INTRODUCTION:

Valsartan is a type I angiotensin II receptor antagonist prescribed for asymptomatic condition such as hypertension. It is poorly absorbed from the lower gastrointestinal tract. The oral bioavailability of valsartan was reported to be 25%^[1]. Thus, it seems that an in gastric residence time may increase the extent of absorption and bioavailability of drug. However, fluctuations of drug concentration in plasma may occur, resulting in side effects or a reduction in drug concentration at receptor side. As the drug is effective when the plasma fluctuations are minimized, therefore sustained release dosage form of valsartan is desirable. The short biological half life of drug (nearly 6hrs) also favors development of sustained release formulations.

There are several approaches have been reported for prolonging the residence time of drug delivery system in a particular region of the gastrointestinal tract, such as floating drug delivery systems, swelling and expending systems, polymeric bioadhesive systems, swelling and expanding systems, modified shape systems, high density systems and other delayed gastric emptying devices^[2]. Floating drug delivery system or hydrodynamically balanced systems were first described by Davis (1968). The floating of FDDS occurs due to their lower bulk density than the gastric contents or due to gaseous phase formed inside in the environment^[3,4]. It is applicable for those drugs which (i) act locally; (ii) have a narrow absorption window in the small intestinal region; and (iii) unstable in the intestinal environment^[5].

In recent years, the semi synthetic polymer HPMC based matrix tablets as carrier for controlled release delivery has been widely and successfully use due to their ease of manufacturing, favorable in vivo performance and versatility in controlling the release of drug with wide range of physicochemical properties^[6]. HPMC is inert, viscoelastic polymer which forms colloids on contact with aqueous media and these have been used for the preparation of dosage form. This non toxic ingredient is combustible and can react vigorously with oxidizing agents. It is used as thickening agent in the food industry, and in the pharmaceutical industry, it is used as excipients, binder, as a component in coating tablets and it functions as controlled release agent to delay the release of a medicinal compound in to the digestive tract. Different grades of HPMC are available based on their viscosity grades, % methoxyl substitution and % hydroxypropoxyl substitution. They can be used alone or in combination with other.

In the present research work an attempt was made to prepare floating tablets of Valsartan using HPMC E-5, HPMC K100, HPMC K15 alone and their combination. The prepared tablets were evaluated for physical characteristics such as hardness, weight variation, drug content uniformity, and floating capacity. All the tablets were evaluated for in vitro release characteristics.

MATERIALS AND METHODS:

Valsartan and HPMC were obtained as gift sample from Lara Drugs Pvt. limited, Sodium bicarbonate was received from B. D Pharmaceutical Works, Howrah, India. Citric acid, MCC and magnesium stearate were obtained from Loba Chemie Pvt. Ltd., Mumbai, India.

Methods:

Preparation Of Floating Tablet:

Floating matrix tablet of Valsartan were prepared by direct compression method according to the formula given in Table 1. Valsartan (80 mg) was mixed with the required quantity of polymers HPMC E5, HPMC K15, HPMC K100 alone or in combinations, sodium bicarbonate (40mg) and citric acid (20mg) in mortar and pastel for 15 min. The powder blend was then lubricated magnesium stearate (2mg) and MCC for additional 3 min and prior to the compression; the prepared powder blend was evaluated for several tests as mentioned below. The powder blend was then compressed into tablets manually on single punch tablet punching machine (Cadmach machinery co.Pvt ltd.) by using 6 mm standard flat punch.

Evaluation of powder blend

Bulk Density and Tapped Density

^{Both poured
(or fluff) bulk (Do) and tapped
bulk densities (D}F ^{) were}determined, according to the method reported by Raghuram et al.,^[7] whereby a quantity (3 g) of granules from each formula, previously lightly shaken to break any agglomerates formed, was introduced into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder allowed falling under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in the volume was noted. The value of bulk density and tapped density were calculated by using equation:

Compressibility Index

The Carr’s compressibility index and Hausner’s ratio were calculated from the values of bulk density and tapped density^[8].

EVALUATION OF TABLET

Prepared tablet were evaluated for quality control tests like weight variation test, hardness test, friability test, content uniformity study, and in vitro release study.

Weight Variation Test

To study weight variation, tablets from each formulation were selected at random and average weight was determined using an electronic balance. Then individual tablets were weighed and the individual weight was compared with an average weight. Weight values were reported in mg. Mean and SD were calculated.

Hardness Test

For each formulation, the hardness of six tablets was determined using a hardness tester (Monsanto, Mumbai, India). Hardness values were reported in kg/cm². Mean and SD were calculated

Friability Test

For each formulation, six tablets were weighed. The tablets were placed in a Roche friabilator (Labindia FT-1020) and subjected to 100 rotations in 4 min. The tablets were then dedusted and reweighed. The friability was calculated as the percent weight loss.

Drug Content Uniformity Study

Five tablets were weighed individually, then placed in a mortar and powdered with a pestle. An amount equivalent to 25 mg drug (100 mg) was extracted with 100 ml of 0.1M HCl (pH 1.2), stirred for 15 min using magnetic stirrer (Labotech, Mumbai, India). The solution was filtered through a filter (0.22 μm pore size), properly diluted with 0.1 M hydrochloric acid and the drug content was measured using UV-VIS spectrophotometer at 225 nm.

Buoyancy Study

The in vitro buoyancy was characterized by floating lag time and total floating time. The test was performed using USP 24 type II apparatus (Labindia DS-8000) at 100 rpm in 900 ml of 0.1M HCl (pH 1.2) maintained at 37±0.5°C. The time required for tablet to rise to the surface of dissolution medium and duration of time the tablet constantly float on dissolution medium were noted as floating lag time and total floating time, respectively (n = 3)^[9].

In Vitro Drug Release Study

The in vitro drug release study was performed using USP 24 type II apparatus (Labindia DS-8000) at 50 rpm in 900 ml of 0.1M HCl (pH 1.2) maintained at 37±0.5°C. The samples were withdrawn at predetermined time intervals for period of 8 hr and replaced with the fresh medium. The samples were filtered through 0.45μm membrane min using magnetic stirrer (Labotech, Mumbai, India). The solution was filtered through a filter (0.22 μm pore size), properly diluted with 0.1 M hydrochloric acid and the drug content was measured using UV-VIS spectrophotometer at 225 nm.

Determination Of Release Kinetics And Release Mechanism

The rate and mechanism of release of valsartan from the prepared floating tablets were analyzed by fitting the dissolution data into following equations:

(5)

To describe the drug release behavior from polymeric systems, the dissolution data were also fitted according to the well-known exponential Korsmeyer-Peppas equation^[].

Where is the fraction of drug release at time t, and k is the kinetic constant, n is the release exponent (indicating the general operating release mechanism). For tablets, depending on the aspect ratios, n value between 0.43 and 0.5 indicating Fickian (case I) diffusion-mediated release, non-Fickian (Anomalous) release, coupled diffusion and polymer matrix relaxation, occurs if 0.5<n<0.89, purely matrix relaxation or erosion-mediated release occurs for n=1 (zero-order kinetics), and super case II type of release for n>0.89.

RESULTS AND DISCUSSION:

Valsartan floating tablets were prepared by Table 1 using HPMC E5, HPMC K15 and HPMC K100 as a polymeric retardant materials and sodium bicarbonate and citric acid as gas forming agent to float the tablets in stomach. Carbon dioxide which is formed by combination of citric acid with sodium bicarbonate is just entrapped by the polymer and decreases the density of tablet below the density of gastric fluid which results in floating of the tablet. The micromeritics parameters of the powder blend of different formulation batches are shown in Table 2. Angle of repose and compressibility index was found to be in the range of 26.90±1.23 to 29.89±1.45 and 5.88±0.210 to 20.00±0.198, respectively. The bulk density and tapped density of the prepared powder blend was fond to be in the range of 0.600±0.032 to 0.705±0.017gm/cm³and 0.666±0.020 to 0.750±0.015gm/cm³, respectively. The result of angle of repose indicates good flow property of the granules and the value of compressibility index further support for the good flow property.

The tablets of all formulations was found to be off white, smooth, flat faced circular with no visible cracks. The physicochemical properties of all the formulations are shown in Table 3. The hardness of the tablets was measured by Monsento hardness tester and was found in between 3.0 ±0.23 to 4.7±0.34kg/cm². The friability was measured by Roche friabilator and was found to be within acceptable range. The weight variation of the tablet formulations was found to be in the range of 197 ±1.54 to 205 ±1.82mg. The drug content estimations showed values in the range of 98 ±1.28 % to 102 ±1.74%, 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. All the tablets were prepared by effervescent approach. Sodium bicarbonate was added as a gas-generating agent. Sodium bicarbonate induced carbon dioxide generation in presence of dissolution medium (0.1M hydrochloric acid). The combination of sodium bicarbonate and citric acid provided desired floating ability and therefore this combination was selected for the formulation of the floating tablets. The floating lag time Table 4 of all formulations is in the range of below 1 minute.

In vitro dissolution studies of all the formulations Table 5 of floating tablets of valsartan were carried out in 0.1N HCl solution (pH 1.2). The in vitro release profile of the different formulations is shown in Figure1 Formulations F1 and F2 containing HPMC E5 20mg and 40mg shows percentage drug release of 97 in 24hrs and 96.2 in 20hrs. F3 and F4 which contained HPMC K100 20mg and 40mg shows percentage drug release of 74.3 and 89 in 24hrs. F5 and F6 which contained HPMC K15 20mg and 40mg shows percentage drug release of 97 and 80.3 in 24 hrs. F7 containing HPMC-E5 20mg and HPMC K100 20mg shows percentage drug release of 96.2 in 20hrs. F8 containing HPMC E5 20mg and HPMC K15 20 mg shows percentage drug release of 93.5 in 24 hrs. It has been observed that the dissolution rate was found to decrease linearly with increasing concentration of Sustained release agent in F1, F2, F5, and F6. In case of F3 and F4 formulations it has been found that the dissolution rate was increased with increase in concentration of sustained release agent. F7 and F8 the dissolution rate was more for F7 when compared with F8 which is a combination of HPMC E5 and HPMC K100.

The In vitro drug release data was subjected to goodness of fit test by linear regression analysis according to zero order; first order kinetic equation, Higuchi’s and Korsmeyer’s models in order to determine the mechanism of drug release. When the regression coefficient values of zero order and first order plots were compared, it was observed that ‘r’ values of zero order plots were in range of 0.840 to 0.988 Whereas ‘r’ values of first order plots in the range of 0.709 to 0.960, indicating drug release form formulations was found to follow zero order kinetics. It is notable that the ‘r’ values of the linear regression for Higuchi’s plot were found to be in the range of 0.776 to 0.988 indicating that the data fits the Higuchi’s model well and the drug release was found to be predominantly controlled by diffusion process.

When the In-vitro dissolution data were fitted to exponential model, the ‘r’ values were found to be in range of 0.787 to 0.976 in most of the formulations, indicating the data fits the exponential model well. Slope ‘n’ value is less than 0.5 which confirms that the drug release through the matrix was fickian model.

able 1: Composition of Different Formulations Tablets

Ingredients	Formulation
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8
Valsartan	80	80	80	80	80	80	80	80
HPMC E5	20	40	_	_	_	_	20	20
HPMC K15	_	_	20	40	_	_	20	_
HPMC K100	_	_	_	_	20	40	_	20
Citric acid	20	20	20	20	20	20	20	20
Sodium bicarbonate	40	40	40	40	40	40	40	40
Magnesium stearate	2	2	2	2	2	2	2	2
Micro crystalline cellulose	38	18	38	18	38	18	18	18
Total weight	200	200	200	200	200	200	200	200

Table 2: Micromeritics Properties of Powder Blend of Different Formulations (F1-F8)

Formulations	Bulk density (gms/ml)	Tapped density (gms/ml)	%Compressibility Index	Hausner ratio	Angle of Repose
F1	0.600±0.051	0.750±0.032	20.00 ±0.198	1.25±0.016	28.23±1.6
F2	0.600±0.032	0.750±0.015	20.00±0.208	1.25±0.015	28.35±1.64
F3	0.600±0.069	0.666±0.020	10.00±0.320	1.11±0.013	27.22±1.31
F4	0.600±0.282	0.705±0.038	15.00±0.342	1.17±0.016	27.13±1.26
F5	0.666±0.012	0.750±0.069	11.11±0.401	1.12±0.019	28.98±1.57
F6	0.705±0.017	0.750±0.027	5.88±0.210	1.06±0.012	26.90±1.23
F7	0.600±0.048	0.705±0.013	15.00±0.237	1.17±0.015	29.89±1.45
F8	0.600±0.055	0.705±0.073	15.00±0.238	1.17±0.018	28.97±1.58

Table 3: Physicochemical Of the Tablets of Different Formulations (F1 to F8)

Formulation	Hardness (kg/cm²)	Friability	Thickness (mm)	Weight variation (mg)	Drug Content%
F1	3.8 ± 0.15	0.160 ±0.03	2.86 ±0.15	205 ±1.82	102 ±1.74
F2	3.0 ±0.23	0.260 ±0.08	2.96 ±0.14	197 ±1.54	99 ±1.48
F3	3.5 ±0.17	0.260 ±0.04	2.94 ±0.12	199 ±1.35	99 ±1.37
F4	3.9 ±0.14	0.260 ±0.01	2.92 ±0.33	201±1.92	100 ±1.0
F5	3.8 ±0.49	0.230 ±0.03	2.89 ±0.43	202 ±1.86	100 ±1.45
F6	4.7±0.34	0.190 ±0.05	2.96 ±0.58	199±1.51	99±1.73
F7	4.2 ±0.25	0.190 ±0.09	2.91 ±0.32	203±1.80	98 ±1.28
F8	4.4 ±0.44	0.250 ±0.02	2.87 ±0.24	200±1.27	99 ±1.97

Table 4: Buoyancy properties of the tablets of different formulations (F1 to F8)

Formulation	Floating lag time(seconds)	Total floating time
F1	32	>12 hrs
F2	21	>12 hrs
F3	28	>12 hrs
F4	22	>12 hrs
F5	24	>12 hrs
F6	45	>12 hrs
F7	38	>12 hrs
F8	41	>12 hrs

TABLE 5: IN VITRO RELEASE KINETICS PARAMETERS

Formulation	Zero order	First order	Higuchi	Korsmeyer Peppas equation		Erosion model
Formulation	Zero order	First order	Higuchi	(r²)	n	Erosion model
F1	0.977	0.802	0.966	0.949	0.263	0.966
F2	0.899	0.864	0.958	0.976	0.198	0.868
F3	0.890	0.801	0.839	0.827	0.215	0.921
F4	0.985	0.960	0.988	0.973	0.267	0.962
F5	0.982	0.850	0.975	0.961	0.286	0.966
F6	0.840	0.709	0.776	0.787	0.245	0.890
F7	0.870	0.852	0.939	0.963	0.205	0.838
F8	0.988	0.873	0.964	0.944	0.290	0.981