INTRODUCTION:

Oral controlled release formulations are complicated by limited gastric residence time .Rapid gastrointestinal transit can prevent complete drug release in the absorption zone and reduce the efficacy of administered dose since the majority of drugs are absorbed in the stomach or the upper part of small intestine¹.Dosage forms that can be retained in the stomach are called gastroretentive drug delivery systems(GRDDS).GRDDS can improve the controlled delivery of drugs that have an absorption window by continuously releasing the drug for a prolonged period of time before it reaches its absorption site thus ensuring its optimal bioavailability².GRDDS has bulk density lower than gastric fluids and thus remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at a desired rate from the system. Floating drug delivery systems offer important advantages: as they are less prone to gastric emptying resulting in reduced intra and inter subject variability in plasma drug levels, effective for delivery of drugs with narrow absorption windows, reduced dosing and increased patient compliance, and improved safety profile for drugs with side effects associated with high C_max.

Frusemide³ is a diuretic used to treat edema, it is incompletely absorbed⁴ from gastrointestinal tract(GI),its absorption window is confined to upper part of GI tract. It also has half life of 1-2 hours and its absolute bioavailability is reported to be about 45-50% of the administered oral dose. Hence, furosemide is a suitable candidate for floating drug delivery system.

EXPERIMENTAL METHODS:

MATERIALS:

Furosemide was received as gift sample from Cipla, Goa. Hydroxy propyl methyl cellulose( HPMC K 4M,HPMC K15M,HPMC K100M),ethyl cellulose, lactose, sodium bicarbonate and citric acid were procured from SD fine Chemicals Ltd., Mumbai. Hydroxy propyl-β-cyclodextrin (HP-β-CD) was procured from Ranbaxy Pharmaceuticals, Delhi. All other chemicals were of analytical grade.

METHODS:

1.Preparation of solid dispersion:

The mixture of drug and polymer (HP-β-CD) in 1:1 ratio was triturated using a small volume of methanol-water(1:1)solution to give a thick paste, which was kneaded thoroughly for 30 min. in a glass mortar and then dried at 45⁰C in an oven. The dried mass was pulverized through sieve no.60 and stored in a desiccator.

2.Preparation of floating tablets:

All formulations were prepared as two layered tablets. The composition of the floating tablets is indicated in table 1.The first layer (floating layer) contained the mixture of sodium bicarbonate, citric acid and HPMC K4M as a matrix material to retain the air bubbles. The second layer provided controlled release of the drug and contain solid dispersion of drug and hydrophilic matrix polymer. The mixture that provided floating was placed in the die cavity and a preparatory pressing was made. Then the second layer was added and the final tablets were compressed with a hardness of 5Kg/cm² on a single punch tablet compression machine (Cadmach).

3.Evaluation of tablets:

Weight variation:

Twenty tablets were selected randomly and the average weight was determined. Then individual tablets were weighed and the individual weight was compared with the average weight.

Hardness and friability:

Hardness of the tablets was determined using the monsanto hardness tester(n=5).The Roche friabilator was used to determine the friability of the tablets. Preweighed sample of tablets (n=10)was placed in the friabilator, which was then operated for 100 revolutions. Tablets were dusted and reweighed. The percentage friability was calculated.

Estimation of drug content:

Ten tablets of each formulation were weighed and powdered. The quantity of powder equivalent to 100mg of drug was transferred to a volumetric flask. Required amount of 0.1N methanolic HCl was added,it was mixed and filtered and the filtrate was suitably diluted with 0.1N methanolic HCl and analysed against blank by U.V. spectrophotometer at 274 nm (Elico, India).

4.Floating Properties:

The time taken for tablet to emerge on surface of medium is called floating lag time(FLT)and the duration of time the tablet constantly remains on the surface the of medium is called the total floating time(TFT).Tablets were placed in a 400 ml flask at pH 1.2 and both the time needed to go upward and float on the surface of the fluid was determined.

5.In Vitro release studies:

In vitro release studies were conducted by using USP eight station dissolution test apparatus (Electrolab).Paddle method was used.900 ml of pH 1.2 was used as the dissolution medium at 37±0.5⁰C and 100 rpm. At predetermined time intervals of 1,2,3,4,5,6,7,8,9and10hr, 5ml sample was withdrawn, filtered, suitably diluted and assayed at 274 nm by UV spectrophotometer(Elico, India).The dissolution data obtained was plotted as cumulative percentage drug release versus time as zero order, log cumulative percentage drug undissolved versus time as first order release kinetics, cumulative percentage drug release versus square root of time as higuchi equation and log fraction of drug release versus log time as per Korsemeyer⁵-peppas⁶equation(the slope of this linear plot represents n value, diffusion exponent).

RESULTS AND DISCUSSION:

The poor bioavailability of orally dosed furosemide, a weakly acidic drug is due to the presence of a biological window in the upper gastrointestinal tract. For the purpose of enhancement of the bioavailability of furosemide, a floating dosage form was designed in this study. Because of the lower solubility of the active material in the gastric medium, it’s solubility was first enhanced by preparing an inclusion complex of furosemide with HP-β-CD in a 1:1 proportion using kneading method.

The tablets were formulated using various polymers such as HPMC K4M,HPMC K15M,HPMC K100M,ethyl cellulose and effervescing agents sodium bicarbonate and citric acid(Table 1).The parameters like thickness, hardness, friability, weight variation and drug content were evaluated for all the formulated batches of tablets. The results were found within the limits as per the official specifications(Table 2).Buoyancy (floating )lag time and total floating time studies revealed satisfactory results for the batches F1,F2,F3,F4,F5,F6,F7,and F8.

In vitro dissolution studies of formulations F1 to F8 in this study indicated that as the polymer concentration and viscosity was increased ,there was a reduction in the drug release rate. Formulations containing higher HPMC viscosity grades i.e.F3 to F6 showed slower drug release when compared to the formulations with lower HPMC viscosity grades i.e. F1 and F2(Table 3).The cumulative percentage drug released from all the formulations was found to be in the order of ethylcellulose>HPMC K4M >HPMC K15M>HPMC K100M. Release of furosemide from the prepared formulations (F3,F4,F5,F6,F8) was found to follow zero order kinetics(Table4),however the formulations (F1,F2,F7) followed first order kinetics(Table 4).Correlation coefficient(r=0.96 to 0.99) indicated good fit of Higuchi model suggesting that diffusion is the predominant mechanism in controlling the drug release. Drug release data was fitted to Korsemeyer-Peppas equation, the values of diffusion exponent ,n(0.57 to 0.88),indicated that the drug release followed non-fickian diffusion mechanism(Table4).The values of T50(time taken for 50% of drug release) and T90( time taken for 90% of drug release )are indicated in table 4.The formulation F6 exhibited highest value of T50(4.5 hrs)and the formulation F7 showed the least value of T50(2.12hrs).The formulation F6 demostrated the highest value of T90(10 hrs)and the formulation F8 showed the least value of T90(5.48hrs).

Among all the formulations, formulation F6 containing drug-polymer ratio (1:2), prepared with HPMC K100M, showed promising result, releasing 90% of drug in 10 hrs, with a floating lag time of 1.5min. and floating time of 12 hrs. Floating property of the tablet is governed by the swelling⁷(hydration) of the tablet when it contacts with the gastric fluid, which in turn results in increase in the bulk volume and the presence of internal voids in the centre of the tablet (porosity).These two factors are essential for the tablet to acquire bulk density less than 1 and to remain buoyant on the gastric fluid. The floating properties of the tablets could be improved with gas generating agent, which is a mixture of sodium bicarbonate and citric acid. It generates gas when it comes in contact with an acidic environment of the stomach.This gas entraps into the matrix of water soluble polymers and the formulation floats in acidic environment of the stomach⁷.

Effervescent layer Release layer
Formulations	Sod. Bicarbonate	Citric acid	HPMC K4M	Furosemide	lactose	HPMC K4M	HPMC K15M	HPMC K-100M	Ethyl cellulose
F1	40	30	150	80	20	40	-	-	-
F2	40	30	150	80	20	80	-	-	-
F3	40	30	150	80	20	-	40	-	-
F4	40	30	150	80	20	-	80	-	-
F5	40	30	150	80	20	-	-	40	-
F6	40	30	150	80	20	-	-	80
F7	40	30	150	80	20	-	-	-	40
F8	40	30	150	80	20	-	-	-	80

Table 1. Composition of furosemide floating tablets(ingredients in mg).

Table 2. Physicochemical characteristics of furosemide floating tablets.

Formulation	Hardness (Kg/cm²)	Friability(%)	Drug content(%)	Buoyancy Lag Time(min)	Total floating time(hr)
F1	5.1± 0.2	0.29±0.003	102.9±0.5	3.5	12
F2	5.3± 0.3	0.43±0.004	100.1±0.7	2	12
F3	5.6± 0.2	0.34±0.001	100.1±0.8	3.5	12
F4	5.9 ±0.2	0.33±0.005	99.9±0.5	3	12
F5	5.1 ±0.3	0.51±0.001	99.5±0.4	2.5	12
F6	5.5 ±0.2	0.52±0.003	99.9±0.7	1.5	12
F7	5.5 ±0.2	0.3±0.001	100.2±0.5	2	8
F8	6± 0.3	0.32±0.005	100.4±0.7	2.5	8

( All values are expressed as mean±S.D.,n=3)

Table 3.Dissolution data (cumulative % dissolved,mean±S.D.;n=3,) of furosemide floating tablets.

Time(hr) Formulation code

	F1	F2	F3	F4	F5	F6	F7	F8
1	30.2±0.77	22.9±1.25	16.9±0.23	15.1±0.12	15.1±0.91	10.8±0.82	19.9± 1.12	21.7±0.36
2	41±0.75	37.2±1.43	25.7±0.15	22±0.85	23.2±1.01	20.1±1.80	34.2 ±0.96	41.5±0.25
3	60.5±1.01	53.1±1.09	34.6±0.67	29.7±0.69	31.5±1.8	24.4±0.46	61.4 ± 0.35	51.9±0.86
4	65.9±1.12	71±1.06	50.4±1.26	36.3±0.58	41.8±0.75	34.2±0.24	78.9 ±0.48	63.8±0.14
6	80±0.24	84±0.24	68.1±0.96	62.8±0.72	59.9±1.35	57.6±0.75	93.5 ± 1.14	91.9 ±1.25
8	104.9±1.36	99.9±0.93	87.8±0.47	83.4±0.52	76.9±0.29	75.6±1.35	100.2±0.36	100.4±0.86
10	105±0.82	105±0.42	101.3±0.45	100.5±0.61	94.2±1.09	90±0.82	100.2±0.59	100.4±0.28

Table 4. Dissolution kinetics and dissolution parameters of furosemide from floating tablets.

Formulation	zero order eqn.(r)	first order eqn.(r)	Higuchi’s eqn.(r)	Peppas eqn.(r)	Peppas eqn.(n)	T50 (hr)	T90 (hr)
F1	0.975	0.995	0.994	0.993	0.57	2.32	6.48
F2	0.965	0.9924	0.993	0.9919	0.72	2.48	7.06
F3	0.993	0.9678	0.978	0.996	0.83	4	8.42
F4	0.996	0.963	0.960	0.985	0.85	4.48	8.54
F5	0.995	0.981	0.978	0.995	0.82	4.48	9.27
F6	0.995	0.9651	0.9621	0.901	0.88	4.5	10
F7	0.951	0.977	0.985	0.98	0.88	2.12	5.54
F8	0.988	0.953	0.982	0.995	0.79	2.54	5.48