INTRODUCTION:

Delivery of orally compromised therapeutic drug molecules to the systemic circulation has gained a significant interest in recent past. However, this route of administration has certain problems such as unpredictable gastric emptying rate, short gastro intestinal (GI) transit time (8-12 hr) and existence of an absorption window in the gastric and upper small intestine for several drugs leading to low and variable oral absorption over shorter period of time. However, these problems can be overcome by preparing the drug in sustained/ controlled release dosage form. The real challenge in the development of an oral controlled release drug delivery system (CRDDS) is not just to control/ sustain the drug release but also to prolong the presence of the dosage form within the gastrointestinal tract (GIT) until the total drug is completely released at the desired period of time^[1].

The drug delivery from CRDDS is in such a way that after oral administration of drug; the drug would be retained in the stomach and release the drug in a controlled manner so that the drug could be available for longer time its absorption sites^[2].

One of the major challenges in the development of oral controlled drug delivery system is to modify the gastrointestinal transit time in order to get complete drug release and longer lasting absorption^[3]. Prolonged gastric retention facilitates the complete drug release in the absorption zone, improves oral bioavailability, reduces drug waste, and improves solubility for drugs that are less soluble in a high pH environment. One of the most feasible approaches for achieving a prolonged and predictable drug delivery in the GI tract is to control the gastric residence time (GRT) and can be achieved by preparing gastro retentive dosage form (GRDF) commonly known as floating drug delivery systems (FDDS). While the system is floating on the gastric contents, the drug is released slowly at desired/ predetermined rate for prolonged period of time from the system. After release of drug, the residual system is emptied from the stomach and these results an increased GRT and a better control of the fluctuations in plasma drug concentration^[4].

The objective of the present investigation is to develop and evaluate gastroretentive floating tablets of Nicorandil as model drug prepared by melt granulation method. As the drug (Nicorandil) is freely soluble in water^[5], combination of hydrophilic, swellable and retarding polymer (Almond Gum, AG) and hydrophobic retarding polymer/wax/lipid (cetosteryl alcohol, CSA) are used to prepare Nicorandil gastroretentive floating tablets. Further, in vitro dissolution study is conducted in order to determine the order of drug release from dosage form and a simple mathematical method is proposed to quantitatively express the deviation from release kinetics.

MATERIALS AND METHODS:

Nicorandil was obtained as a gift sample from Torrent Pharmaceuticals (P) Ltd., Gujarat, India; Cetosteryl alcohol obtained from Loba Chemical, Mumbai, India; Sodium bicarbonate, Citric acid and Lactose were purchased from SD fine chemicals, Mumbai, India; Talc from Accord labs, Hyderabad, India. All other chemicals and reagents used were analytical grade.

Calculation of theoretical release profile of Nicorandil from controlled release formulations^[6-7]:

The following procedures were commonly used to calculate Loading (Immediate release) dose and Maintenance dose:

Where, C_ss= Steady state concentration, V_d=Volume of Distribution, F=Fraction of bioavailable dose, X_o=Conventional dose (20 mg), K_e=First order elimination rate constant (0.521 hr^-1)^[8], (Toe) = Dosing interval (24 hr), T_p=Time to reach peak plasma concentration (0.448 hr)^[9]. By substituting the kinetic values of Nicorandil in the above equations the results as follows, DI = 1.599 mg, K_s= 0.833 mg/hr, Dm = 19.173 mg (for rest of 23 hr excluding DI), DI* = 1.226 mg, and DT=20.399 ≈ 21 mg.

Hence, an oral controlled release floating matrix tablets of Nicorandil should contain a total dose of 21 mg for 24 hrs and should release 1.226 mg (6.01 %) in the first hour like conventional dosage form and rest of the dose (20.339-1.226=19.173 mg) in remaining 23 hrs, i.e. 0.833 mg (4.08%) per hour thereafter (up to 24 hrs). The theoretical drug release profile can be generated using the above value which was shown in Table 5.

Preparation of effervescent floating tablets by melt granulation technique:

Nicorandil effervescent floating tablets were prepared by direct compression technique using combination of AG and lipid/ wax polymer. All the ingredients except wax were passed through sieve 60. The composition of various formulations of effervescent tablets with their codes was listed in Table 1. In all cases the amount of the active ingredient was fixed as 21 mg with the total weight of the tablet was 300 mg. As per each formulation of batch code, required quantity of wax was weighed and melted separately in a large china dish on hot plate and drug was added to it with stirring. To this mixture, other sieved ingredients except talc were added and stirred well to mix. Then mass was removed from the hot plate and subjected to scrapping until it attained room temperature. The coherent mass was passed through 22 mesh (#), and the resulting granules were resifted over 44 meshes to separate granules and fines. The % loss of mass during melt granulation was found between 10 to 20 % of total weight. The granules were lubricated by adding talc extra granularly. The lubricated granules were then compressed into a tablet using 10 mm standard flat-face punches on 6 station tabletting machine.

Table 1: Composition of Nicorandil floating tablets using different amounts of AG and CSA (NCRD = Nicorandil, AG = Almond gum, CSA = Cetosteryl alcohol, NaHCO₃ = Sodium bicarbonate, CA = Citric acid, SA = Stearic acid).

Ingre-dients	Quantity per tablet (mg)
Ingre-dients	MCS 1	MCS 2	MCS 3	MCS 4	MCS 5	MCS 6	MCS 7	MCS 8	MCS 9	MCS 10	MCS 11	MCS 12
NCRD	21	21	21	21	21	21	21	21	21	21	21	21
AG	100	90	80	70	60	50	70	70	70	80	90	100
CSA	50	60	70	80	90	100	90	100	110	80	80	80
NaHCO₃	30	30	30	30	30	30	30	30	30	30	30	30
CA	10	10	10	10	10	10	10	10	10	10	10	10
SA	5	5	5	5	5	5	5	5	5	5	5	5
Lactose	78	78	78	78	78	78	68	58	48	68	58	48
Talc	6	6	6	6	6	6	6	6	6	6	6	6

Evaluation of floating tablets:

Buoyancy/Floating test^[10]

In vitro buoyancy was determined at 37 ± 0.5°C by observing floating lag time (FLT) and in vitro floating time (IFT). The tablets were placed in 250 ml beaker containing 100 ml of 0.1 N HCL. The time required for the tablets to rise to the surface and float was determined as FLT and the time during which the dosage form remain buoyant were measured as IFT.

In vitro release studies^[11]

In vitro drug release studies of all prepared floating matrix tablets were conducted for a period of 24 hrs using an eight station USP XXII type 2 (paddle type) apparatus. The dissolution medium consisted of 0.1N HCl (900 ml), equilibrate the dissolution medium to 37±0.5°C, and rotating the paddle at 50 rpm. At specified time interval, samples of 5 ml of specimen and replace the aliquots withdrawn for analysis with equal volumes of fresh dissolution medium at 37°C to maintain sink condition and to maintain the volume constant. After filtration and appropriate dilution (if necessary), the absorbance of sample preparations was measured in 1cm cell on UV spectrophotometer at 272 nm using 0.1N hydrochloric acid as blank. Triplicate runs were carried out and the results were averaged.

RESULTS AND DISCUSSION:

Direct compression was employed for the preparation of Nicorandil floating tablets by melt granulation method. The prepared tablets are subjected for in vitro buoyancy studies (at 37±0.5°C) and results (Figure 1) reveals that, all the formulations exhibit short FLT ranged from 72 to 126 seconds. The tablets of all formulations floated (IFT) in dissolution fluid for duration more than 24 hrs as well as maintained the integrity of formulations (non-disintegration).

The dissolution profile of all the batches were extended up to 24 hrs but showed a variation in drug release along with AG and CSA concentration (Figure 2). In order to select the optimized concentration of AG and CSA, the formulations MCS1, MCS2, MCS3, MCS4, MCS5, and MCS6 were prepared and the drug release was found to be 99.686 %, 99.174 %, 98.786 %, 97.264 %, 94.042 % and 91.528 %, respectively at the end of 24 hours. The fact can be reasoned in the way that, an increase in the hydrophobic polymer content results in decrease the drug release rate due to decrease in the total porosity of the matrices (initial porosity plus porosity due to the dissolution of the drug) and also increases the tortuosity of the matrix and drug diffusion path-length which in turn slows down diffusion and erosion from/of the matrix. These behaviour can be explained in terms of release mechanism and suggested that, because of the high hydrophobicity of lipid materials, penetration of dissolution fluid was hindered through the matrix and can progress in the dosage form by dissolving the grains of drug in contact with it and leading to diminished drug release over an extended period. Further, the dissolution of the drug particles on the surface of the matrix allows the formation of channels, from which the drug was slowly released followed by formation of a denser gel and slower erosion.

Figure 1: Floating lag time (FLT) of formulations MCS1 to MCS12

Formulations MCS7, MCS8 and MCS9 were prepared with ascending concentration of CSA by maintaining static concentration of AG (70 mg) and the drug release at the end of 24 hr was observed approximately as 95.361%, 92.763 % and 89.325 %, respectively. The formulations MCS10, MCS11 and MCS12 were prepared with ascending concentration of AG (80 mg, 90 mg and 100 mg, respectively) by maintaining static concentration of CSA (80 mg) and the drug release at the end of 24 hr was observed as 96.463%, 92.763 % and 89.325 %, respectively. It was observed that, at constant level of AG (70 mg), increment of CSA significantly retard the drug release. The release profiles of Nicorandil from floating tablets made at different lipid-wax concentrations showed that the increase in the amount of CSA when maintained a static AG concentration yielded a slower drug release. Interestingly, the same result was observed with ascending concentration of AG when maintained a static concentration of CSA i.e with increased AG concentration and at a constant level of CSA, yielded a slower drug release. The reason in former case may be, when the CSA content in the matrix was increased may cause slower penetration of the dissolution medium in matrices as a result of increased lipophilicity and leading to diminished drug release. The reason in later case may be, an increase in hydrophilic polymer concentration causes higher degree of swelling when contact with dissolution media which was accountable for increased viscosity of gel as well as gel layer with long diffusion path which cause a decrease in effective diffusion coefficient of drug and reduction in drug release rate from the swelled tablet containing higher concentration of hydrophilic polymer. The drug release from all the formulations followed by zero order as the R²value closed to one for zero order than first order drug release (Table 2), indicating the drug release followed nearly independent of initial drug concentration in the matrix.

Mathematical method for quantitative expression of deviation from zero order drug release:

The formulation MCS4 released the drug in the same manner of theoretical release profile as calculated using Robinson Erickson equation and selected as best formulation (Table 4). Drug release kinetics for formulation MCS4 was showed the highest linearity for R² explained by zero-order kinetics (0.999) than first order kinetics (0.756) calculated by Microsoft Excel-2007. It was notable that R²value closed to one for zero order, indicating the drug release followed nearly independent of initial drug concentration in the matrix.

In the present study, a simple, novel approach of mathematical method to quantitatively express the deviation in the drug release profile of a test product following zero order release from an ideal zero order profiles was developed. Concerning the mathematical modeling of drug release from systems, one must identify the percent deviation from ideal drug release was important phenomenon for the investigated device and these calculations were facile use. The method was based on back-calculation of predicted cumulative percentage of drug release using respective regression equations and then calculate the area under the curve (AUC) using Trapezoidal rule at different percent deviation say 0, ±5, ±10, ±15, ±20, ±25, and ±30%. The entire dissolution profile of test (MCS4) was compared by taking the absolute difference (residual) between the predicted and observed calculated AUC data. The advantage of this method was simultaneous interpretation of drug release kinetics and determination of mathematical consistency of drug release from their respective ideal release behaviour.

Theoretical computation:

The first step was to calculate the theoretical cumulative percentage of drug released for 24 hr at predetermined time intervals using the zero order equation. The straight line of theoretical cumulative percentage of drug released versus time (hr) was considered as a reference line (Figure 2). From the graph, the dissolution of drug from dosage form that do not disaggregate and release the drug followed zero order release at time 't' and 't-a' can be predicted by the following equation,

Where, F_t = cumulative percentage of drug released at time 't', k₀= zero order release constant and a = difference between two successive sampling time points.

Figure 2: Area under the curve for an ideal zero-order system

Table 2: Drug release profiles of Nicorandil from floating tablets ((R²)₀ and (R²)₁ are square of correlation coefficient of zero and first order, respectively)

Time (hr)	MCS 1	MCS2	MCS3	MCS4	MCS5	MCS6	MCS7	MCS8	MCS9	MCS10	MCS11	MCS12
1	0	0	0	0	0	0	0	0	0	0	0	0
2	4.79	5.11	5.36	5.81	5.22	4.53	5.43	4.86	3.99	5.65	5.12	4.16
3	6.85	7.865	8.27	9.718	8.184	6.937	8.648	7.974	6.115	9.215	8.426	6.472
4	9.09	10.21	11.14	13.99	13.79	10.27	11.57	12.37	8.97	12.37	13.53	9.63
5	11.87	13.79	15.47	17.82	18.39	13.63	15.66	14.27	12.65	17.48	16.58	13.37
6	15.46	17.69	19.54	21.61	20.38	18.53	20.87	22.86	14.26	27.16	25.35	15.74
9	20.44	22.14	23.16	25.02	28.63	20.86	27.43	28.52	16.89	33.25	30.56	18.77
12	30.55	32.66	34.74	36.02	37.73	32.52	36.53	35.25	33.46	41.53	37.62	32.66
15	43.26	45.37	47.27	49.62	51.27	41.27	48.66	43.31	38.54	50.27	47.42	42.825
18	57.46	60.66	62.55	60.02	58.64	55.37	58.32	57.47	56.33	63.46	60.33	59.17
24	70.63	73.46	75.25	73.16	69.27	68.37	70.66	70.56	61.17	73.65	72.15	65.72
(R²)₀	0.993	0.997	0.998	0.999	0.996	0.998	0.998	0.995	0.992	0.991	0.994	0.996
(R²)₁	0.656	0.672	0.712	0.756	0.819	0.838	0.794	0.837	0.833	0.798	0.845	0.858

Because the relationship between the percentage of drug released and time was linear, the entire dissolution profile can be calculated and compared using the area under the curve (AUC) which was calculated by the Trapezoidal rule. In order to calculate AUC, the curve was divided into trapeziums based on data and the sum of areas of all trapeziums gives AUC up to last sampling points. If the data (time) points were not evenly separated, the ideal drug release profile and AUC were calculated according to the specific sampling time. AUC was the total integrated area under the drug concentration versus time profile and calculated by Trapezoidal rule as follows,

Where, C_a = Cumulative % of drug released at time 't_a' and C_a-1 = Cumulative % of drug released at successive sampling time 't_a-1'.

To predict proportionality between the fractional amount of drug released and time from an ideal zero order drug release profile, the shaded area ( time period from 't' to 't- a' ) of Figure 3, with zero percent deviation can be calculated by the following equations,

Where, k₀ = zero-order release rate constant, t = time in hr, and a = difference between two successive sampling time points.

For an ideal 24 hr drug release from the dosage form, the zero order release rate constant may be calculated by,

For example, an ideal 24 hr zero-order system with 0 % deviation (if a = 1), AUC at first hour (t=1 hr) was calculated as follows,

The same shaded area ( time period from 't' to 't-a' ) of Fig. 3, with 'α' percent deviation from the zero order release profile can be predicted by the following equations,

For example, with +5 % deviation (α =5%) from ideal 24 hr zero-order system (a = 1), AUC at first hour (t=1) was calculated as follows,

Similarly, the AUCs calculated at all time points for the reference line and the lines showing ±5, ±10, ±15, ±20, ±25 and ±30% deviations from the reference line were shown in Table 3. In addition, the average absolute difference between AUCs (AADA) of the reference line and that of the lines showing ± α % deviations can be predicted by the following equation (Eq. 15)

For an ideal 24 hr zero-order system was equal to 100/24,

Eq. (15) denotes that AADA was a linear (Y=mX, where m was slope) function of 'α' with slope of 'n(2t - n) / 48' and the intercept was zero.

Considering the example, for 24 hr system, t = 1, a = 1 and α = +5%,

The calculated values of AADA for different percentage deviations were shown in Table 4.

Rearrangement of Eq. (15)

For an ideal t₁₀₀ hr, zero-order drug release (where t₁₀₀ was the time required for 100% drug release), k_o was equal to 100/ t₁₀₀ and substituted into the above equation to get,

The above equation denotes a linear (Y=mX+c, where 'm' was slope and 'c' was intercept) function of 't' with slope of 'a/t_100%' and intercept of 'a²/2t_100%'.

For an ideal 24 hr zero order system (t_100%=24 hr), the above equation can be written as follows,

Table 3: Area under the curve (AUC) at different percentage deviations from ideal zero-order release.

Time (hr)	Area under the curve at positive percent deviation
Time (hr)	0	+5%	+10%	+15%	+20%	+25%	+30%
0	0	0	0	0	0	0	0
1	2.083	2.188	2.292	2.396	2.500	2.604	2.708
2	6.250	6.563	6.875	7.188	7.500	7.813	8.125
3	10.417	10.938	11.459	11.980	12.500	13.021	13.542
4	14.584	15.313	16.042	16.771	17.501	18.230	18.959
5	18.751	19.688	20.626	21.563	22.501	23.438	24.376
6	22.917	24.063	25.209	26.355	27.501	28.647	29.793
9	93.753	98.441	103.128	107.816	112.504	117.191	121.879
12	131.254	137.817	144.380	150.942	157.505	164.068	170.630
15	168.755	177.193	185.631	194.069	202.506	210.944	219.382
18	206.257	216.569	226.882	237.195	247.508	257.821	268.134
24	525.017	551.268	577.518	603.769	630.020	656.271	682.522
Time (hr)	Area under the curve at negative percent deviation
Time (hr)	0	-5%	-10%	-15%	-20%	-25%	-30%
0	0	0	0	0	0	0	0
1	2.083	1.979	1.875	1.771	1.667	1.563	1.458
2	6.250	5.938	5.625	5.313	5.000	4.688	4.375
3	10.417	9.896	9.375	8.854	8.334	7.813	7.292
4	14.584	13.855	13.125	12.396	11.667	10.938	10.209
5	18.751	17.813	16.876	15.938	15.000	14.063	13.125
6	22.917	21.772	20.626	19.480	18.334	17.188	16.042
9	93.753	89.065	84.378	79.690	75.002	70.315	65.627
12	131.254	124.691	118.129	111.566	105.003	98.441	91.878
15	168.755	160.318	151.880	143.442	135.004	126.567	118.129
18	206.257	195.944	185.631	175.318	165.005	154.692	144.380
24	525.017	498.766	472.515	446.264	420.013	393.763	367.512

Table 4: Average absolute difference of AUCs (AADA) at different percentage deviations from ideal zero order release.

Time (hr)	AADAs values for percentage deviation from zero-order
Time (hr)	5	10	15	20	25	30
0	0	0	0	0	0	0
1	0.1042	0.2083	0.3125	0.4167	0.5209	0.6250
2	0.3125	0.6250	0.9375	1.2500	1.5626	1.8751
3	0.5209	1.0417	1.5626	2.0834	2.6043	3.1251
4	0.7292	1.4584	2.1876	2.9168	3.6460	4.3751
5	0.9375	1.8751	2.8126	3.7501	4.6877	5.6252
6	1.1459	2.2917	3.4376	4.5835	5.7294	6.8752
9	4.6877	9.3753	14.0630	18.7506	23.4383	28.1259
12	6.5627	13.1254	19.6881	26.2508	32.8136	39.3763
15	8.4378	16.8755	25.3133	33.7511	42.1889	50.6266
18	10.3128	20.6257	30.9385	41.2513	51.5642	61.8770
24	26.2508	52.5017	78.7525	105.0034	131.2542	157.5050

Rearrangement of above Eq.

For example, the α value (% deviation) of the test formulation (a = 1) at first hour (t=1) with respective AADA was calculated as follows,

DISCUSSION:

In order to understand the order of drug release from prepared gastroretentive tablets, the data were fitted to zero order and first order equations. The square of correlation coefficient (R²) values is highest for selected formulation MCS4 confirms the drug release from the dosage form follows zero order which indicates that the drug release was nearly independent of its concentration in the matrices.

The cumulative percentage Nicorandil released as a function of time was calculated for 24 hrs from gastroretentive tablets using AG as swellable and retarding polymer and CSA as retarding waxy polymer. An ideal 24 hr zero order release profile were back-calculated by zero order equation and treated as reference line (Figure 3). The comparative dissolution profiles of the ideal 24 hr zero order and test product was presented in Figure 3. AUCs of both the curves were calculated using Trapezoidal rule and further absolute difference of AUCs (AADA) were calculated. From the absolute difference of AUCs, the percentage deviations (α) at each time data point for the test product from the ideal 24 hr zero order release profile were calculated. Table 4 summarizes the theoretical consideration and experimental determinations of cumulative percentage of drug release including AADA and percent deviation (α) values at different time intervals calculated form applicability and common assumptions using discussed mathematical models.

From the results it was observed that, the cumulative percentage of drug release (CPDR) profile of test and their AUC values in the initial stage (up to 6 hrs) were slightly higher than ideal 24 hr zero order drug release profile. So, negative absolute difference of AUCs (AADA) was observed. After 6 hrs, positive absolute difference of AUCs (α)was observed, in which the cumulative percentage of drug release (CPDR) profile of test were slightly higher than ideal 24 hr zero order drug release profile. The percentage deviation (α ) from ideal zero order was high (max. of 40% at first hour) in the initial stage (up to 6 hrs) and then decreased gradually (min. of 1.737% at sixth hour) (Fig. 3). The reason in former case may be due to rapid and extensive drug release from all surfaces of tablet before buoyant, into the surrounding media generating many pores and cracks which facilitate further release of drug and also formation of channels within the matrix in the case of a water soluble drug like Nicorandil, later on the drug release facilitated form the tablet exposed surface after buoyant. However, as the time proceeds, the gastroretentive tablet become buoyant there by slowly penetrate the dissolution media into matrix core through pores and the hydrophilic matrixing agent which forms a gel layer and lead to diminished drug release over an extended period. This may also be interpreted by the fact that, there was difficulty/ delay to form polymeric gel layer in the early stages of drug release, resulting in the quick release of drug. Further, increases the strength of gel layer and finally the drug release was slow/retard. Hence, at the later stage, the percentage deviation from an ideal zero order release was decreased and became less than 2 %. The release rate constants were calculated from the slope of the zero order plot for both ideal and test curve (Table 5). It was a crucial point for the practical importance of a drug release from the device and to consider these aspects to predict precisely the resulting drug release rates from ideal systems. This method was the best combination of accuracy and ease of interpretation to calculate percent deviation from an ideal release.

Table 5: Percentage deviation for the test product from an ideal 24 hr zero order drug release (CPDR is cumulative percentage of drug release).

Time (hr)	Ideal zero order		Test product		Absolute difference of AUCs	% deviation from zero-order (α)
Time (hr)	CPDR	AUC	CPDR	AUC	Absolute difference of AUCs	% deviation from zero-order (α)
0	0	0	0	0	0	0
1	4.167	2.084	5.812	2.906	0.823	39.504
2	8.334	6.251	9.718	7.765	1.515	24.232
3	12.501	10.418	13.991	11.855	1.437	13.795
4	16.668	14.585	17.821	15.906	1.322	9.062
5	20.835	18.752	21.612	19.717	0.965	5.147
6	25.002	22.919	25.021	23.317	0.398	1.737
9	37.503	93.758	36.017	91.557	2.201	2.347
12	50.004	131.261	49.621	128.457	2.804	2.136
15	62.505	168.764	60.147	164.652	4.112	2.436
18	75.006	206.267	73.158	199.958	6.309	3.059
24	100.01	525.042	97.264	511.266	13.776	2.624
Slope	4.167		3.982
Intercept	0		1.331

Figure 3: Comparative dissolution profiles of the ideal zero order and test product

CONCLUSION:

The study presents is used to develop Nicorandil floating tablets and further used to develop a mathematical model for the quantitative expression of the deviation drug release. As the selected dosage forms follow zero order for drug release from tablets, it is checked for percent deviation from an ideal zero order drug release. At initial stage the percent deviation high and decreased later on. It can be concluded that the experimental values were in close agreement with predicted values, indicating the success of the design to evaluate and optimize the Nicorandil floating tablets. The proposed method may be extended to other kinetic models such as first-order, Higuchi, and Korsmeyer-Peppas models.

ACKNOWLEDGMENT:

The authors wish to thank Torrent Pharmaceuticals (P) Ltd., Gujarat, for the supply of Nicorandil as gift sample. The authors also like to thank management of SSPC, for providing facilities used in the research.

REFERENCES:

1. Prajapati, S.T, Patel L.D and Patel D.M. Gastric floating matrix tablets: design and optimization using combination of polymers. Acta Pharm. 58; 2008: 221–229.

2. Amit Kumar N., Ruma Maji and Biswarup Das. Gastroretentive drug delivery system: a review. Asian Journal of Pharmaceutical and Clinical Research. 3(1); 2010: 2-10.

3. Viswanatha R.M., Jayashankar R.V., Ramesh Y., Venkateswarlu I., Sanjeeva kumar A. and Madhu Sudana Rao G. A review of gastroretentive drug delivery system on different absorption windows. RJPBCS. 2(3); 2011: 720-732.

4. Vishal Bhardwaj, Nirmala A. and Harikumar S.L. Floating drug delivery system: A review. Pharmacophore. 4(1); 2013: 26-38.

5. Raghuram R.K., Srinivas Mutalik and Srinivas Reddy. Once-daily sustained-release matrix tablets of Nicorandil: Formulation and In vitro evaluation. AAPS Pharm. Sci. Tech. 4(4); 2003:1-9.

6. Saleem M.A., Dhaval Malvania, Jaydeep Pate,; Murali Y.D. and Naheed Md. Preparation and evaluation of Timolol maleate matrix tablet using hydrogel forming polysaccharides. IJPSR. 3(8); 2012: 2786-2794.

7. Pankaj H. Prajapati, Vijay V. Nakum and Chhagan N. Patel. Formulation and evaluation of floating matrix tablet of Stavudine. Int. J. Phar. Inv. 2(2); 2012: 83-89.

8. Sandip Chavhan, Sanjay Anantwa and Dilip Derle. Design and evaluation of once daily sustained release matrix tablets of Nicorandil. IJPPS. 3(2); 2011: 13-18.

9. Jagadeesh G. Hiremath, Rajashekar Valluru, Narhare Jaiprakash, Sridhar A. Katta and Prashantha P. Matad. Pharmaceutical aspects of Nicorandil, IJPPS. 2(4); 2010: 24-29.

10. Ashok P.H. and Rachana D. Development and evaluation of gastroretentive floating tablets of an antidepressant drug by thermoplastic granulation technique, Beni-Suef University Journal of Basic and Applied Science. 3; 2014: 122-132.

11. Ju-Young Kim, Chun-Woong Park, Beom-Jin Lee, Eun-Seok Park and Yun-Seok Rhee. Design and evaluation of Nicorandil extended-release tablet. Asian Journal of Pharmaceutical Science. 10; 2015: 108-113.

Received on 30.11.2018 Accepted on 31.12.2018

Asian J. Pharm. Tech. 2019; 9(1):15-22.

DOI: 10.5958/2231-5713.2019.00004.7