INTRODUCTION:

In recent years, gastric retentive drug delivery systems are more effective drug delivery system. When, some of the drugs were formulated as controlled release dosage forms they can’t attain the sufficient bioavailability and effective plasma level due to its less gastro intestinal transit time¹. By retention of such drugs in the stomach, we can prolong the overall gastrointestinal transit time and increase the bioavailability. This would be particularly valuable for the drugs that exhibit an absorption window in the upper part of the small intestine². There are a number of approaches that can be used to prolong gastric retention time, such as floating drug delivery systems, swelling and expanding systems, polymeric bio-adhesive systems, and modified shape systems, high density systems and other delayed gastric emptying devices. From the formulation considerations, FDDS appears to be the most flexible and potent approach to prolong gastric residence time of drug³.

Nizatidine [N-[2-[[[2-(dimethylamino) methyl]-4-thiazolyl] methyl thio] ethyl]-N’-methyl-2-nitro-1, 1-ethenediamine] is competitive, reversible inhibitor of the histamine H₂ receptors of the gastric acid secreting cells⁴. It is also used for the treatment of acid-reflux disorders (GERD), peptic ulcer disease, active benign gastric ulcer and active duodenal ulcers.

It has a very short biological half-life 1-2 hours and low absolute oral bioavailability. It does not have any demonstrable anti-androgenic effects and drug interactions compared to any other class of H₂- receptor antagonists⁵. It also finds applications in the field of local delivery of drug to the stomach and proximal small intestine and importantly in treating microorganisms (Helicobacter pylori), which colonize the stomach because the major factors governing reduced luminal drug delivery are gastric acidity, gastric emptying and the epithelial mucus layer and therefore it helps to provide better availability of new products with new therapeutic possibilities and increased patient compliance⁶.

The aim of the present study is to design and evaluate the effervescent floating tablets of Nizatidine by using different polymers like Chitosan, HPMC and Carbopol940 and gas generating agents like sodium bicarbonate and calcium carbonate.

MATERIALS AND METHODS:

Nizatidine was obtained as a gift sample from Dr. Reddy’s laboratories, Hyderabad. HPMCK100M was purchased from SD Fine Chem. Ltd. Mumbai. Carbopol940 was purchased from Loba chem. Mumbai. Chitosan was purchased from India Sea Food, Cochin. Lactose, Sodium bicarbonate, Calcium carbonate, magnesium stearate and talc are purchased from Qualigens fine chemicals, Mumbai. All excipients were analytical grade.

Table I: Compositions of different floating tablets of Nizatidine

Ingredients(mg per tablet)	NF1	NF2	NF3	NF4	NF5	SF1	SF2	SF3	SF4	SF5	HF
Nizatidine	150	150	150	150	150	150	150	150	150	150	150
Chitosan	75	60	45	30	15	-	-	-	-	-	-
Carbopol 940	-	-	-	-	-	75	60	45	30	15	-
HPMC K100M	-	15	30	45	60	-	15	30	45	60	75
NaHCO₃	22.5	22.5	22.5	22.5	22.5	22.5	22.5	22.5	22.5	22.5	22.5
CaCO₃	15	15	15	15	15	15	15	15	15	15	15
Lactose	31.5	31.5	31.5	31.5	31.5	31.5	31.5	31.5	31.5	31.5	31.5
Magnesium stearate	3	3	3	3	3	3	3	3	3	3	3
Talc	3	3	3	3	3	3	3	3	3	3	3
Total weight	300	300	300	300	300	300	300	300	300	300	300

Table 2: Pre-compression parameters of floating formulations NF1-HF

Formulation code	Angle of repose(°)	Bulk density(g/cc)	Tapped density(g/cc)	Carr’s index (%)	Hausner ratio
NF1	28.36	0.389±0.01	0.542±0.004	28.9	1.42
NF2	26.06	0.396±0.00	0.535±0.007	25.4	1.344
NF3	20.76	0.396±0.01	0.457±0.017	13.35	1.15
NF4	24.21	0.385±0.01	0.437±0.02	11.90	1.14
NF5	27.73	0.398±0.00	0.442±0.007	9.95	1.11
SF1	28.73	0.375±0.01	0.432±0.04	13.19	1.15
SF2	24.83	0.412±0.01	0.449±0.05	8.24	1.09
SF3	28.66	0.426±0.02	0.453±0.01	5.96	1.06
SF4	23.72	0.396±0.04	0.453±0.01	12.39	1.40
SF5	27.38	0.423±0.006	0.483±0.05	12.42	1.14
HF	26.83	0.418±0.009	0.453±0.04	12.18	1.14

Fig 1: Buoyancy of floating formulations NH4, HF, and SF4 at 8hr

Table 3: Post-compression parameters of floating formulations NF1-HF

Formulation code	Average weight (mg)	Hardness (kg/cm²)	Thickness(mm)	Friability (%)	Drug content(mg)
NF1	300±2.1	6.2±0.2	2.50±0.00	0.667±0.01	98.5±0.9
NF2	302±1.6	6.1±0.4	2.49±0.01	0.793±0.08	97.2±0.1
NF3	300±2.3	6.1±0.2	2.50±0.01	0.797±0.03	98.8±0.2
NF4	299±2.5	6.3±0.5	2.50±0.00	0.367±0.04	97.8±0.4
NF5	300±1.9	6.2±0.4	2.48±0.01	0.500±0.07	103.5±0.5
SF1	299±1.6	5.9 ±0.6	2.49±0.02	0.533±0.04	98.6±0.8
SF2	301±1.9	5.5±0.4	2.50±0.00	0.368±0.02	103±0.1
SF3	301±1.4	5.7±0.3	2.49±0.01	0.434±0.05	98.8±0.6
SF4	300±2.0	5.5±0.2	2.50±0.01	0.337±0.04	102.7±0.5
SF5	301±1.5	5.8±0.3	2.48±0.02	0.503±0.05	97.4±0.8
HF	300±2.1	6.1±0.1	2.49±0.03	0.434±0.08	97.12±0.7

Fig 2: Swelling index of formulations NF1-HF

Fig 3: Swelling index of formulations SF1-HF

Fig 4: Comparison of in vitro dissolution profile of NF1-HF

EVALUATION OF TABLETS

The prepared floating tablets were evaluated for hardness, friability, thickness, uniformity of the weight and content uniformity. Hardness was determined by using Pfizer hardness tester. Friability was determined using Roche friability testing apparatus. Thickness was measured using Vernier calipers. Uniformity of the weight and content uniformity were performed according to the I.P method^{8, 9}. The results were reported in Table 3.

Buoyancy studies

The buoyancy of tablets was determined by placing them in 100ml beaker containing a pH 1.2 (acidic) buffer. The same batch of tablet was placed in USP XXIII dissolution apparatus -II at 50 rpm using 900ml 0.1N HCL at 37±0.5⁰C. Then the floating lag time (i.e., time required for the tablet to rise to the surface) was measured by visual observation¹⁰. The results were summarized in Table 4.The buoyancy characteristics of the floating formulations were shown in Figure 1.

Swelling index

Accurately weight the individual tablet and kept in a 25ml buffer containing petri-dish. The swollen tablets were taken out every 2hr and blotted with filter paper to remove excess water present on the surface and weighed carefully. Percentage swelling (swelling index) was calculated by using below formula¹¹. Swelling index of various formulations was depicted in Figure 2 and Figure 3.

Swelling Index = Wg-Wo/Wo,

W₀= Initial weight of tablet, Wg =Final weight of tablet

Table 4: Buoyancy properties of floating formulations NF1-HF

Formulation code	Floating lag time(sec)	Floating time(hr)	Integrity of table
NF1	-	-	Disintegrated within 1 hr
NF2	-	-	Altered shape after 1hr
NF3	480	>12	Intact
NF4	300	>12	Intact
NF5	180	>12	Intact
SF1	240	>12	Intact
SF2	120	>12	Intact
SF3	90	>12	Intact
SF4	66	>12	Intact
SF5	45	>12	Intact
HF	41	>12	Intact

In vitro dissolution study

The in vitro dissolution studies of Nizatidine floating tablets were carried out in USP- type II dissolution test apparatus. The drug release study was carried out in 0.1NHCl for 12hr in 900ml of dissolution medium with agitation speed 50 rpm, maintained at 37±0.5^oC. At predetermined time intervals 5ml of samples were withdrawn and filtered through Whattmann filter paper. The volume withdrawn at each interval was replaced with same quantity of fresh dissolution medium. The samples were analyzed for drug release by measuring the absorbance at 315nm in UV- spectrophotometer.

All the studies are conducted triplicate¹². The amount of drug present in the sample was calculated with the help of appropriate calibration curve constructed from reference standards. Dissolution profiles for various formulations were depicted in Figure 4 and Figure 5.

DRUG RELEASE KINETICS

To analyze the mechanism of release and release rate kinetics from floating tablets, the obtained dissolution data were fitted into various mathematical models viz., Zero order, First order, and Higuchi equation¹³. Korsmeyer- Peppas model was also applied to find out the mechanism of drug release.

Q_t=K _Ht ^½(Higuchi equation)

log M_t/ M_∞= log k +n log t(Koresmeyer’s Peppas equation)

Where Q_t is the amount of drug released at time t, K_His the Higuchi dissolution constant, M_t is the amount of drug released at time t, M_∞ is the amount of drug released after infinite time, k is a constant incorporating structural and geometric characteristics of the drug dosage form and n is the different exponent indicative of the drug release mechanisms. When n is 0.45, the diffusion phenomenon dominates and when n value reaches 0.89 and above, it may be characterized by the case II relaxation release transport and super case II transport. Values of n between 0.45 and 0.89 can be regarded as indicators of anomalous transport^{14, 15}.

RESULTS AND DISCUSSION:

The floating tablets of Nizatidine were prepared by direct compression method according to the composition given in Table 1. The powder blends were characterized with respect to angle of repose, bulk density and tapped density. The angle of repose of powder blend was less than 29°indicate satisfactory flow behavior. The physical properties of power blends were given in Table 2. The prepared floating tablets were evaluated for hardness, friability, thickness, uniformity of the weight and content uniformity. The average weight of the floating tablets was found to be in the range of 299-302mg. The hardness of the floating tablets was found to be in the range of 5.5-6.2 kg/cm². The friability of all the formulations was less than 1%. The mean thickness of tablets was in the range of 2.48-2.50mm. The drug content was found to be uniform in formulated tablets and was found to be within 99±2% of labeled claim. Evaluation data of floating matrix tablets were given in Table 3. The hardness and friability values indicted good handling properties of the prepared tablets. Tablets composed of polymeric matrices on contact with the buffer medium build a gel layer around the tablet core and governs the drug release. The formulations NF1 and NF2 don’t float and lost their integrity after 1hr. The formulations NF3-NF5, SF1-SF5, HF were shows good swelling and buoyancy characteristics with less floating lag time. In NF formulations as the ratio of the HPMC increases the floating lag time decrease due to the gelation capacity of polymer. In SF formulations, decreases the concentration of carbopol increase the floating capacity of the tablets. The results of floating lag time and floating time were given in Table 4. The prepared floating tablets were studied to in vitro dissolution studies. Chitosan is a natural polysaccharide polymer .When chitosan was used as a matrix polymer in floating tablets (NF1), it causes erosion of the tablet in buffers solution within 1hr. It was concluded that chitosan alone was not proper choice to produce required integrity of the tablet and control the drug release. The blend of chitosan with HPMC of different ratios such as 4:1, 3:2, 2:3, and 1:4 were used to get controlled release. The formulation NF2 (4:1) release the drug up to 3 hr but lost its integrity. The NF3 (3:2), NF4 (2:3) showed controlled release, but the target of 12hr release was not achieved. The formulation NF5 (4:1) showed good controlled release up to 12hr. HPMC is a semi synthetic polymer contain good matrix characteristics. When HPMC (50%) is used as matrix polymer in floating tablets (HF), release the drug more than12 hr. Carbopol940 is a synthetic polymer. When Carbopol (50%) is used as matrix polymer in floating tablets (SF1) showed the release of the drug up to 3hr in the buffer solution because of the faster swelling nature of polymer. So, blend of carbopol with HPMC different ratios such as 4:1, 3:2, 2:3, and 1:4 were used to get swelling and controlled release. The formulations SF2 (3:2), SF3 (2:3) releases the drug in controlled manner up to 11hr. The formulations SF4, SF5 release the drug with more controlled manner than HF formulation. The in vitro drug release data of all formulations was subjected to goodness of fit test by linear regression analysis according to zero order, first order kinetic equations, Higuchi’s and Korsmeyer -peppas models to ascertain the mechanism of drug release. The formulations SF4, SF5, NF4, NF5 and HF follow first order kinetics to release the drug. The formulations NF1, NF2, NF3, SF1, SF2 and SF3 follow zero order kinetics to release the drug. In Higuchi and Peppa’s plot the correlation coefficient(r) values in the range 0.943 to 0.999, it confirmed that the drug release by diffusion mechanism. The diffusion coefficient n value ranged from 0.505 to 0.926, it is evident that the drug is released by non-fickian diffusion mechanism (n =0.5to1.0).

CONCLUSION:

Nizatidine floating tablets formulated by using HPMCK100M, shows controlled drug release with good buoyancy characteristics. Chitosan polymer alone was not proper choice to produce integrity of the tablet and prolonged drug release. The polymeric blend containing 80% HPMC and 20% chitosan gave controlled drug release up to 12hr. Floating tablets prepared by polymeric blend 40% carbopol and 60% HPMC release the drug more controlled manner than HPMC alone.

ACKNOWLEDGEMENT:

Authors are thankful to Principal and Management of Chalapathi Institute of Pharmaceutical Science, Guntur for their help and support.

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Received on 26.06.2013 Modified on 05.07.2013

Research J. Pharm. and Tech. 6(9): September 2013; Page 1032-1036