INTRODUCTION:

Reduction of side effects and maximization of the therapeutic index of drug is the main aim of all the types of drug delivery system. Gastro retentive dosage forms are defined as a system that persists in the stomach for a sufficient time interval against all the physiological barriers, releasing drug in a controlled manner, and finally metabolized in the body [1,2,3]. Among the various drug delivery systems available in the market oral route occupies about 50% ,that is, it is having more patient compliance because of the fact that ease of administration and handling [4,5]. Drugs having a short half-life are eliminated quickly from the blood circulation. Various oral controlled delivery systems have been designed which can overcome the problems of unpredictable gastric emptying due to physiological problems or presence of food and also release of drug to maintain its plasma concentration for a longer period of time [6,7,]. This led to the development of oral gastroretentive floating dosage forms. Ivabradine HCl is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarization in the sinus node and regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation [8,9,10,].

MATERIALS AND METHODS:

Materials:

Chemicals used in this study were of pharma grade. Ivabradine HCl and all the remaining chemicals were obtained from Bafna Pharmaceuticals LTD., Chennai.

Method:

Direct compression method:

Floating tablets were prepared by direct compression technique. All the ingredients were weighed accurately. Drug was passed through the sieve no. 60, and the all other excipients including the polymer were passed through sieve no. 30 separately. The drug and all other ingredients except magnesium stearate were taken in the poly bag and mixed thoroughly for nearly about 10 minutes. Finally the powder blend was lubricated with magnesium stearate. And the blend was then compressed in to tablets using 8 mm flat punch on a 10 stationary punching tablet machine with hardness in a range of 30-35 Newton’s. And each tablet weighs 70mg.

Ingredients	Formulation code
Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Ivabradine HCl	10	10	10	10	10	10	10	10	10
HPMC K100	30	25	20				20	20	10
Xanthan gum				30	25	20	10	5	10
Sodium bicarbonate	6	6	6	6	6	6	6	6	6
Citric acid	3	3	3	3	3	3	3	3	3
Microcrystalline cellulose	13.5	18.5	23.5	13.5	18.5	23.5	8.5	18.5	23.5
Pregelatinised starch	5	5	5	5	5	5	5	5	5
Aerosil	1	1	1	1	1	1	1	1	1
Purified talc	1	1	1	1	1	1	1	1	1
Magnesium stearate	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5

Evaluation of blend [11]:

Prepared blend was analyzed to determine the flow property, Angle of repose, Bulk density, Tapped density, Carr’s index and Hausner’s ratio . All the results were shown in Table No.2

Physical evaluation of Tablets [12]:

Tablets from all the formulations were evaluated for its various properties like appearance, thickness, hardness, weight variation, drug content uniformity. Observed results were in Table No.3.below.

Floating property and water uptake study [13,14]:

The time taken for the dosage form to emerge on to the surface of the medium is called buoyancy lag time (BLT). Duration of the time by which the dosage form constantly emerges on surface of the medium is called total floating lag time (FLT). The swelling of the polymers can be measured by their ability to absorb water and swell. The swelling property of the formulation was determined by various techniques. The water uptake study of the tablet was done using USP dissolution apparatus . The medium used was distilled water, 900 ml rotated at 50 rpm. The medium was maintained at 370.5˚ C throughout the study. After a selected time intervals, the tablets were withdrawn blotted to remove excess water and weighed,

Swelling characteristics of the tablets were expressed in terms of water uptake (WU). And it was expressed in %.

Table No.4 shows the results.

WU = Weight of the swollen tablet – Initial weight of the tablet × 100

Initial weight of the tablet

Invitro dissolution studies [15]:

The invitro release of floating tablets of Ivabradine HCl was determined by using USP type dissolution apparatus and the dissolution was carried out in the prescribed manner. Using 900 ml of 0.1 N HCl at 37˚C 0.5˚ C. 5ml samples were taken out at particular time intervals and passed through a Whatmann filter paper no.44. The samples were replaced with fresh dissolution medium. Absorbance was measured

at 218 nm using double beam spectrophotometer. Results were shown in Table No.3

Drug release kinetics [16]:

To analyze the mechanism of drug release from the prepared formulations, the data obtained from invitro release studies were subjected to Zero order, First order, Higuchi’s and Korsmeyer’s models

RESULTS AND DISCUSSION:

Table No.2.Flow properties of powder blend:

Formulation code	Angle of repose	Bulk density (gm/cm)	Tapped density (gm/c²)	Hausner’s ratio	Carr’s index (%)
F1	32.50	0.4629	0.5555	1.2004	16.66
F2	31.92	0.4901	0.5434	1.1087	14.81
F3	29.72	0.4545	0.5208	1.1458	12.73
F4	34.52	0.4587	0.5681	1.4651	19.25
F5	31.61	0.4385	0.5208	1.1876	15.80
F6	30.64	0.4777	0.5208	1.1033	9.37
F7	30.11	0.4440	0.5518	1.2427	19.54
F8	32.36	0.5000	0.5263	1.1904	15.99
F9	31.36	0.4640	0.5345	1.1519	15.19

Angle of repose for the prepared powder blend was between 29.72 - 34.52, Hausner’s ratio for the prepared powder blend was between 1.1033 - 1.2004,Carr’s index of the powder blend was found between 9.37 - 19.54 % and hence the prepared powder blend have good flow property[11].

Table No.3 Evaluation of Floating tablet

Formulation code	Thickness + S.D (mm) (n=5)	Hardness + S.D (Newton’s) (n=5)	Friability (%)	Average weight variation (n=20)	Drug content (%)	Invitro release studies.(8^th hr)
F1	1.54+0.02	32+0.03	0.42+0.004	66.72+0.18	98.47	88.06
F2	1.52+0.01	31+0.04	0.48+0.002	66.18+0.34	95.43	92.16
F3	1.54+0.04	32+0.06	0.45+0.001	66.52+0.22	96.78	95.86
F4	1.52+0.05	30+0.05	0.39+0.01	66.84+0.34	97.82	78.36
F5	1.54+0.07	31+0.04	0.47+0.04	66.71+0.25	96.84	84.61
F6	1.53+0.03	32+0.02	0.41+0.004	66.57+0.27	98.47	90.01
F7	1.52+0.05	32+0.05	0.40+0.003	66.79+0.34	97.64	94.56
F8	1.54+0.01	31+0.04	0.46+0.004	66.74+0.31	98.46	99.84
F9	1.54+0.07	30+0.05	0.42+0.003	66.54+0.40	98.15	96.42

All the physicochemical parameters such as hardness, thickness, friability, weight variation, drug content uniformity evaluated were in the prescribed limit [12].

Table No.4. Floating property and water uptake study.

Formulation code	Floating lag time (sec)	Total floating duration (hrs)	Water uptake study (On 8^th hr)
F1	70	11	112
F2	68	10	105
F3	70	10	95
F4	110	14	128
F5	95	12	121
F6	95	12	111
F7	55	10	110
F8	45	10	104
F9	50	10	104

All the formulations of the Ivabradine HCl showed good results on Buoyancy lag time; as all the formulations had floated within a time less than 2 minutes [13]

By increasing the polymer concentration the water uptake was increased and thus correspondingly swelling also increased. Maximum swelling and water uptake was shown in the formulation 4 and in that polymer used was Xanthan gum [14]

From the invitro release studies it was observed that when the concentration of polymer is increasing then the drug release will be decreasing in the formulations Table no.3.From the invitro release kinetics studies it was understood that F1,F2, F7,F8, F9 best fit to Peppa’s kinetics and F3,F4,F5,F6 best fit for zero order kinetics. Release mechanism of drug was determined by using “n” values. The optimized formulation F8 follows Fickian transport mechanism.

CONCLUSION:

HPMC K100 has a significant role in controlling the release of drug from a dosage form. Xanthan gum a natural polymer when comes in contacts with the gastric fluid, it swells and thus control the release of drug through it. Sodium bicarbonate and citric acid ratios were important on the FLT. From the invitro release studies it was noted that in the F8 formulation 99.84% drug release was achieved with a minimum FLT and with good swelling index. Hence F8 formulation is concluded as the optimized formulation among all the 9 formulations. From the studies it was concluded that the polymer concentration is very important for the release of the drug from the tablet. And it is possible to formulate floating dosage form of Ivabradine HCl using a combination of natural and synthetic polymers.

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Received on 24.05.2014 Modified on 05.06.2014

Research J. Pharm. and Tech. 7(9): Sept. 2014 Page 973-975