hrs. These 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 32.75% at the end of 8hrs

CONCLUSION:

Floating tablets are a novel type of tablet dosage forms for oral administration. It is advantageous to have an enhanced retention time in the stomach over solid and liquid dosage forms.

The conclusion drawn from the above studies are as given below

· Addition of polymer (HPMC) to the formulation and the use of melt granulation method showed that there is sustained drug release.

· Addition of polymers (HPMC and ethyl cellulose) and the use of melt granulation method showed that there is differential sustained drug release.

· Addition of polymers (HPMC and ethyl cellulose) to the formulation in 1:1 ratio and the use of melt granulation method showed that there is sufficient release of drug.

· Addition of polymers (HPMC and ethyl cellulose) to the formulation in 1:3 ratio and the use of melt granulation method showed that there is increased drug release.

· Drug release profile of oral floating tablets of rosuvastatin of formulations 1, 2, 3, 4 follows first order release pattern.

The above discussed results clearly depicts that the use of OFT is, in the improvement of dissolution rate of poorly soluble drugs like rosuvastatin whose bioavailability and dissolution rates are limited.

However further studies like spectrophotometric studies to know whether there are any interactions between dug and polymers.

Preparation of Oral Floating Tablets by other approaches using different polymers, characterization of its long term stability and in vitro dissolution studies are necessary.

REFERENCES:

1. Lee J., Park. J and Choi. H. Optimization of Sotalol Floating and Bioadhesive Extended Release Tablet Formulations. J. Microencapsulation. 1999, 16; 715

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3. Chien YW. Novel Drug Delivery Systems, 2nd edn., New York; Marcel Dekker Inc., 1992;

4. Robinson JR and Lee VHS. Controlled Drug Delivery,2nd edn., New York; Marcel Dekker Inc., 1987;

5. Jain NK. Controlled and Novel Drug Delivery, 1st edn., New Delhi, CBS Publishers, 2004

6. Ateshkadi A., Lam. N., Johnson CA. Helicobacter pylori and peptic ulcer disease., Clin. Pharm., 1993, 12; 34-48.

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12. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL, Editors. The Theory and Practice of Industrial Pharmacy, 3rd Edn., Mumbai: Varghese Publishing House; 1984, 283.

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Received on 11.08.2012 Modified on 20.09.2012

Research J. Pharm. and Tech. 5(11): Nov. 2012; Page 1389-1392

Formulation	Hardness (kg/cm²)	Friability (%)	Weight Variation (mg)	Thickness (mm)	Diameter (mm)
F1	4.0	2.2	156±5.5	2.1±0.04	7
F2	3.9	1.8	156.5±4.5	1.95±0.05	7
F3	4.1	1.9	152±3.5	1.8±0.02	7
F4	4.3	1.3	153±3	2.04±0.02	7