INTRODUCTION:

Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years.¹Regular research is going on in field of use of natural occurring biocompatible polymeric material in designing of dosage form for oral controlled release administration.^2-4 Natural gums are biodegradable and nontoxic, which hydrate and swell on contact with aqueous media, and these have been used for the preparation of dosage form.⁵Guar gum a polysaccharide derivative with glycoside linkage has been used as matrix former for controlled release of isoniazide⁶ and diltiazem.⁷ Pectins, including high and low ester and amidated, are used in food all over the world. It is an edible plant polysaccharide, has been shown to be useful for the construction of drug delivery systems for specific drug delivery.⁸ Xanthan gum is a high molecular weight extracellular polysaccharide, produced on commercial scale by the viscous fermentation of gram negative bacterium Xanthomonas campesteris. The molecule consists of a backbone identical to that of cellulose, with side chains attached to alternate glucose residues. It is a hydrophilic polymer, which until recently had been limited for use in thickening, suspending and emulsifying water based systems.⁹ Furosemide (4-chloro-2-furfurylamino-5-sulphamoyl benzoic acid) is a drug with a diuretic action which acts at the renal level on the ascending limb of the loop of Henle.¹⁰

This drug is used in the treatment of oedema of pulmonary, cardiac or hepatic origin as well as in the treatment of hypertension and in the chronic treatment of cardiac infarction.¹¹ The present invastigation is aimed to formulate the matrix tablet of forosemide with guar gum, pectin and xanthin gum.

MATERIAL AND METHODS:

Furosemide was obtained as gift sample from Arbro Pharmaceuticals, New Delhi. The Pharmacopoeial grade of Guar gum (GM), Pectin (P) and Xanthan gum (XG) was obtained from Rajesh Chemicals, Mumbai. Other materials used were of analytical grade, and procured from commercial sources.

Preparation of SR matrix tablets:

SR matrix tablets of Furosemide were prepared by using different drug: polymer ratios viz. 1:1, 1:2, 1:3, 1:4 for P₁, P₂, P₃, P₄, 1:1, 1:2, 1:3, 1:4 for G₁, G₂, G₃, G₄ and 1:1, 1:2, 1:3, 1:4 for P₁, P₂, P₃, P₄ respectively. GM, P and XG were used as matrix forming material, while lactose was used as diluent, Magnesium stearate was incorporated as lubricant. All ingredients were passed through a # 100 sieve, weighed, and blended. The lubricated formulations were compressed by a direct compression technique, using 12 mm flat faced punches. [Table 1,2,3]

Evaluation of Fabricated Matrix Tablets:

All prepared matrix tablets were evaluated for uniformity of weight as per I.P. method. Friability was determined using Roche friabilator. Hardness was measured by using Pfizer hardness tester. Thickness was measured by Vernier caliper.^{12, 13, 14} [Table 4,5,6]

Table 1: Formulation composition of Pectin matrix tablets.

Ingredients	Formulations
	P₁	P₂	P₃	P₄
Furosemide (mg.)	40	40	40	40
Pectin (mg.)	40	80	120	160
Magnesium Sterate (mg.)	2.5	2.5	2.5	2.5
Lactose (mg.)	167.5	127.5	87.5	47.5

Swelling Behaviour of SR Matrix Tablets:

The extent of swelling was measured in terms of % weight gain by the tablet. The swelling behavior of all formulation was studied. One tablet from each formulation was kept in a petridish containing pH 7.2 phosphate buffer. At the end of 1 h, the tablet was withdrawn, soaked with tissue paper, and weighed.¹⁶ Then for every 2 h, weights of the tablet were noted, and the process was continued till the end of 16 h. % weight gain by the tablet was calculated by formula;

S.I = {(Mt-Mo) / Mo} X 100,

Where, S.I = swelling index, Mt = weight of tablet at time’s' and Mo = weight of tablet at time t = 0.

Table 2: Formulation composition of Guar gum matrix tablets.

Ingredients	Formulations
	G₁	G₂	G₃	G₄
Furosemide (mg.)	40	40	40	40
Guar gum (mg.)	40	80	120	160
Magnesium Sterate (mg.)	2.5	2.5	2.5	2.5
Lactose (mg.)	167.5	127.5	87.5	47.5

In vitro drug release study:

In vitro drug release was studied using USP I apparatus, with 900 ml of dissolution medium maintained at 37±1°C for 15 h, at 50 rpm. 0.1 N HCl (pH 1.2) was used as a dissolution medium for the first 2 h, followed by pH 7.2 phosphate buffer for further 13 h. 5ml of sample was withdrawn after every hour, and was replaced by an equal volume of fresh dissolution medium of same pH. Collected samples were analyzed spectrophotometrically at 272 nm, and cumulative percent drug release was calculated. The study was performed in triplicate.

Table 3: Formulation composition of Xanthan gum matrix tablets.

Ingredients	Formulations
	X₁	X₂	X₃	X₄
Furosemide (mg.)	40	40	40	40
Xanthan gum (mg.)	40	80	120	160
Magnesium Sterate (mg.)	2.5	2.5	2.5	2.5
Lactose (mg.)	167.5	127.5	87.5	47.5

The data obtained in the in-vitro dissolution study is grouped according to three modes of data treatment as follows:

1. Cumulative percentage drug released Vs time in hrs.

2. Cumulative percentage drug released Vs square root of time in hrs. (Higuchi’s classical diffusion)

Fig.1: Cumulative Percentage drug released Vs Time (Hours) curve of various formulations.

RESULT AND DISCUSSION:

The formulated matrix tablets met the pharmacopoeial requirement of uniformity of weight. All the tablets conformed to the requirement of assay, as per I.P. Hardness, percentage friability and thickness was all within acceptable limits.

All formulations showed very low drug release in 0.1N HCl (pH 1.2). This was due to the low solubility of furosemide at pH 1.2. Sustained, but complete drug release was displayed by all formulations in phosphate buffer (pH 7.2). Thus it can be concluded, that drug dissolution was a function of drug solubility, at various pH ranges. Indeed, pH dependent solubility of furosemide is well known. The reported solubility for furosemide is less than 4 X 10^-4% w/v at pH 1.2 to 3.¹⁷ The fact was also observed by Nochodchi, et al.,¹⁵ When pH rises above pKa, rapid increase in solubility occurs.

Table 4: Various evaluation parameters for fabricated pectin tablets.

Parameter	Pectin
Parameter	P₁	P₂	P₃	P₄
Friability (%)	0.96	1.00	0.91	0.86
Hardness (Kg/cm²)	5.54± 0.0204	5.20± 0.0114	5.12± 0.0213	5.01± 0.0110
Thickness (mm)	6.15± 0.032	6.14± 0.026	6.16± 0.032	6.12± 0.041
Swelling index (T=15)	10	26	39	55

The swelling index was calculated with respect to time. As time increases, the swelling index was increased, because weight gain by tablet was increased proportionally with rate of hydration up to 3 h. Later on, it decreases gradually due to dissolution of outermost gelled layer of tablet into dissolution medium. The direct relationship was observed between swelling index and gum concentration, and as gum concentration increases, swelling index was increased. It has been observed that the cumulative percent drug release decreases with increasing concentration of gum and swelling index. The reason attributed to this fact is slow erosion of the gelled layer from the tablets containing higher amount of guar gum. This slow release is because of the formation of a thick gel structure that delays drug release from tablet matrix, where hydration of individual xanthan gum particles results in extensive swelling. As a result of rheology of hydrated product, the swollen particles coalesce. This results in a continuous viscoelastic matrix that fills the interstices, maintaining the integrity of the tablet, and retarding further penetration of the dissolution medium.

Table 5: Various evaluation parameters for fabricated guar gum tablets.

Parameter	Guar gum
Parameter	G₁	G₂	G₃	G₄
Friability (%)	0.99	0.79	0.96	0.95
Hardness (Kg/cm²)	4.94±0.0312	5.01±0.0222	4.89±0.0152	4.95±0.0321
Thickness (mm)	6.12±0.041	6.13±0.041	6.10±0.026	6.09±0.026
Swelling index	24	42.6	54.4	62.8

From the findings, obtained so far it can be concluded that guar gum in the concentration ratio of 1:4 (G₄) was promising concentration for oral controlled release tablet of furosemide.

Based on the results obtained, it is possible to design promising oral controlled release matrix tablet containing furosemide. Furosemide is used in the treatment of oedema of pulmonary, cardiac or hepatic origin as well as in the treatment of hypertension and in the chronic treatment of cardiac infarction.

Fig.2: Cumulative % drug released Vs √Time (Hours) curve (Higuchi’s release mechanism) of various formulations.

Furosemide matrix tablets with natural polymers were prepared by direct compression method. All the formulations were subjected to various evaluation studies. The results of evaluation of tablet showed that the dimensions, hardness, friability, weight variation, and in-vitro dissolution ratewere found within the specified limit. The controlled-release formulations of furosemide were intended to reduce the diuresis peak while maintaining the quantity of urine excreted within 24 hours equal to that excreted with fast-release formulations. Natural gums are biodegradable and nontoxic, which hydrate and swell upon contact with aqueous media, and these have been used for the preparation of dosage form.

Table 6: Various evaluation parameters for fabricated xanthan tablets.

Parameter	Xanthan
Parameter	X₁	X₂	X₃	X₄
Friability (%)	0.88	0.85	0.79	1.00
Hardness (Kg/cm²)	5.83± 0.0381	5.24± 0.0116	5.72± 0.0421	5.43± 0.0325
Thickness (mm)	6.11± 0.041	6.15± 0.032	6.14± 0.026	6.16± 0.032
Swelling index	26	31.6	36.5	44

The overall sustained release performance of used gums was found to be in order; Guar gum > Xanthan gum > Pectin.

REFERENCE:

1. Ansel HC and Loyyd VA. Pharmaceutical dosage forms and Drug Delivery System. Lippincott’s Williams and Wilking, Hong Kong. 1999; 8: 275-280.

2. Bonferoni MC and Rosi ST. Journal of Control Release. 1993; 26: 119.

3. Sujja AJ, Munday DL, and Khan KA. Development and evaluation of a multiple-unit oral sustained release dosage form for S(+)-ibuprofen: preparation and release kinetics. Int. J. Pharm. 1999; 193(1): 73-84.

4. Khullar P, Khar RK and Agarwal SP. Guar Gum as a hydrophilic matrix for preparation of Theophylline Controlled Release dosage form. Ind. J. Pharm. Sc. 1999; 61(6): 342-345.

5. Nokano M and Ogata A. In vitro release characteristics of matrix tablets: Study of Karaya gum and Guar gum as release modulators. Ind. J. Pharm. Sc. 2006; 68(6): 824-826.

6. Jain NK, Kulkarni K and Talwar N. Controlled-release tablet formulation of isoniazid. Pharmazie. 1992; 47: 277.

7. Altaf S. and Jones DB. Controlled release matrix tablets of isoniazide, diltiazem and nafronyl oxalate. Pharm. Res. 1998; 15: 1196.

8. Linshu L, Marshall L and Fishman B. Pectin in controlled drug delivery – a review. Journal of Control Release. 2007; 14: 15-24.

9. Gwen MJ and Joseph RR. and Rhodes CT. Modern Pharmaceutics, Marcel Dekker, Inc., New York. 1996; 72(3): 581.

10. Ebihara et al., Controlled release formulations to increase the bioadhesive properties, Drug Res. 1983; 33: 163.

11. Verhoeven, J. et al., controlled-release formulations, a hydrophilic matrix containing furosemide. Int. J. Pharm. 1988; 45: 65.

12. Indian Pharmacopoeia. Ministry of health. The controller of publications, New Delhi. 1996; 4ed.; 735.

13. Indian Pharmacopoeia. Ministry of health. The controller of publications, New Delhi. 1996; 4ed; 432.

14. Lachman L, Liberman HA and Kanig JL. The Theory and Practice of Industrial Pharmacy. Varghese Publishing House, Mumbai, 1991; 3rd Edn; 88.

15. Akbari J, Nokhodchi A and Farid D. Development and evaluation of buccoadhesive propranolol hydrochloride tablet formulations: effect of fillers. Int. J. Pharm. 2004; 59(2): 155.

16. Andreopoulos AG and Tarantili PA. Xanthan Gum as a Carrier for Controlled Release of Drugs. J. Biomed. Appl. 2001; 16: 35.

17. Reynolds JEF. Martindale: The Extra Pharmacopoeia, 1996; 31st Edn., The Pharmaceutical Press, London, 1588.

Received on 20.07.2008 Modified on 22.08.2008

Research J. Pharm. and Tech. 1(4): Oct.-Dec. 2008;Page 374-376